Electrophysiological Endophenotypes for Schizophrenia

PubMed Central

Owens, Emily; Bachman, Peter; Glahn, David C; Bearden, Carrie E

2016-01-01

Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABA-ergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating datasets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype. PMID:26954597

Association of Aging-Related Endophenotypes With Mortality in 2 Cohort Studies: the Long Life Family Study and the Health, Aging and Body Composition Study.

PubMed

Singh, Jatinder; Schupf, Nicole; Boudreau, Robert; Matteini, Amy M; Prasad, Tanushree; Newman, Anne B; Liu, YongMei; Christensen, Kaare; Kammerer, Candace M

2015-12-01

One method by which to identify fundamental biological processes that may contribute to age-related disease and disability, instead of disease-specific processes, is to construct endophenotypes comprising linear combinations of physiological measures. Applying factor analyses methods to phenotypic data (2006-2009) on 28 traits representing 5 domains (cognitive, cardiovascular, metabolic, physical, and pulmonary) from 4,472 US and Danish individuals in 574 pedigrees from the Long Life Family Study (United States and Denmark), we constructed endophenotypes and assessed their relationship with mortality. The most dominant endophenotype primarily reflected the physical activity and pulmonary domains, was heritable, was significantly associated with mortality, and attenuated the association of age with mortality by 24.1%. Using data (1997-1998) on 1,794 Health, Aging and Body Composition Study participants from Memphis, Tennessee, and Pittsburgh, Pennsylvania, we obtained strikingly similar endophenotypes and relationships to mortality. We also reproduced the endophenotype constructs, especially the dominant physical activity and pulmonary endophenotype, within demographic subpopulations of these 2 cohorts. Thus, this endophenotype construct may represent an underlying phenotype related to aging. Additional genetic studies of this endophenotype may help identify genetic variants or networks that contribute to the aging process. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Associations between psychosis endophenotypes across brain functional, structural, and cognitive domains.

PubMed

Blakey, R; Ranlund, S; Zartaloudi, E; Cahn, W; Calafato, S; Colizzi, M; Crespo-Facorro, B; Daniel, C; Díez-Revuelta, Á; Di Forti, M; Iyegbe, C; Jablensky, A; Jones, R; Hall, M-H; Kahn, R; Kalaydjieva, L; Kravariti, E; Lin, K; McDonald, C; McIntosh, A M; Picchioni, M; Powell, J; Presman, A; Rujescu, D; Schulze, K; Shaikh, M; Thygesen, J H; Toulopoulou, T; Van Haren, N; Van Os, J; Walshe, M; Murray, R M; Bramon, E

2018-06-01

A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related. This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes. The P300 amplitude and latency were not associated (regression coef. -0.06, 95% CI -0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10-0.28, p 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships. The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.

Executive functioning and local-global visual processing: candidate endophenotypes for autism spectrum disorder?

PubMed

Van Eylen, Lien; Boets, Bart; Cosemans, Nele; Peeters, Hilde; Steyaert, Jean; Wagemans, Johan; Noens, Ilse

2017-03-01

Heterogeneity within autism spectrum disorder (ASD) hampers insight in the etiology and stimulates the search for endophenotypes. Endophenotypes should meet several criteria, the most important being the association with ASD and the higher occurrence rate in unaffected ASD relatives than in the general population. We evaluated these criteria for executive functioning (EF) and local-global (L-G) visual processing. By administering an extensive cognitive battery which increases the validity of the measures, we examined which of the cognitive anomalies shown by ASD probands also occur in their unaffected relatives (n = 113) compared to typically developing (TD) controls (n = 100). Microarrays were performed, so we could exclude relatives from probands with a de novo mutation in a known ASD susceptibility copy number variant, thus increasing the probability that genetic risk variants are shared by the ASD relatives. An overview of studies investigating EF and L-G processing in ASD relatives was also provided. For EF, ASD relatives - like ASD probands - showed impairments in response inhibition, cognitive flexibility and generativity (specifically, ideational fluency), and EF impairments in daily life. For L-G visual processing, the ASD relatives showed no anomalies on the tasks, but they reported more attention to detail in daily life. Group differences were similar for siblings and for parents of ASD probands, and yielded larger effect sizes in a multiplex subsample. The group effect sizes for the comparison between ASD probands and TD individuals were generally larger than those of the ASD relatives compared to TD individuals. Impaired cognitive flexibility, ideational fluency and response inhibition are strong candidate endophenotypes for ASD. They could help to delineate etiologically more homogeneous subgroups, which is clinically important to allow assigning ASD probands to different, more targeted, interventions. © 2016 Association for Child and Adolescent Mental Health.

Cognitive dysfunction and anxious-impulsive personality traits are endophenotypes for drug dependence.

PubMed

Ersche, Karen D; Turton, Abigail J; Chamberlain, Samuel R; Müller, Ulrich; Bullmore, Edward T; Robbins, Trevor W

2012-09-01

Not everyone who takes drugs becomes addicted, but the likelihood of developing drug addiction is greater in people with a family history of drug or alcohol dependence. Relatively little is known about how genetic risk mediates the development of drug dependence. By comparing the phenotypic profile of individuals with and without a family history of addiction, the authors sought to clarify the extent to which cognitive dysfunction and personality traits are shared by family members--and therefore likely to have predated drug dependence--and which aspects are specific to drug-dependent individuals. The authors assessed cognitive function and personality traits associated with drug dependence in stimulant-dependent individuals (N=50), their biological siblings without a history of drug dependence (N=50), and unrelated healthy volunteers (N=50). Cognitive function was significantly impaired in the stimulant-dependent individuals across a range of domains. Deficits in executive function and response control were identified in both the stimulant-dependent individuals and in their non-drug-dependent siblings. Drug-dependent individuals and their siblings also exhibited elevated anxious-impulsive personality traits relative to healthy comparison volunteers. Deficits in executive function and response regulation as well as anxious-impulsive personality traits may represent endophenotypes associated with the risk of developing cocaine or amphetamine dependence. The identification of addiction endophenotypes may be useful in facilitating the rational development of therapeutic and preventive strategies.

Neurocognitive endophenotypes in CGG KI and Fmr1 KO mouse models of Fragile X-Associated disorders: an analysis of the state of the field

PubMed Central

Hunsaker, Michael R.

2013-01-01

It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on the FMR1 gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to the Fmr1 knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X-Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). PMID:24627796

Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.

PubMed

Greenwood, Tiffany A; Lazzeroni, Laura C; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2016-01-01

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. Copyright © 2015 Elsevier B.V. All rights reserved.

Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study.

PubMed

Millard, Steven P; Shofer, Jane; Braff, David; Calkins, Monica; Cadenhead, Kristin; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel; Gur, Ruben; Lazzeroni, Laura C; Light, Gregory A; Olincy, Ann; Nuechterlein, Keith; Seidman, Larry; Siever, Larry; Silverman, Jeremy; Stone, William S; Sprock, Joyce; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Ming; Turetsky, Bruce; Radant, Allen; Tsuang, Debby W

2016-07-01

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially. Published by Elsevier B.V.

Prioritizing Schizophrenia Endophenotypes for Future Genetic Studies: An Example Using Data from the COGS-1 Family Study

PubMed Central

Millard, Steven P.; Shofer, Jane; Braff, David; Calkins, Monica; Cadenhead, Kristin; Freedman, Robert; Green, Michael F.; Greenwood, Tiffany A.; Gur, Raquel; Gur, Ruben; Lazzeroni, Laura C.; Light, Gregory A.; Olincy, Ann; Nuechterlein, Keith; Seidman, Larry; Siever, Larry; Silverman, Jeremy; Stone, William; Sprock, Joyce; Sugar, Catherine A.; Swerdlow, Neal R.; Tsuang, Ming; Turetsky, Bruce; Radant, Allen; Tsuang, Debby W.

2016-01-01

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving statistical power of locating genetic regions associated with schizophrenia that may be the easiest to identify initially. PMID:27132484

Subtyping Children with Speech Sound Disorders by Endophenotypes

ERIC Educational Resources Information Center

Lewis, Barbara A.; Avrich, Allison A.; Freebairn, Lisa A.; Taylor, H. Gerry; Iyengar, Sudha K.; Stein, Catherine M.

2011-01-01

Purpose: The present study examined associations of 5 endophenotypes (i.e., measurable skills that are closely associated with speech sound disorders and are useful in detecting genetic influences on speech sound production), oral motor skills, phonological memory, phonological awareness, vocabulary, and speeded naming, with 3 clinical criteria…

Subjective Responses to Alcohol Consumption as Endophenotypes: Advancing Behavioral Genetics in Etiological and Treatment Models of Alcoholism

PubMed Central

Ray, Lara A.; MacKillop, James; Monti, Peter M.

2015-01-01

Individual differences in subjective responses to alcohol consumption represent genetically-mediated biobehavioral mechanisms of alcoholism risk (i.e., endophenotype). The objective of this review is three-fold: (1) to provide a critical review the literature on subjective response to alcohol and to discuss the rationale for its conceptualization as an endophenotype for alcoholism; (2) to examine the literature on the neurobiological substrates and associated genetic factors subserving individual differences in subjective response to alcohol; and (3) to discuss the treatment implications of this approach and to propose a framework for conceptualizing, and systematically integrating, endophenotypes into alcoholism treatment. PMID:20590398

Genome-wide scans of genetic variants for psychophysiological endophenotypes: a methodological overview.

PubMed

Iacono, William G; Malone, Stephen M; Vaidyanathan, Uma; Vrieze, Scott I

2014-12-01

This article provides an introductory overview of the investigative strategy employed to evaluate the genetic basis of 17 endophenotypes examined as part of a 20-year data collection effort from the Minnesota Center for Twin and Family Research. Included are characterization of the study samples, descriptive statistics for key properties of the psychophysiological measures, and rationale behind the steps taken in the molecular genetic study design. The statistical approach included (a) biometric analysis of twin and family data, (b) heritability analysis using 527,829 single nucleotide polymorphisms (SNPs), (c) genome-wide association analysis of these SNPs and 17,601 autosomal genes, (d) follow-up analyses of candidate SNPs and genes hypothesized to have an association with each endophenotype, (e) rare variant analysis of nonsynonymous SNPs in the exome, and (f) whole genome sequencing association analysis using 27 million genetic variants. These methods were used in the accompanying empirical articles comprising this special issue, Genome-Wide Scans of Genetic Variants for Psychophysiological Endophenotypes. Copyright © 2014 Society for Psychophysiological Research.

Speed, Variability, and Timing of Motor Output in ADHD: Which Measures are Useful for Endophenotypic Research?

PubMed Central

Altink, Marieke E.; Oosterlaan, Jaap; Beem, Leo; Buschgens, Cathelijne J. M.; Buitelaar, Jan; Sergeant, Joseph A.

2007-01-01

Attention-Deficit/Hyperactivity Disorder (ADHD) shares a genetic basis with motor coordination problems and probably motor timing problems. In line with this, comparable problems in motor timing should be observed in first degree relatives and might, therefore, form a suitable endophenotypic candidate. This hypothesis was investigated in 238 ADHD-families (545 children) and 147 control-families (271 children). A motor timing task was administered, in which children had to produce a 1,000 ms interval. In addition to this task, two basic motor tasks were administered to examine speed and variability of motor output, when no timing component was required. Results indicated that variability in motor timing is a useful endophenotypic candidate: It was clearly associated with ADHD, it was also present in non-affected siblings, and it correlated within families. Accuracy (under- versus over-production) in motor timing appeared less useful: Even though accuracy was associated with ADHD (probands and affected siblings had a tendency to under-produce the 1,000 ms interval compared to controls), non-affected siblings did not differ from controls and sibling correlations were only marginally significant. Slow and variable motor output without timing component also appears present in ADHD, but not in non-affected siblings, suggesting these deficits not to be related to a familial vulnerability for ADHD. Deficits in motor timing could not be explained by deficits already present in basic motor output without a timing component. This suggests abnormalities in motor timing were predominantly related to deficient motor timing processes and not to general deficient motor functioning. The finding that deficits in motor timing run in ADHD-families suggests this to be a fruitful domain for further exploration in relation to the genetic underpinnings of ADHD. PMID:18071893

Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed Central

Huebinger, Ryan M.; Shewale, Shantanu J.; Koenig, Jessica L.; Mitchel, Jeffrey S.; O’Bryant, Sid E.; Waring, Stephen C.; Diaz-Arrastia, Ramon; Chasse, Scott

2015-01-01

Although 24 Alzheimer’s disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10-7. Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated. PMID:26625115

Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

PubMed

Barber, Robert C; Phillips, Nicole R; Tilson, Jeffrey L; Huebinger, Ryan M; Shewale, Shantanu J; Koenig, Jessica L; Mitchel, Jeffrey S; O'Bryant, Sid E; Waring, Stephen C; Diaz-Arrastia, Ramon; Chasse, Scott; Wilhelmsen, Kirk C

2015-01-01

Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

Structural Brain Abnormalities in Adolescents with Autism Spectrum Disorder and Patients with Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Brieber, Sarah; Neufang, Susanne; Bruning, Nicole; Kamp-Becker, Inge; Remschmidt, Helmut; Herpertz-Dahlmann, Beate; Fink, Gereon R.; Konrad, Kerstin

2007-01-01

Background: Although autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) are two distinct neurodevelopmental diseases, they share behavioural, neuropsychological and neurobiological characteristics. For the identification of endophenotypes across diagnostic categories, further investigations of phenotypic overlap…

Neurocognitive Endophenotypes in Schizophrenia: Modulation by Nicotinic Receptor Systems

PubMed Central

Mackowick, Kristen M.; Barr, Mera S.; Wing, Victoria C.; Rabin, Rachel A.; Ouellet-Plamondon, Clairelaine; George, Tony P.

2013-01-01

Cigarette smoking is the leading preventable cause of death in the Western world, with a considerably higher prevalence observed in schizophrenia compared to the general population. Despite the negative health consequences of smoking heavily, it has been proposed that individuals with schizophrenia may maintain smoking behaviours to remediate symptoms associated with the disorder. Neurocognitive deficits are a core feature of schizophrenia and are present in approximately 80% of patients. Further, these deficits constitute an endophenotype of schizophrenia, as they are stable across disease phases, and heritable. The neurocognitive deficits that are present in schizophrenia are especially debilitating, since they are associated with poor clinical and functional outcomes and community integration. Interestingly, these deficits may also constitute a vulnerability factor towards the initiation and maintenance of tobacco use. Contributing to the potential shared vulnerability between schizophrenia and tobacco dependence is a dysregulation of the nicotinic acetylcholine receptor (nAChR) system. Pre-clinical evidence has shown that nicotine affects several neurotransmitter systems, including dopamine (DA), glutamate, and γ-aminobutyric acid (GABA), and certain neuropsychological deficits associated with these neurotransmitters (reaction time, spatial working memory, sustained attention, and sensory gating) are improved after nicotine administration in patients with schizophrenia. These positive effects on neurocognition appear to be more pronounced in smokers with schizophrenia, and may be an important mechanism that explains the co-morbidity of schizophrenia and tobacco dependence. PMID:23871750

Cognitive Endophenotypes of Dyslexia

ERIC Educational Resources Information Center

Moll, Kristina; Loff, Ariana; Snowling, Margaret J.

2013-01-01

The study investigated cognitive deficits associated with dyslexia and familial risk of dyslexia (endophenotypes) by comparing children from families with and without a history of dyslexia. Eighty-eight school-aged children were assessed on measures of phonology, language and rapid automatized naming. A series of regression analyses with family…

The Consortium on the Genetics of Schizophrenia: Neurocognitive Endophenotypes

PubMed Central

Gur, Raquel E.; Calkins, Monica E.; Gur, Ruben C.; Horan, William P.; Nuechterlein, Keith H.; Seidman, Larry J.; Stone, William S.

2007-01-01

The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be “neurocognitive” and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease. PMID:17101692

Endophenotypes, Epigenetics, Polygenicity and More: Irv Gottesman’s Dynamic Legacy

PubMed Central

Braff, David L.; Tamminga, Carol A.

2017-01-01

First, we describe the hallmark contributions of Irv Gottesman’s pioneering scholarship for schizophrenia research including concepts of polygenicity, gene × environment interactions, epigenetics and the endophenotype concept. Gottesman and colleagues’ twin studies showed that genes, not social factors, mediate schizophrenia risk. He then showed that schizophrenia is highly polygenic. Next, he introduced the concept of epigenetics into schizophrenia research. Gottesman then introduced the quantitative endophenotype concept. Endophenotypes are laboratory-based measures that show deficits in schizophrenia patients and lesser deficits in their first degree “unaffected” relatives and are viewed as being more proximal to genes and having a simpler genetic architecture than are “fuzzy” qualitative diagnostic disorders. Endophenotypes offer an exciting path to gene discovery, neural circuits, genetic architecture and new treatment pathways of schizophrenia and related psychotic disorders. Second, we were asked to discuss 2 of many endophenotype Consortia and related studies, in order to illustrate the impact of Gottesman’s work. We describe the Consortium on the Genetics of Schizophrenia (COGS) exploring neurocognitive and neurophysiological endophenotypes in family and case-control studies. Association, linkage, sequencing and epigenetic studies are described. The Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) uses an array of endophenotypes including brain imaging in studies across the psychosis dimension, allowing for dimensional analyses. BSNIP results have led to the concept of biotypes, advancing the field. Irv Gottesman was imaginatively prescient in generating novel insights and predicting many major issues which challenge schizophrenia researchers who still use his concepts to guide current research approaches. PMID:27872267

Lexical decision as an endophenotype for reading comprehension: An exploration of an association

PubMed Central

NAPLES, ADAM; KATZ, LEN; GRIGORENKO, ELENA L.

2012-01-01

Based on numerous suggestions in the literature, we evaluated lexical decision (LD) as a putative endophenotype for reading comprehension by investigating heritability estimates and segregation analyses parameter estimates for both of these phenotypes. Specifically, in a segregation analysis of a large sample of families, we established that there is little to no overlap between genes contributing to LD and reading comprehension and that the genetic mechanism behind LD derived from this analysis appears to be more complex than that for reading comprehension. We conclude that in our sample, LD is not a good candidate as an endophenotype for reading comprehension, despite previous suggestions from the literature. Based on this conclusion, we discuss the role and benefit of the endophenotype approach in studies of complex human cognitive functions. PMID:23062302

The importance of endophenotypes in schizophrenia research.

PubMed

Braff, David L

2015-04-01

Endophenotypes provide a powerful neurobiological platform from which we can understand the genomic and neural substrates of schizophrenia and other common complex neuropsychiatric disorders. The Consortium on the Genetics of Schizophrenia (COGS) has conducted multisite studies on carefully selected key neurocognitive and neurophysiological endophenotypes in 300 families (COGS-1) and then in a follow up multisite case-control study of 2471 subjects (COGS-2). Endophenotypes are neurobiologically informed quantitative measures that show deficits in probands and their first degree relatives. They are more amenable to statistical analysis than are "fuzzy" qualitative clinical traits or confoundingly heterogeneous diagnostic categories. Endophenotypes are also viewed as uniquely informative in traditional diagnosis-based as well as emerging NIMH Research Domain (RDoC) contexts, offering a bridge between the two approaches to psychopathology classification and research. Endo- or intermediate phenotypes are heritable, and in the COGS-1 cohort their level of heritability is in the same range as is the heritability of schizophrenia itself, using the same statistical methods and subjects to assess both. Because we can demonstrate endophenotypes link to both gene networks and neural circuits on the one hand and also to real-life function, endophenotypes provide a critically important bridge for "connecting the dots" between genes, cells, circuits, information processing, neurocognition and functional impairment and personalized treatment selection in schizophrenia patients. By connecting schizophrenia risk genes with neurobiologically informed endophenotypes, and via the use of association, linkage, sequencing, stem cell and other strategies, we can provide our field with new neurobiologically informed information in our efforts to understand and treat schizophrenia. Evolving views, data and new analytic strategies about schizophrenia risk, pathology and treatment are described in this Viewpoint and in the accompanying Special Issue reports. Published by Elsevier B.V.

'Reading the Mind in the Eyes': an fMRI study of adolescents with autism and their siblings.

PubMed

Holt, R J; Chura, L R; Lai, M-C; Suckling, J; von dem Hagen, E; Calder, A J; Bullmore, E T; Baron-Cohen, S; Spencer, M D

2014-11-01

Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the 'Reading the Mind in the Eyes' task (the Eyes task) have been identified in individuals with ASC in previous studies. Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC-control and sibling-control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC-control and sibling-control differences across multiple thresholds. Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups. Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.

Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study

PubMed Central

Webb, Christian A; Dillon, Daniel G; Pechtel, Pia; Goer, Franziska K; Murray, Laura; Huys, Quentin JM; Fava, Maurizio; McGrath, Patrick J; Weissman, Myrna; Parsey, Ramin; Kurian, Benji T; Adams, Phillip; Weyandt, Sarah; Trombello, Joseph M; Grannemann, Bruce; Cooper, Crystal M; Deldin, Patricia; Tenke, Craig; Trivedi, Madhukar; Bruder, Gerard; Pizzagalli, Diego A

2016-01-01

Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5–44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5–8 Hz) and alpha2 (10.5–12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities. PMID:26068725

Potential cognitive endophenotypes in multigenerational families: segregating ADHD from a genetic isolate

PubMed Central

Pineda, David A.; Lopera, Francisco; Puerta, Isabel C.; Trujillo-Orrego, Natalia; Aguirre-Acevedo, Daniel C.; Hincapié-Henao, Liliana; Arango, Clara P.; Acosta, Maria T.; Holzinger, Sandra I.; Palacio, Juan David; Pineda-Alvarez, Daniel E.; Velez, Jorge I.; Martinez, Ariel F.; Lewis, John E.

2014-01-01

Endophenotypes are neurobiological markers cosegregating and associated with illness. These biomarkers represent a promising strategy to dissect ADHD biological causes. This study was aimed at contrasting the genetics of neuropsychological tasks for intelligence, attention, memory, visual-motor skills, and executive function in children from multigenerational and extended pedigrees that cluster ADHD in a genetic isolate. In a sample of 288 children and adolescents, 194 (67.4%) ADHD affected and 94 (32.6%) unaffected, a battery of neuropsychological tests was utilized to assess the association between genetic transmission and the ADHD phenotype. We found significant differences between affected and unaffected children in the WISC block design, PIQ and FSIQ, continuous vigilance, and visual-motor skills, and these variables exhibited a significant heritability. Given the association between these neuropsychological variables and ADHD, and also the high genetic component underlying their transmission in the studied pedigrees, we suggest that these variables be considered as potential cognitive endophenotypes suitable as quantitative trait loci (QTLs) in future studies of linkage and association. PMID:21779842

The Persistence of Cognitive Deficits in Remitted and Unremitted ADHD: A Case for the State-Independence of Response Inhibition

ERIC Educational Resources Information Center

McAuley, Tara; Crosbie, Jennifer; Charach, Alice; Schachar, Russell

2014-01-01

Background: Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the…

Relationship between endophenotype and phenotype in ADHD

PubMed Central

Rommelse, Nanda NJ; Altink, Marieke E; Martin, Neilson C; Buschgens, Cathelijne JM; Faraone, Stephen V; Buitelaar, Jan K; Sergeant, Joseph A; Oosterlaan, Jaap

2008-01-01

Background It has been hypothesized that genetic and environmental factors relate to psychiatric disorders through the effect of intermediating, vulnerability traits called endophenotypes. The study had a threefold aim: to examine the predictive validity of an endophenotypic construct for the ADHD diagnosis, to test whether the magnitude of group differences at the endophenotypic and phenotypic level is comparable, and to investigate whether four factors (gender, age, IQ, rater bias) have an effect (moderation or mediation) on the relation between endophenotype and phenotype. Methods Ten neurocognitive tasks were administered to 143 children with ADHD, 68 non-affected siblings, and 120 control children (first-borns) and 132 children with ADHD, 78 non-affected siblings, and 113 controls (second-borns) (5 – 19 years). The task measures have been investigated previously for their endophenotypic viability and were combined to one component which was labeled 'the endophenotypic construct': one measure representative of endophenotypic functioning across several domains of functioning. Results The endophenotypic construct classified children with moderate accuracy (about 50% for each of the three groups). Non-affected children differed as much from controls at the endophenotypic as at the phenotypic level, but affected children displayed a more severe phenotype than endophenotype. Although a potentially moderating effect (age) and several mediating effects (gender, age, IQ) were found affecting the relation between endophenotypic construct and phenotype, none of the effects studied could account for the finding that affected children had a more severe phenotype than endophenotype. Conclusion Endophenotypic functioning is moderately predictive of the ADHD diagnosis, though findings suggest substantial overlap exists between endophenotypic functioning in the groups of affected children, non-affected siblings, and controls. Results suggest other factors may be crucial and aggravate the ADHD symptoms in affected children. PMID:18234079

Atypical activation during the Embedded Figures Task as a functional magnetic resonance imaging endophenotype of autism

PubMed Central

Holt, Rosemary J.; Chura, Lindsay R.; Calder, Andrew J.; Suckling, John; Bullmore, Edward T.; Baron-Cohen, Simon

2012-01-01

Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal and frontal brain regions. Autism and sibling groups, however, did not differ in terms of activation during this task. This suggests that the pattern of atypical activation identified may represent a functional endophenotype of autism, related to familial risk for the condition shared between individuals with autism and their siblings. We also found that reduced activation in autism relative to control subjects in regions including associative visual and face processing areas was strongly correlated with the clinical severity of impairments in reciprocal social interaction. Behavioural performance was intact in autism and sibling groups. Results are discussed in terms of atypical information processing styles or of increased activation in temporal and frontal regions in autism and the broader phenotype. By separating the aspects of atypical activation as markers of familial risk for the condition from those that are autism-specific, our findings offer new insight into the factors that might cause the expression of autism in families, affecting some children but not others. PMID:23065480

A linkage and family-based association analysis of a potential neurocognitive endophenotype of bipolar disorder.

PubMed

Savitz, Jonathan; van der Merwe, Lize; Solms, Mark; Ramesar, Rajkumar

2007-01-01

The identification of the genetic variants underpinning bipolar disorder (BPD) has been impeded by a complex pattern of inheritance characterized by genetic and phenotypic heterogeneity, genetic epistasis, and gene-environment interactions. In this paper two strategies were used to ameliorate these confounding factors. A unique South African sample including 190 individuals of the relatively, reproductively isolated Afrikaner population was assessed with a battery of neuropsychological tests in an attempt to identify a BPD-associated quantitative trait or endophenotype. BPD individuals performed significantly worse than their unaffected relatives on visual and verbal memory tasks, a finding congruent with the literature. Afocused linkage and family-based association study was carried out using this memory-related endophenotype. In the largest 77-strong Afrikaner pedigree significant evidence for linkage was detected on chromosome 22q11, a region previously implicated in BPD. The quantitative transmission disequilibrium tests-based association analysis suggested that functional variants of the DRD4 and MAO-A genes modulate memory-related cognition. We speculate that polymorphisms at these loci may predispose to a subtype of BPD characterized by memory-related deficits.

Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia.

PubMed

Gottesman, I I; Erlenmeyer-Kimling, L

2001-08-01

In an effort to share the experiences of 'genotype-hunters'-who have approached the difficult task of forecasting future schizophrenia in the young offspring or other relatives of index cases, in new samples guided by the prior probabilities of 15% in offspring or 50% in identical co-twins-with 'early-interventionists'-who focus on purported prodromal symptoms in children who would be treated pharmacologically to prevent the development of schizophrenia-we provide a focused review that emphasizes the hazards of false positives in both approaches. Despite the advantages prospective high-risk strategies have had from clinical and laboratory findings that implicate some prodromal signs and endophenotypes, e.g. attention, memory, and information processing evaluations, the yields are not sufficient for practical applications involving antipsychotic drugs for undiagnosed children. Even more caution than usual is required, given the suggestions that the developing neocortex is vulnerable to dopaminergic exposure.

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission

PubMed Central

Scoriels, L; Salek, R M; Goodby, E; Grainger, D; Dean, A M; West, J A; Griffin, J L; Suckling, J; Nathan, P J; Lennox, B R; Murray, G K; Bullmore, E T; Jones, P B

2015-01-01

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders. PMID:25826115

A Review of Selected Candidate Endophenotypes for Depression

PubMed Central

Goldstein, Brandon L.; Klein, Daniel N.

2014-01-01

Endophenotypes are proposed to occupy an intermediate position in the pathway between genotype and phenotype in genetically complex disorders such as depression. To be considered an endophenotype, a construct must meet a set of criteria proposed by Gottesman and Gould (2003). In this qualitative review, we summarize evidence for each criterion for several putative endophenotypes for depression: neuroticism, morning cortisol, frontal asymmetry of cortical electrical activity, reward learning, and biases of attention and memory. Our review indicates that while there is strong support for some depression endophenotypes, other putative endophenotypes lack data or have inconsistent findings for core criteria. PMID:25006008

Dopaminergic foundations of schizotypy as measured by the German version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE)—a suitable endophenotype of schizophrenia

PubMed Central

Grant, Phillip; Kuepper, Yvonne; Mueller, Eva A.; Wielpuetz, Catrin; Mason, Oliver; Hennig, Juergen

2013-01-01

The concept of schizotypy or “psychosis proneness” captures individual differences in perceptual, cognitive, and affective experiences that may relate to a range of psychotic disorders. The concept is an important way to assess the contribution of pre-existing psychological and genetically based biological features to the development of illnesses such as schizophrenia (so called endophenotypes). The Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) is a widely used multi-dimensional measure of the construct and consists of four scales which mirror several groups of psychotic symptoms: Unusual Experiences (UnEx; positive symptoms), Cognitive Disorganization (CogDis; cognitive symptoms), Introvertive Anhedonia (IntAn; negative symptoms), and Impulsive Nonconformity (ImpNon; impulsive and antisocial symptoms). For the purpose of evaluating the suitability of schizotypy as an endophenotype of schizophrenia the current version of the O-LIFE was translated into German: its psychometric properties (including re-test reliability and construct validity) were examined in a large sample (n > 1200) and compared to those of the English original. The German version was both highly reliable and consistent with the original. The study aimed to show that schizotypy as measured by the O-LIFE can indeed be regarded as an endophenotype of schizophrenia in terms of genetic associations regarding relevant dopamine-related candidate polymorphisms of schizotypy [i.e., Val158Met-polymorphism of the COMT gene, uVNTR of the MAOA gene, Taq1A-polymorphism of the DRD2 gene, VNTR of the SLC6A3 (DAT) gene]. We also wanted to compare the genetic associations of the O-LIFE to those published using other operationalizations of schizotypy. Our results show a large number of significant associations and borderline-significant trends between the O-LIFE sub-scales and a range of genes, thereby supporting using the O-LIFE in the search for endophenotypic markers. PMID:23355817

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

PubMed

Light, Gregory A; Swerdlow, Neal R; Rissling, Anthony J; Radant, Allen; Sugar, Catherine A; Sprock, Joyce; Pela, Marlena; Geyer, Mark A; Braff, David L

2012-01-01

Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research.

Characterization of Neurophysiologic and Neurocognitive Biomarkers for Use in Genomic and Clinical Outcome Studies of Schizophrenia

PubMed Central

Light, Gregory A.; Swerdlow, Neal R.; Rissling, Anthony J.; Radant, Allen; Sugar, Catherine A.; Sprock, Joyce; Pela, Marlena; Geyer, Mark A.; Braff, David L.

2012-01-01

Background Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. Methods Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. Results Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. Conclusions The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research. PMID:22802938

A review of selected candidate endophenotypes for depression.

PubMed

Goldstein, Brandon L; Klein, Daniel N

2014-07-01

Endophenotypes are proposed to occupy an intermediate position in the pathway between genotype and phenotype in genetically complex disorders such as depression. To be considered an endophenotype, a construct must meet a set of criteria proposed by Gottesman and Gould (2003). In this qualitative review, we summarize evidence for each criterion for several putative endophenotypes for depression: neuroticism, morning cortisol, frontal asymmetry of cortical electrical activity, reward learning, and biases of attention and memory. Our review indicates that while there is strong support for some depression endophenotypes, other putative endophenotypes lack data or have inconsistent findings for core criteria. Copyright © 2014 Elsevier Ltd. All rights reserved.

Discovery biology of neuropsychiatric syndromes (DBNS): a center for integrating clinical medicine and basic science.

PubMed

Viswanath, Biju; Rao, Naren P; Narayanaswamy, Janardhanan C; Sivakumar, Palanimuthu T; Kandasamy, Arun; Kesavan, Muralidharan; Mehta, Urvakhsh Meherwan; Venkatasubramanian, Ganesan; John, John P; Mukherjee, Odity; Purushottam, Meera; Kannan, Ramakrishnan; Mehta, Bhupesh; Kandavel, Thennarasu; Binukumar, B; Saini, Jitender; Jayarajan, Deepak; Shyamsundar, A; Moirangthem, Sydney; Vijay Kumar, K G; Thirthalli, Jagadisha; Chandra, Prabha S; Gangadhar, Bangalore N; Murthy, Pratima; Panicker, Mitradas M; Bhalla, Upinder S; Chattarji, Sumantra; Benegal, Vivek; Varghese, Mathew; Reddy, Janardhan Y C; Raghu, Padinjat; Rao, Mahendra; Jain, Sanjeev

2018-04-18

There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes (schizophrenia, bipolar disorder, obsessive compulsive disorder, Alzheimer's dementia and substance use disorders), identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository. The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments [detailed clinical assessments, endophenotype measures (neuroimaging- structural and functional, neuropsychology, psychophysics-electroencephalography, functional near infrared spectroscopy, eye movement tracking)], with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing. We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area.

The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes.

PubMed

Bas-Hoogendam, Janna Marie; Harrewijn, Anita; Tissier, Renaud L M; van der Molen, Melle J W; van Steenbergen, Henk; van Vliet, Irene M; Reichart, Catrien G; Houwing-Duistermaat, Jeanine J; Slagboom, P Eline; van der Wee, Nic J A; Westenberg, P Michiel

2018-06-01

Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so-called "endophenotypes". These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety. The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD. The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self-reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms. By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD. © 2018 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd.

Obsessive-compulsive disorder spectrum as a scientific "metaphor".

PubMed

Pallanti, Stefano; Hollander, Eric

2008-09-01

As a result of clinical, epidemiological, neuroimaging, and therapy studies that took place in the late 1980s, obsessive-compulsive disorder (OCD) has been well-characterized in the field of anxiety disorders. Other disorders attracted attention for their similarities to OCD, and were located in the orbit of the disorder. OCD has become known as the "primary domain" of a scientific "metaphor" comprising the putative cluster of OCD-related disorders (OCRDs). It is a "paradigm" with which to explore basal ganglia dysfunction. The OCRDs share common phenomenology, comorbidities, lifetime course, demographics, possible genetics, and frontostriatal dysfunction (particularly caudate hyperactivity.) The adoption of this metaphor analogy has proven useful. However, 15 years since its emergence, the spectrum of obsessive-compulsive disorders remains controversial. Questions under debate include whether OCD is a unitary or split condition, whether it is an anxiety disorder, and whether there exists only one spectrum or several possible spectrums. Further work is needed to clarify obsessive-compulsive symptoms, subtypes, and endophenotypes. There is need to integrate existing databases, better define associated symptom domains, and create a more comprehensive endophenotyping protocol for OCRDs. There is also a need to integrate biological and psychological perspectives, concepts, and data to drive this evolution. By increasing research in this field, the OCD spectrum may evolve from a fragmented level of conceptualization as a "metaphor" to one that is more comprehensive and structured.

Identification of two heritable cross-disorder endophenotypes for Tourette Syndrome

PubMed Central

Darrow, Sabrina M.; Hirschtritt, Matthew E.; Davis, Lea K.; Illmann, Cornelia; Osiecki, Lisa; Grados, Marco; Sandor, Paul; Dion, Yves; King, Robert; Pauls, David; Budman, Cathy L.; Cath, Danielle C.; Greenberg, Erica; Lyon, Gholson J.; Yu, Dongmei; McGrath, Lauren M.; McMahon, William M.; Lee, Paul C.; Delucchi, Kevin L.; Scharf, Jeremiah M.; Mathews, Carol A.

2016-01-01

Objective Phenotypic heterogeneity in Tourette syndrome (TS) is partly due to complex genetic relationships between TS, obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. Method 3494 individuals recruited for genetic studies were assessed for TS, OCD, and ADHD symptoms. Symptom-level factor and latent class analyses were conducted in TS families and replicated in an independent sample. Classes were characterized by comorbidity rates and proportion of parents. Heritability and TS-, OCD-, and ADHD-associated polygenic load were estimated. Results We identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high (disinhibition factor= 0.35, SE=0.03, p= 4.2 ×10−34; symmetry factor= 0.39, SE=0.03, p= 7.2 ×10−31; symmetry class=0.38, SE=0.10, p=0.001). Mothers of TS probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a TS genome-wide association study (GWAS) were associated with symmetry (p= 0.02), while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were associated with disinhibition (p =0.03), while TS and ADHD risk scores were not. Conclusions We identified two heritable TS-related endophenotypes that cross traditional diagnostic boundaries. The symmetry phenotype correlated with TS polygenic load, and was present in otherwise “TS-unaffected” mothers, suggesting that this phenotype may reflect additional TS (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses. PMID:27809572

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

PubMed

Darrow, Sabrina M; Hirschtritt, Matthew E; Davis, Lea K; Illmann, Cornelia; Osiecki, Lisa; Grados, Marco; Sandor, Paul; Dion, Yves; King, Robert; Pauls, David; Budman, Cathy L; Cath, Danielle C; Greenberg, Erica; Lyon, Gholson J; Yu, Dongmei; McGrath, Lauren M; McMahon, William M; Lee, Paul C; Delucchi, Kevin L; Scharf, Jeremiah M; Mathews, Carol A

2017-04-01

Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts. Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated. The authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not. The analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

Neurocognitive performance as an endophenotype for bipolar disorder.

PubMed

Raust, Aurelie; Daban, Claire; Cochet, Barbara; Henry, Chantal; Bellivier, Frank; Scott, Jan

2014-01-01

Identification of the underlying liability to develop bipolar disorders (BD) is hindered by the genetic complexity and phenotypic heterogeneity of the disease. The use of endophenotypes has been acknowledged as a promising approach that may detect the hidden manifestations of a genetic liability for an illness. One of the most commonly proposed endophenotypes in BD is neurocognitive performance. We identified and examined previously published review articles that had any data pertaining to endophenotypes in BD and combined this with an extensive review of studies of cognitive deficits in BD from 2000 onwards. Using criteria for a valid endophenotype, we identifed that the domains of executive functioning and verbal memory are the most promising candidate endophenotypes for BD. However, they do not meet the criteria for specificity as similar deficits present in schizophrenia and/or severe or psychotic major depressions. Further research is needed as the findings regarding endophenotypes show between-study heterogeneity. In the future, examination of quantitative traits may offer a more promising approach to the study of endophenotypes rather than solely focusing on diagnostic categories.

The genetic epidemiology of personality disorders

PubMed Central

Reichborn-Kjennerud, Ted

2010-01-01

Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified. Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes. PMID:20373672

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety.

PubMed

Yen, Yi-Chun; Anderzhanova, Elmira; Bunck, Mirjam; Schuller, Julia; Landgraf, Rainer; Wotjak, Carsten T

2013-01-01

We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms.

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety

PubMed Central

Yen, Yi-Chun; Anderzhanova, Elmira; Bunck, Mirjam; Schuller, Julia; Landgraf, Rainer; Wotjak, Carsten T.

2013-01-01

We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms. PMID:23966915

Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity.

PubMed

Beauchaine, Theodore P; Constantino, John N

2017-09-11

In psychopathology research, endophenotypes are a subset of biomarkers that indicate genetic vulnerability independent of clinical state. To date, an explicit expectation is that endophenotypes be specific to single disorders. We evaluate this expectation considering recent advances in psychiatric genetics, recognition that transdiagnostic vulnerability traits are often more useful than clinical diagnoses in psychiatric genetics, and appreciation for etiological complexity across genetic, neural, hormonal and environmental levels of analysis. We suggest that the disorder-specificity requirement of endophenotypes be relaxed, that neural functions are preferable to behaviors as starting points in searches for endophenotypes, and that future research should focus on interactive effects of multiple endophenotypes on complex psychiatric disorders, some of which are 'phenocopies' with distinct etiologies.

Altered Reward Reactivity as a Behavioural Endophenotype in Eating Disorders: A Pilot Investigation in Twins.

PubMed

Kanakam, Natalie; Krug, Isabel; Collier, David; Treasure, Janet

2017-05-01

Altered reward reactivity is a potential risk endophenotype for eating disorders (EDs). The aim of this study was to examine reward reactivity in female twins with EDs and compare it with a twin control group. A sample of 112 twins [n = 51 met lifetime DSM-IV ED criteria (anorexia nervosa n = 26; bulimic disorders n = 24), n = 19 unaffected cotwins and n = 42 control twins] was administered measures assessing reward reactivity, including the Game of Dice Task, the Behavioural Inhibition/Activation (BIS/BAS) Scales and the Appetitive Motivation Scale (AMS). Within pair, correlations for monozygotic and dizygotic twins were calculated and generalised estimating equations compared probands with non-ED cotwins and controls. The BAS and the AMS were reduced in EDs and negatively associated with restrictive symptoms. In addition, monozygotic twins pairs demonstrated significant within pair similarity for the BAS and AMS. Conversely, there was less evidence to support the BIS or risky decision-making as measured by the Game of Dice Task as an endophenotype in EDs. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Genetic and environmental influences on adolescent rumination and its association with depressive symptoms.

PubMed

Chen, Jie; Li, Xinying

2013-11-01

Rumination is an important cognitive vulnerability for adolescent and adult depression. However, little is known about the aetiological origins of rumination, as well as its association with depression. Adolescent rumination (self-report) and depressive symptoms (self- and parent-report) were assessed in 674 pairs of same-gender Chinese adolescent twins (11-17 years of age). Females accounted for 53.7 % of the sample. There were significant correlations between self-reported rumination and self-reported depression (r = 0.41), as well as parent-reported adolescent depression (r = 0.22). Genetic influences were significant and modest on all three measures, ranging from 24 % to 42 %. The three measures were also significantly influenced by shared environment, ranging from 20 % to 28 %, and non-shared environmental factors, ranging from 30 % to 56 %. Moreover, the genetic correlations between rumination and depression were significant (within-rater: r(g) = 0.99; cross-rater: r(g) = 0.59) and largely accounted for the phenotypic correlations (within-rater: 68 %; cross-rater: 77 %), while non-shared environmental correlations were also significant (within-rater: r(e) = 0.26; cross-rater: r(e) = 0.12) and accounted for the remainder of the phenotypic correlations (within-rater: 32 %; cross-rater: 23 %). The shared environmental correlations were non-significant. No significant gender and age differences were found in aetiological models. These findings suggest that rumination may be an endophenotype reflecting genetic risk for depression.

Genomewide Association Scan of a Mortality Associated Endophenotype for a Long and Healthy Life in the Long Life Family Study.

PubMed

Singh, Jatinder; Minster, Ryan L; Schupf, Nicole; Kraja, Aldi; Liu, YongMei; Christensen, Kaare; Newman, Anne B; Kammerer, Candace M

2017-10-01

Identification of genes or fundamental biological pathways that regulate aging phenotypes and longevity could lead to possible interventions to increase healthy longevity. Using data from the Long Life Family Study, we performed genomewide association analyses on an endophenotype construct, LF1, comprising a linear combination of traits across health domains. LF1 primarily reflected traits from the pulmonary and physical activity domains. We detected a significant association between LF1 and a locus on chromosome 10p15 (p-value = 4.65 × 10-8) and suggestive evidence (p-value < 5 × 10-6) for association on chromosomes 1, 2, 8, 12, 15, 18, and 22. Using data from the Health, Aging and Body Composition Study, we subsequently replicated the association for the 1p13 region near the NBPF6 locus (p-value = 3.65 × 10-4). Our analyses indicate that loci influencing a healthy aging endophenotype construct predominantly comprised of pulmonary and physical function domains may be located on chromosome 1p13 near the NBPF6 locus. Further investigation of this possible locus and other suggestive loci may reveal novel biological pathways that influence healthy aging. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

New insights into the endophenotypic status of cognition in bipolar disorder: genetic modelling study of twins and siblings.

PubMed

Georgiades, Anna; Rijsdijk, Fruhling; Kane, Fergus; Rebollo-Mesa, Irene; Kalidindi, Sridevi; Schulze, Katja K; Stahl, Daniel; Walshe, Muriel; Sahakian, Barbara J; McDonald, Colm; Hall, Mei-Hua; Murray, Robin M; Kravariti, Eugenia

2016-06-01

Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder. To quantify the shared genetic variability between bipolar disorder and cognitive measures. Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder. Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|-|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|-|1.00|), which remained significant after covarying for affective symptoms. Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder. © The Royal College of Psychiatrists 2016.

The Consortium on the Genetics of Endophenotypes in Schizophrenia: Model Recruitment, Assessment, and Endophenotyping Methods for a Multisite Collaboration

PubMed Central

Calkins, Monica E.; Dobie, Dorcas J.; Cadenhead, Kristin S.; Olincy, Ann; Freedman, Robert; Green, Michael F.; Greenwood, Tiffany A.; Gur, Raquel E.; Gur, Ruben C.; Light, Gregory A.; Mintz, Jim; Nuechterlein, Keith H.; Radant, Allen D.; Schork, Nicholas J.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Stone, William S.; Swerdlow, Neal R.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Braff, David L.

2007-01-01

Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health–funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. Results: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). Discussion: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia. PMID:17035358

Influence of the Novelty-Seeking Endophenotype on the Rewarding Effects of Psychostimulant Drugs in Animal Models

PubMed Central

Carmen Arenas, M.; Aguilar, María A.; Montagud-Romero, Sandra; Mateos-García, Ana; Navarro-Francés, Concepción I.; Miñarro, José; Rodríguez-Arias, Marta

2016-01-01

Novelty seeking (NS), defined as a tendency to pursue novel and intense emotional sensations and experiences, is one of the most relevant individual factors predicting drug use among humans. High novelty seeking (HNS) individuals present an increased risk of drug use compared to low novelty seekers. The NS endophenotype may explain some of the differences observed among individuals exposed to drugs of abuse in adolescence. However, there is little research about the particular response of adolescents to drugs of abuse in function of this endophenotype, and the data that do exist are inconclusive. The present work reviews the literature regarding the influence of NS on psychostimulant reward, with particular focus on adolescent subjects. First, the different animal models of NS and the importance of this endophenotype in adolescence are discussed. Later, studies that have used the most common animal models of reward (self-administration, conditioned place preference paradigms) to evaluate how the NS trait influences the rewarding effects of psychostimulants are reviewed. Finally, possible explanations for the enhanced risk of developing substance dependence among HNS individuals are discussed. In conclusion, the studies referred to in this review show that the HNS trait is associated with: (1) increased initial sensitivity to the rewarding effects of psychostimulants, (2) a higher level of drug craving when the subject is exposed to the environmental cues associated with the drug, and (3) enhanced long-term vulnerability to relapse to drug consumption after prolonged abstinence. PMID:26391743

Testing for Neuropsychological Endophenotypes in Siblings Discordant for ADHD

PubMed Central

Bidwell, L. Cinnamon; Willcutt, Erik G.; DeFries, John C.; Pennington, Bruce F.

2007-01-01

Objective Neurocognitive deficits associated with attention deficit-hyperactivity disorder (ADHD) may be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD. Methods This study administered 17 measures from prominent neuropsychological theories of ADHD (executive function, processing speed, arousal regulation and motivation/delay aversion) in dizygotic (DZ) twin pairs discordant for ADHD and control twin pairs (ages 8–18) in order to compare performance between twins affected with ADHD (n = 266), their unaffected co-twins (n = 228), and control children from twin pairs without ADHD or learning difficulties (n = 332). Results ADHD subjects show significant impairment on executive function, processing speed, and response variability measures compared to control subjects. Unaffected cotwins of ADHD subjects are significantly impaired on nearly all the same measures as their ADHD siblings, even when subclinical symptoms of ADHD are controlled. Conclusion Executive function, processing speed, and response variability deficits may be useful endophenotypes for genetic studies of ADHD. PMID:17585884

Downregulated Kynurenine 3-Monooxygenase Gene Expression and Enzyme Activity in Schizophrenia and Genetic Association With Schizophrenia Endophenotypes

PubMed Central

Wonodi, Ikwunga; Stine, O. Colin; Sathyasaikumar, Korrapati V.; Roberts, Rosalinda C.; Mitchell, Braxton D.; Hong, L. Elliot; Kajii, Yasushi; Thaker, Gunvant K.; Schwarcz, Robert

2013-01-01

Context Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. Objectives To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Design Case-control postmortem and clinical study. Setting Maryland Brain Collection, outpatient clinics. Participants Postmortem specimens from schizophrenia patients (n=32) and control donors (n=32) and a clinical sample of schizophrenia patients (n=248) and healthy controls (n=228). Main Outcome Measures Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). Results In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Conclusion Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits. PMID:21727251

Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.

PubMed

Wonodi, Ikwunga; Stine, O Colin; Sathyasaikumar, Korrapati V; Roberts, Rosalinda C; Mitchell, Braxton D; Hong, L Elliot; Kajii, Yasushi; Thaker, Gunvant K; Schwarcz, Robert

2011-07-01

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Case-control postmortem and clinical study. Maryland Brain Collection, outpatient clinics. Postmortem specimens from schizophrenia patients (n = 32) and control donors (n = 32) and a clinical sample of schizophrenia patients (n = 248) and healthy controls (n = 228). Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.

The Genetic Covariation between Fear Conditioning and Self-Report Fears

PubMed Central

Hettema, John M.; Annas, Peter; Neale, Michael C.; Fredrikson, Mats; Sci, Dr Med; Kendler, Kenneth S.

2008-01-01

Background Fear conditioning is a traditional model for the acquisition of phobias, while behavioral therapies utilize processes underlying extinction to treat phobic and other anxiety disorders. Furthermore, fear conditioning has been proposed as an endophenotype for genetic studies of anxiety disorders. While prior studies have demonstrated that fear conditioning and self-report fears are heritable, no studies have determined whether they share a common genetic basis. Methods We obtained fear conditioning data from 173 twin pairs from the Swedish Twin Registry who also provided self-report ratings of 16 common fears. Using multivariate structural equation modeling, we analyzed factor-derived scores for the subjective fear ratings together with the electrophysiologic skin conductance responses during habituation, acquisition, and extinction to determine the extent of their genetic covariation. Results Phenotypic correlations between experimental and self-report fear measures were modest and, and counter-intuitively, negative; that is, subjects who reported themselves as more fearful had smaller electrophysiologic responses. Best-fit models estimated a significant (negative) genetic correlation between them, although genetic factors underlying fear conditioning accounted for only 9% of individual differences in self-report fears. Conclusions Experimentally-derived fear conditioning measures share only a small portion of the genetic factors underlying individual differences in subjective fears, cautioning against relying too heavily on the former as an endophenotype for genetic studies of phobic disorders. PMID:17698042

Evidence of Common Genetic Overlap Between Schizophrenia and Cognition

PubMed Central

Hubbard, Leon; Tansey, Katherine E.; Rai, Dheeraj; Jones, Peter; Ripke, Stephan; Chambert, Kimberly D.; Moran, Jennifer L.; McCarroll, Steven A.; Linden, David E. J.; Owen, Michael J.; O’Donovan, Michael C.; Walters, James T. R.; Zammit, Stanley

2016-01-01

Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophrenia en masse contribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n = 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n = 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P = .001) and lower full IQ (P = .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P = 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (r G = −.379, P = 6.62E-05) and full IQ (r G = −.202, P = 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis. PMID:26678674

Evidence of Common Genetic Overlap Between Schizophrenia and Cognition.

PubMed

Hubbard, Leon; Tansey, Katherine E; Rai, Dheeraj; Jones, Peter; Ripke, Stephan; Chambert, Kimberly D; Moran, Jennifer L; McCarroll, Steven A; Linden, David E J; Owen, Michael J; O'Donovan, Michael C; Walters, James T R; Zammit, Stanley

2016-05-01

Cognitive impairment is a core feature of schizophrenia but there is limited understanding of the genetic relationship between cognition in the general population and schizophrenia. We examine how common variants associated with schizophreniaen massecontribute to childhood cognitive ability in a population-based sample, and the extent to which common genetic variants associated with childhood cognition explain variation in schizophrenia. Schizophrenia polygenic risk scores were derived from the Psychiatric Genomics Consortium (n= 69 516) and tested for association with IQ, attention, processing speed, working memory, problem solving, and social cognition in over 5000 children aged 8 from the Avon Longitudinal Study of Parents and Children birth cohort. Polygenic scores for these cognitive domains were tested for association with schizophrenia in a large UK schizophrenia sample (n= 11 853). Bivariate genome-wide complex trait analysis (GCTA) estimated the amount of shared genetic factors between schizophrenia and cognitive domains. Schizophrenia polygenic risk score was associated with lower performance IQ (P= .001) and lower full IQ (P= .013). Polygenic score for performance IQ was associated with increased risk for schizophrenia (P= 3.56E-04). Bivariate GCTA revealed moderate genetic correlation between schizophrenia and both performance IQ (rG= -.379,P= 6.62E-05) and full IQ (rG= -.202,P= 5.00E-03), with approximately 14% of the genetic component of schizophrenia shared with that for performance IQ. Our results support the presence of shared common genetic factors between schizophrenia and childhood cognitive ability. We observe a genetic relationship between schizophrenia and performance IQ but not verbal IQ or other cognitive variables, which may have implications for studies utilizing cognitive endophenotypes for psychosis. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

Whole-brain functional hypoconnectivity as an endophenotype of autism in adolescents

PubMed Central

Moseley, R.L.; Ypma, R.J.F.; Holt, R.J.; Floris, D.; Chura, L.R.; Spencer, M.D.; Baron-Cohen, S.; Suckling, J.; Bullmore, E.; Rubinov, M.

2015-01-01

Endophenotypes are heritable and quantifiable markers that may assist in the identification of the complex genetic underpinnings of psychiatric conditions. Here we examined global hypoconnectivity as an endophenotype of autism spectrum conditions (ASCs). We studied well-matched groups of adolescent males with autism, genetically-related siblings of individuals with autism, and typically-developing control participants. We parcellated the brain into 258 regions and used complex-network analysis to detect a robust hypoconnectivity endophenotype in our participant group. We observed that whole-brain functional connectivity was highest in controls, intermediate in siblings, and lowest in ASC, in task and rest conditions. We identified additional, local endophenotype effects in specific networks including the visual processing and default mode networks. Our analyses are the first to show that whole-brain functional hypoconnectivity is an endophenotype of autism in adolescence, and may thus underlie the heritable similarities seen in adolescents with ASC and their relatives. PMID:26413477

The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes

PubMed Central

Harrewijn, Anita; Tissier, Renaud L.M.; van der Molen, Melle J.W.; van Steenbergen, Henk; van Vliet, Irene M.; Reichart, Catrien G.; Houwing‐Duistermaat, Jeanine J.; Slagboom, P. Eline; van der Wee, Nic J.A.; Westenberg, P. Michiel

2018-01-01

abstract Objectives Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so‐called “endophenotypes”. These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety. Methods The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD. Results The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self‐reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms. Conclusions By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD. PMID:29700902

Integrating Behavioral Economics and Behavioral Genetics: Delayed Reward Discounting as an Endophenotype for Addictive Disorders

PubMed Central

MacKillop, James

2013-01-01

Delayed reward discounting is a behavioral economic index of impulsivity, referring to how much an individual devalues a reward based on its delay in time. As a behavioral process that varies considerably across individuals, delay discounting has been studied extensively as a model for self-control, both in the general population and in clinical samples. There is growing interest in genetic influences on discounting and, in particular, the prospect of discounting as an endophenotype for addictive disorders (i.e., a heritable mechanism partially responsible for conferring genetic risk). This review assembles and critiques the evidence supporting this hypothesis. Via numerous cross-sectional studies and a small number of longitudinal studies, there is considerable evidence that impulsive discounting is associated with addictive behavior and appears to play an etiological role. Moreover, there is increasing evidence from diverse methodologies that impulsive delay discounting is temporally stable, heritable, and that elevated levels are present in nonaffected family members. These findings suggest that impulsive discounting meets the criteria for being considered an endophenotype. In addition, recent findings suggest that genetic variation related to dopamine neurotransmission is significantly associated with variability in discounting preferences. A significant caveat, however, is that the literature is modest in some domains and, in others, not all the findings have been supportive or consistent. In addition, important methodological considerations are necessary in future studies. Taken together, although not definitive, there is accumulating support for the hypothesis of impulsive discounting as an endophenotype for addictive behavior and a need for further systematic investigation. PMID:23344986

Lipoprotein lipase variants associated with an endophenotype of hypertension: hypertension combined with elevated triglycerides.

PubMed

Chen, Pei; Jou, Yuh-Shan; Fann, Cathy S J; Chen, Jaw-Wen; Chung, Chia-Min; Lin, Chin-Yu; Wu, Sheng-Yeu; Kang, Mei-Jyh; Chen, Ying-Chuang; Jong, Yuh-Shiun; Lo, Huey-Ming; Kang, Chih-Sen; Chen, Chien-Chung; Chang, Huan-Cheng; Huang, Nai-Kuei; Wu, Yi-Lin; Pan, Wen-Harn

2009-01-01

Previously, we observed that young-onset hypertension was independently associated with elevated plasma triglyceride(s) (TG) levels to a greater extent than other metabolic risk factors. Thus, focusing on the endophenotype--hypertension combined with elevated TG--we designed a family-based haplotype association study to explore its genetic connection with novel genetic variants of lipoprotein lipase gene (LPL), which encodes a major lipid metabolizing enzyme. Young-onset hypertension probands and their families were recruited, numbering 1,002 individuals from 345 families. Single-nucleotide polymorphism discovery for LPL, linkage disequilibrium (LD) analysis, transmission disequilibrium tests (TDT), bin construction, haplotype TDT association and logistic regression analysis were performed. We found that the CC- haplotype (i) spanning from intron 2 to intron 4 and the ACATT haplotype (ii) spanning from intron 5 to intron 6 were significantly associated with hypertension-related phenotypes: hypertension (ii, P=0.05), elevated TG (i, P=0.01), and hypertension combined with elevated TG (i, P=0.001; ii, P<0.0001), according to TDT. The risk of this hypertension subtype increased with the number of risk haplotypes in the two loci, using logistic regression model after adjusting within-family correlation. The relationships between LPL variants and hypertension-related disorders were also confirmed by an independent association study. Finally, we showed a trend that individuals with homozygous risk haplotypes had decreased LPL expression after a fatty meal, as opposed to those with protective haplotypes. In conclusion, this study strongly suggests that two LPL intronic variants may be associated with development of the hypertension endophenotype with elevated TG. Copyright 2008 Wiley-Liss, Inc.

Executive functions as a potential neurocognitive endophenotype in anxiety disorders: A systematic review considering DSM-IV and DSM-5 diagnostic criteria classification.

PubMed

Muller, Juliana de Lima; Torquato, Kamilla Irigaray; Manfro, Gisele Gus; Trentini, Clarissa Marceli

2015-01-01

Evidence in the literature indicates that neurocognitive impairments may represent endophenotypes in psychiatric disorders. This study aimed to conduct a systematic review on executive functions as a potential neurocognitive endophenotype in anxiety disorder diagnosis according to the DSM-IV and DSM-5 classifications. A literature search of the LILACS, Cochrane Library, Index Psi Periódicos Técnico-Científicos, PubMed and PsycInfo databases was conducted, with no time limits. Of the 259 studies found, 14 were included in this review. Only studies on obsessive-compulsive disorder (OCD) were found. The executive function components of decision-making, planning, response inhibition, behavioral reversal/alternation, reversal learning and set-shifting/cognitive flexibility were considered to be a neurocognitive endophenotypes in OCD. Further studies on executive functions as a neurocognitive endophenotype in other anxiety disorders are needed since these may have different neurocognitive endophenotypes and require other prevention and treatment approaches.

Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder.

PubMed

Rommelse, Nanda N J; Franke, Barbara; Geurts, Hilde M; Hartman, Catharina A; Buitelaar, Jan K

2010-03-01

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20-50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.

Endophenotypes for Intelligence in Children and Adolescents

ERIC Educational Resources Information Center

van Leeuwen, Marieke; van den Berg, Stephanie M.; Hoekstra, Rosa A.; Boomsma, Dorret I.

2007-01-01

The aim of this study was to identify promising endophenotypes for intelligence in children and adolescents for future genetic studies in cognitive development. Based on the available set of endophenotypes for intelligence in adults, cognitive tasks were chosen covering the domains of working memory, processing speed, and selective attention. This…

Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype.

PubMed

Cooper, Christine A; Jain, Nimansha; Gallagher, Michael D; Weintraub, Daniel; Xie, Sharon X; Berlyand, Yosef; Espay, Alberto J; Quinn, Joseph; Edwards, Karen L; Montine, Thomas; Van Deerlin, Vivianna M; Trojanowski, John; Zabetian, Cyrus P; Chen-Plotkin, Alice S

2017-01-01

Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein ( SNCA ) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Genotype at rs356182, near SNCA , correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts ( P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum ( P = 0.005). Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA . Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Impressions of Humanness for Android Robot May Represent an Endophenotype for Autism Spectrum Disorders

ERIC Educational Resources Information Center

Kumazaki, Hirokazu; Warren, Zachary; Swanson, Amy; Yoshikawa, Yuichiro; Matsumoto, Yoshio; Ishiguro, Hiroshi; Sarkar, Nilanjan; Minabe, Yoshio; Kikuchi, Mitsuru

2018-01-01

Identification of meaningful endophenotypes may be critical to unraveling the etiology and pathophysiology of autism spectrum disorders (ASD). We investigated whether impressions of "humanness" for android robot might represent a candidate characteristic of an ASD endophenotype. We used a female type of android robot with an appearance…

A Review of the Differences in Developmental, Psychiatric, and Medical Endophenotypes Between Males and Females with Autism Spectrum Disorder

PubMed Central

Rubenstein, Eric; Wiggins, Lisa D.; Lee, Li-Ching

2015-01-01

Autism spectrum disorder (ASD) is over four times more prevalent in males compared to females. Increased understanding of sex differences in ASD endophenotypes could add insight into possible etiologies and the assessment and management of the disorder. Consequently, the purpose of this review is to describe current literature regarding sex differences in the developmental, psychiatric, and medical endophenotypes of ASD in order to illustrate current knowledge and areas in need of further research. Our review found that repetitive behaviors and restricted interests are more common in males than females with ASD. Intellectual disability is more common in females than males with ASD. Attention to detail may be more common in males than females with ASD and epilepsy may be more common in females than males with ASD, although limited research in these areas prevent definitive conclusions from being drawn. There does not appear to be a sex difference in other developmental, psychiatric, and medical symptoms associated with ASD, or the research was contradictory or too sparse to establish a sex difference. Our review is unique in that it offers detailed discussion of sex differences in three major endophenotypes of ASD. Further research is needed to better understand why sex differences exist in certain ASD traits and to evaluate whether phenotypic sex differences are related to different pathways of development, assessment, and treatment of the disorder. PMID:26146472

Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.

PubMed

Marchese, Maria; Conti, Valerio; Valvo, Giulia; Moro, Francesca; Muratori, Filippo; Tancredi, Raffaella; Santorelli, Filippo M; Guerrini, Renzo; Sicca, Federico

2014-02-27

With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly. We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly. Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile ("extreme" macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with "extreme" macrocephaly, autism, intellectual disability and seizures. We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with "extreme" macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.

Highly impulsive rats: modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction

PubMed Central

Jupp, Bianca; Caprioli, Daniele; Dalley, Jeffrey W.

2013-01-01

Impulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction. PMID:23355644

Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia?

PubMed

Solowij, Nadia; Michie, Patricia T

2007-01-01

Currently, there is a lot of interest in cannabis use as a risk factor for the development of schizophrenia. Cognitive dysfunction associated with long-term or heavy cannabis use is similar in many respects to the cognitive endophenotypes that have been proposed as vulnerability markers of schizophrenia. In this overview, we examine the similarities between these in the context of the neurobiology underlying cognitive dysfunction, particularly implicating the endogenous cannabinoid system, which plays a significant role in attention, learning and memory, and in general, inhibitory regulatory mechanisms in the brain. Closer examination of the cognitive deficits associated with specific parameters of cannabis use and interactions with neurodevelopmental stages and neural substrates will better inform our understanding of the nature of the association between cannabis use and psychosis. The theoretical and clinical significance of further research in this field is in enhancing our understanding of underlying pathophysiology and improving the provision of treatments for substance use and mental illness.

Does Performance on the Standard Antisaccade Task Meet the Co-Familiality Criterion for an Endophenotype?

ERIC Educational Resources Information Center

Levy, Deborah L.; Bowman, Elizabeth A.; Abel, Larry; Krastoshevsky, Olga; Krause, Verena; Mendell, Nancy R.

2008-01-01

The "co-familiality" criterion for an endophenotype has two requirements: (1) clinically unaffected relatives as a group should show both a shift in mean performance and an increase in variance compared with controls; (2) performance scores should be heritable. Performance on the antisaccade task is one of several candidate endophenotypes for…

Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease

PubMed Central

Zou, F.; Carrasquillo, M. M.; Pankratz, V. S.; Belbin, O.; Morgan, K.; Allen, M.; Wilcox, S. L.; Ma, L.; Walker, L. P.; Kouri, N.; Burgess, J. D.; Younkin, L. H.; Younkin, Samuel G.; Younkin, C. S.; Bisceglio, G. D.; Crook, J. E.; Dickson, D. W.; Petersen, R. C.; Graff-Radford, N.; Younkin, Steven G.; Ertekin-Taner, N.

2010-01-01

Background: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels. Methods: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls). Results: We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with ∼twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3′ end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 × 10−8). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression. Conclusions: These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles. GLOSSARY AD = Alzheimer disease; CI = confidence interval; GWAS = genome-wide association study; LOAD = late-onset Alzheimer disease; mRNA = messenger RNA; OR = odds ratio; SNP = single nucleotide polymorphism. PMID:20142614

Animal models to improve our understanding and treatment of suicidal behavior.

PubMed

Gould, T D; Georgiou, P; Brenner, L A; Brundin, L; Can, A; Courtet, P; Donaldson, Z R; Dwivedi, Y; Guillaume, S; Gottesman, I I; Kanekar, S; Lowry, C A; Renshaw, P F; Rujescu, D; Smith, E G; Turecki, G; Zanos, P; Zarate, C A; Zunszain, P A; Postolache, T T

2017-04-11

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic-pituitary-adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio.

Neuropsychological Endophenotype Approach to Genome-wide Linkage Analysis Identifies Susceptibility Loci for ADHD on 2q21.1 and 13q12.11

PubMed Central

Rommelse, Nanda N.J.; Arias-Vásquez, Alejandro; Altink, Marieke E.; Buschgens, Cathelijne J.M.; Fliers, Ellen; Asherson, Philip; Faraone, Stephen V.; Buitelaar, Jan K.; Sergeant, Joseph A.; Oosterlaan, Jaap; Franke, Barbara

2008-01-01

ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores ≥ 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders. PMID:18599010

A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin.

PubMed

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Holmans, Peter; Bertelsen, Sarah; Holtzman, David; Morris, John C; Bales, Kelly; Pickering, Eve H; Kauwe, John; Goate, Alison; Cruchaga, Carlos

2016-01-01

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin

PubMed Central

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Holmans, Peter; Bertelsen, Sarah; Holtzman, David; Morris, John C; Bales, Kelly; Pickering, Eve H; Kauwe, John; Goate, Alison; Cruchaga, Carlos

2016-01-01

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer’s disease (AD). However the role of CLU on AD pathogenesis is not totally understood. We used CSF and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/Aβ ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p=3.98×10−7) and interleukin 6 (IL6, p=9.94×10−6, in the entire dataset and in the APOE ε4- individuals p=7.40×10−8). Gene-ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. PMID:26545630

Infant social attention: an endophenotype of ASD-related traits?

PubMed

Jones, Emily J H; Venema, Kaitlin; Earl, Rachel K; Lowy, Rachel; Webb, Sara J

2017-03-01

As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child's environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population. We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work. Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects. Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD. © 2016 Association for Child and Adolescent Mental Health.

Facial recognition deficits as a potential endophenotype in bipolar disorder.

PubMed

Vierck, Esther; Porter, Richard J; Joyce, Peter R

2015-11-30

Bipolar disorder (BD) is considered a highly heritable and genetically complex disorder. Several cognitive functions, such as executive functions and verbal memory have been suggested as promising candidates for endophenotypes. Although there is evidence for deficits in facial emotion recognition in individuals with BD, studies investigating these functions as endophenotypes are rare. The current study investigates emotion recognition as a potential endophenotype in BD by comparing 36 BD participants, 24 of their 1st degree relatives and 40 healthy control participants in a computerised facial emotion recognition task. Group differences were evaluated using repeated measurement analysis of co-variance with age as a covariate. Results revealed slowed emotion recognition for both BD and their relatives. Furthermore, BD participants were less accurate than healthy controls in their recognition of emotion expressions. We found no evidence of emotion specific differences between groups. Our results provide evidence for facial recognition as a potential endophenotype in BD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Neural Markers in Pediatric Bipolar Disorder and Familial Risk for Bipolar Disorder.

PubMed

Wiggins, Jillian Lee; Brotman, Melissa A; Adleman, Nancy E; Kim, Pilyoung; Wambach, Caroline G; Reynolds, Richard C; Chen, Gang; Towbin, Kenneth; Pine, Daniel S; Leibenluft, Ellen

2017-01-01

Bipolar disorder (BD) is highly heritable. Neuroimaging studies comparing unaffected youth at high familial risk for BD (i.e., those with a first-degree relative with the disorder; termed "high-risk" [HR]) to "low-risk" (LR) youth (i.e., those without a first-degree relative with BD) and to patients with BD may help identify potential brain-based markers associated with risk (i.e., regions where HR+BD≠LR), resilience (HR≠BD+LR), or illness (BD≠HR+LR). During functional magnetic resonance imaging (fMRI), 99 youths (i.e., adolescents and young adults) aged 9.8 to 24.8 years (36 BD, 22 HR, 41 LR) performed a task probing face emotion labeling, previously shown to be impaired behaviorally in youth with BD and HR youth. We found three patterns of results. Candidate risk endophenotypes (i.e., where BD and HR shared deficits) included dysfunction in higher-order face processing regions (e.g., middle temporal gyrus, dorsolateral prefrontal cortex). Candidate resilience markers and disorder sequelae (where HR and BD, respectively, show unique alterations relative to the other two groups) included different patterns of neural responses across other regions mediating face processing (e.g., fusiform), executive function (e.g., inferior frontal gyrus), and social cognition (e.g., default network, superior temporal sulcus, temporo-parietal junction). If replicated in longitudinal studies and with additional populations, neural patterns suggesting risk endophenotypes could be used to identify individuals at risk for BD who may benefit from prevention measures. Moreover, information about risk and resilience markers could be used to develop novel treatments that recruit neural markers of resilience and attenuate neural patterns associated with risk. Clinical trial registration information-Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder and Child and Adolescent Bipolar Disorder Brain Imaging and Treatment Study; http://clinicaltrials.gov/; NCT00025935 and NCT00006177. Published by Elsevier Inc.

[Autism and language: some molecular aspects].

PubMed

Benítez-Burraco, A

Autism is a cognitive disorder that includes among its distinguishing symptoms a deficit in the pragmatic component of language. Yet, it seems that there are certain subtypes where other deficiencies have been seen to affect the phonological, lexical, syntactical and morphological components of language. Linkage and association analyses aimed at identifying the genes that constitute causal or risk factors for the disorder have allowed researchers to identify certain loci that appear to be linked or associated to a statistically significant degree with autism endophenotypes of a linguistic nature. The target genes in this type of analysis play a number of different biological roles related with the development and functioning of the nervous system. On certain occasions, the loci thus identified coincide with others that had previously been linked to diverse language disorders (one paradigmatic case would be that of the chromosomal region 7q31 in relation to specific language disorder). This suggests that such disorders and autism might share a partially common genetic foundation that would account for the similarities observed between them at the phenotypic level.

Trait anxiety affects decision-making differently in healthy men and women: towards gender-specific endophenotypes of anxiety.

PubMed

de Visser, L; van der Knaap, L J; van de Loo, A J A E; van der Weerd, C M M; Ohl, F; van den Bos, R

2010-05-01

Excessive levels of trait anxiety are a risk factor for psychiatric conditions, including anxiety disorders and substance abuse. High trait anxiety has been associated with altered cognitive functioning, in particular with an attentional bias towards aversive stimuli. Decision-making is a crucial aspect of cognitive functioning that relies on the correct processing and control of emotional stimuli. Interestingly, anxiety and decision-making share underlying neural substrates, involving cortico-limbic pathways, including the amygdala, striatum and medial and dorsolateral prefrontal cortices. In the present study, we investigated the relationship between trait anxiety, measured by the State-Trait Anxiety Inventory, and complex decision-making, measured by the Iowa Gambling Task, in healthy male and female volunteers. The main focus of this study was the inclusion of gender as a discriminative factor. Indeed, we found distinct gender-specific effects of trait anxiety: in men, both low and high anxiety groups showed impaired decision-making compared to medium anxiety individuals, whereas in women only high anxiety individuals performed poorly. Furthermore, anxiety affected decision-making in men early in the task, i.e. the exploration phase, as opposed to an effect on performance in women during the second part of the test, i.e. the exploitation phase. These findings were related to different profiles of trait anxiety in men and women, and were independent of performance in the Wisconsin Card Sorting Test and cortisol levels. Our data show gender-specific effects of trait anxiety on emotional decision-making. We suggest gender-specific endophenotypes of anxiety to exist, that differentially affect cognitive functioning. 2010 Elsevier Ltd. All rights reserved.

Early social enrichment provided by communal nest increases resilience to depression-like behavior more in female than in male mice.

PubMed

D'Andrea, Ivana; Gracci, Fiorenza; Alleva, Enrico; Branchi, Igor

2010-12-20

Early experiences produce persistent changes in behavior and brain function. Being reared in a communal nest (CN), consisting of a single nest where three mouse mothers keep their pups together and share care-giving behavior from birth to weaning, provides an highly stimulating social environment to the developing pup since both mother-offspring and peer-to-peer interactions are markedly increased. Here we show that being reared in a CN affects adult behavior of CD-1 mice in a gender-dependent fashion, with reduced depression-like responses in females and increased anxiety-like behavior in males. In particular, CN females showed higher sucrose preference at baseline condition, drinking more sweet solution compared to female mice reared in a standard laboratory condition (SN). In the isolation test, both SN and CN females showed a reduction in sucrose preference after exposure to isolation stress. However, after 24h, only CN females significantly recovered. Finally, in the forced swim test, compared to SN, CN females spent longer time floating, a behavioral response that in the CN model has been inversely associated with display of endophenotypes of depression. With regard to the emotional response, CN males displayed an increased anxiety-like behavior in comparison to SN, spending less time in the open arms and displaying reduced head-dippings in the elevated plus-maze test. No difference was found in females. Overall, our findings show that gender and early experiences interact in modulating adult behavior. In particular, we show that early experiences modified developmental trajectories shaping adult endophenotypes of depression more markedly in females than in males. Copyright 2010 Elsevier B.V. All rights reserved.

Comparison of the Heritability of Schizophrenia and Endophenotypes in the COGS-1 Family Study

PubMed Central

Light, Gregory; Greenwood, Tiffany A.; Swerdlow, Neal R.; Calkins, Monica E.; Freedman, Robert; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Sprock, Joyce; Stone, William S.; Sugar, Catherine A.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Braff, David L.

2014-01-01

Background: Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a “heritability gap” between the diagnosis and related endophenotypes. Methods: Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families. Results: The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively. Conclusions: Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis. PMID:24903414

Contributions from specific and general factors to unique deficits: two cases of mathematics learning difficulties

PubMed Central

Haase, Vitor G.; Júlio-Costa, Annelise; Lopes-Silva, Júlia B.; Starling-Alves, Isabella; Antunes, Andressa M.; Pinheiro-Chagas, Pedro; Wood, Guilherme

2014-01-01

Mathematics learning difficulties are a highly comorbid and heterogeneous set of disorders linked to several dissociable mechanisms and endophenotypes. Two of these endophenotypes consist of primary deficits in number sense and verbal numerical representations. However, currently acknowledged endophenotypes are underspecified regarding the role of automatic vs. controlled information processing, and their description should be complemented. Two children with specific deficits in number sense and verbal numerical representations and normal or above-normal intelligence and preserved visuospatial cognition illustrate this point. Child H.V. exhibited deficits in number sense and fact retrieval. Child G.A. presented severe deficits in orally presented problems and transcoding tasks. A partial confirmation of the two endophenotypes that relate to the number sense and verbal processing was obtained, but a much more clear differentiation between the deficits presented by H.V. and G.A. can be reached by looking at differential impairments in modes of processing. H.V. is notably competent in the use of controlled processing but has problems with more automatic processes, such as nonsymbolic magnitude processing, speeded counting and fact retrieval. In contrast, G.A. can retrieve facts and process nonsymbolic magnitudes but exhibits severe impairment in recruiting executive functions and the concentration that is necessary to accomplish transcoding tasks and word problem solving. These results indicate that typical endophenotypes might be insufficient to describe accurately the deficits that are observed in children with mathematics learning abilities. However, by incorporating domain-specificity and modes of processing into the assessment of the endophenotypes, individual deficit profiles can be much more accurately described. This process calls for further specification of the endophenotypes in mathematics learning difficulties. PMID:24592243

Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study.

PubMed

Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2014-11-01

Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes. Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families. The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively. Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014.

[18F]FDOPA PET as an Endophenotype for Parkinson’s Disease Linkage Studies

PubMed Central

Racette, Brad A.; Good, Laura; Antenor, Jo Ann; McGee-Minnich, Lori; Moerlein, Stephen M.; Videen, Tom O.; Perlmutter, Joel S.

2008-01-01

Parkinson Disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[18F]fluorodopa ([18F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [18F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [18F]FDOPA posterior putamen uptake was defined as less than three standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD”. The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14±0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36±1.23. The [18F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree. PMID:16528749

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

PubMed Central

Archer, Trevor; Oscar-Berman, Marlene; Blum, Kenneth

2011-01-01

Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the “drug response phenotype,” rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring. PMID:22224195

Randomization and resilience of brain functional networks as systems-level endophenotypes of schizophrenia.

PubMed

Lo, Chun-Yi Zac; Su, Tsung-Wei; Huang, Chu-Chung; Hung, Chia-Chun; Chen, Wei-Ling; Lan, Tsuo-Hung; Lin, Ching-Po; Bullmore, Edward T

2015-07-21

Schizophrenia is increasingly conceived as a disorder of brain network organization or dysconnectivity syndrome. Functional MRI (fMRI) networks in schizophrenia have been characterized by abnormally random topology. We tested the hypothesis that network randomization is an endophenotype of schizophrenia and therefore evident also in nonpsychotic relatives of patients. Head movement-corrected, resting-state fMRI data were acquired from 25 patients with schizophrenia, 25 first-degree relatives of patients, and 29 healthy volunteers. Graphs were used to model functional connectivity as a set of edges between regional nodes. We estimated the topological efficiency, clustering, degree distribution, resilience, and connection distance (in millimeters) of each functional network. The schizophrenic group demonstrated significant randomization of global network metrics (reduced clustering, greater efficiency), a shift in the degree distribution to a more homogeneous form (fewer hubs), a shift in the distance distribution (proportionally more long-distance edges), and greater resilience to targeted attack on network hubs. The networks of the relatives also demonstrated abnormal randomization and resilience compared with healthy volunteers, but they were typically less topologically abnormal than the patients' networks and did not have abnormal connection distances. We conclude that schizophrenia is associated with replicable and convergent evidence for functional network randomization, and a similar topological profile was evident also in nonpsychotic relatives, suggesting that this is a systems-level endophenotype or marker of familial risk. We speculate that the greater resilience of brain networks may confer some fitness advantages on nonpsychotic relatives that could explain persistence of this endophenotype in the population.

Temperament and character as schizophrenia-related endophenotypes in non-psychotic siblings.

PubMed

Smith, Matthew J; Cloninger, C Robert; Harms, Michael P; Csernansky, John G

2008-09-01

Quantitative endophenotypes are needed to better understand the pathogenesis of schizophrenia. The psychobiological model of temperament and character suggests that personality traits are heritable and regulated by brain systems influencing schizophrenia susceptibility. Thus, measures of temperament and character may serve as schizophrenia-related endophenotypes in individuals with schizophrenia and their non-psychotic siblings. Individuals with schizophrenia (n=35), their non-psychotic siblings (n=34), controls (n=63), and their siblings (n=56) participated in a study of the clinical, neurocognitive and neuromorphological characteristics of schizophrenia. A mixed-model approach assessed group differences on the Temperament and Character Inventory (TCI). Neurocognitive deficits and psychopathology were correlated with the TCI. Configurations of TCI domains were examined using a generalized linear model. Individuals with schizophrenia and their non-psychotic siblings had higher harm avoidance than controls and their siblings. Individuals with schizophrenia had lower self-directedness and cooperativeness, and higher self-transcendence than their non-psychotic siblings, controls, and the siblings of controls. Neurocognition was not related to temperament and character in individuals with schizophrenia or either control group. In non-psychotic siblings, self-directedness and cooperativeness were correlated with working memory and crystallized IQ. Evidence supports harm avoidance as a schizophrenia-related endophenotype. An increased risk of schizophrenia may be associated with asociality (configured as high harm avoidance and low reward dependence), schizotypy (configured as low self-directedness, low cooperativeness, and high self-transcendence), and neurocognitive deficits (poor executive functioning, working/episodic memory, attention, and low IQ). The non-psychotic siblings demonstrated features of a mature character profile including strong crystallized IQ, which may confer protection against psychopathology.

Animal models to improve our understanding and treatment of suicidal behavior

PubMed Central

Gould, T D; Georgiou, P; Brenner, L A; Brundin, L; Can, A; Courtet, P; Donaldson, Z R; Dwivedi, Y; Guillaume, S; Gottesman, I I; Kanekar, S; Lowry, C A; Renshaw, P F; Rujescu, D; Smith, E G; Turecki, G; Zanos, P; Zarate, C A; Zunszain, P A; Postolache, T T

2017-01-01

Worldwide, suicide is a leading cause of death. Although a sizable proportion of deaths by suicide may be preventable, it is well documented that despite major governmental and international investments in research, education and clinical practice suicide rates have not diminished and are even increasing among several at-risk populations. Although nonhuman animals do not engage in suicidal behavior amenable to translational studies, we argue that animal model systems are necessary to investigate candidate endophenotypes of suicidal behavior and the neurobiology underlying these endophenotypes. Animal models are similarly a critical resource to help delineate treatment targets and pharmacological means to improve our ability to manage the risk of suicide. In particular, certain pathophysiological pathways to suicidal behavior, including stress and hypothalamic–pituitary–adrenal axis dysfunction, neurotransmitter system abnormalities, endocrine and neuroimmune changes, aggression, impulsivity and decision-making deficits, as well as the role of critical interactions between genetic and epigenetic factors, development and environmental risk factors can be modeled in laboratory animals. We broadly describe human biological findings, as well as protective effects of medications such as lithium, clozapine, and ketamine associated with modifying risk of engaging in suicidal behavior that are readily translatable to animal models. Endophenotypes of suicidal behavior, studied in animal models, are further useful for moving observed associations with harmful environmental factors (for example, childhood adversity, mechanical trauma aeroallergens, pathogens, inflammation triggers) from association to causation, and developing preventative strategies. Further study in animals will contribute to a more informed, comprehensive, accelerated and ultimately impactful suicide research portfolio. PMID:28398339

Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1.

PubMed

Sacco, Roberto; Papaleo, Veruska; Hager, Jorg; Rousseau, Francis; Moessner, Rainald; Militerni, Roberto; Bravaccio, Carmela; Trillo, Simona; Schneider, Cindy; Melmed, Raun; Elia, Maurizio; Curatolo, Paolo; Manzi, Barbara; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Reichelt, Karl-Ludvig; Persico, Antonio M

2007-03-08

The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies alpha-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identified in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research. Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by chi2, endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT. TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001). TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP.

Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1

PubMed Central

Sacco, Roberto; Papaleo, Veruska; Hager, Jorg; Rousseau, Francis; Moessner, Rainald; Militerni, Roberto; Bravaccio, Carmela; Trillo, Simona; Schneider, Cindy; Melmed, Raun; Elia, Maurizio; Curatolo, Paolo; Manzi, Barbara; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Reichelt, Karl-Ludvig; Persico, Antonio M

2007-01-01

Background The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies α-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identifed in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research. Methods Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by χ2, endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT. Results TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001). Conclusion TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP. PMID:17346350

Heterogeneity of response to antipsychotics from multiple disorders in the schizophrenia spectrum.

PubMed

Garver, D L; Holcomb, J A; Christensen, J D

2000-12-01

Antipsychotic response after the initiation of neuroleptic treatment shows wide variation in schizophrenic patient populations. In this overview, the authors suggest that the variance in antipsychotic drug response within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinnings. Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological markers with possible etiologic significance are reviewed. Such studies had assessed recently hospitalized, neuroleptic-free patients undergoing exacerbation of nonaffective psychotic disorders. Prior to initiation of neuroleptic, the cohort of patients had been assessed for the quantity of the dopamine metabolite homovanillic acid in plasma (pHVA) and had undergone the first of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle volumes. A second MRI was subsequently performed during a period of (partial) remission to determine within-patient stability of ventricular volumes. These selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-means clustering. The speed and completeness of neuroleptic-induced antipsychotic response were related to 3 clusters of patients delineated by modal distributions of pHVA and of apparent rates of ventricular change. At least 3 unique "endophenotypes" of the "group of the schizophrenias" can be defined with respect to speed and completeness of antipsychotic response. Each endophenotype appears to show at least one unique biological feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A delayed-response psychosis had low-to-normal pHVA, clinically demonstrated persistent negative symptoms, and was associated with an excessive rate of change in ventricle volume between exacerbations of psychosis and (partial) remissions. Finally, a nonresponsive psychosis could be characterized as having both low-to-normal pHVA and rate of change of ventricle volumes similar to that of controls. Additional studies revealed that each of the endophenotypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found in their family members who had psychotic disorders. Similarly, the prominent negative symptoms of the delayed-response probands were reflected as a prominent trait in their family members also afflicted with psychosis. The endophenotypes tended to "breed true" in terms of prognosis and negative symptoms. Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related to differences in the etiology and consequent pathophysiology of illness.

Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers

PubMed Central

Deming, Yuetiva; Li, Zeran; Kapoor, Manav; Harari, Oscar; Del-Aguila, Jorge L.; Black, Kathleen; Carrell, David; Cai, Yefei; Fernandez, Maria Victoria; Budde, John; Ma, Shengmei; Saef, Benjamin; Howells, Bill; Huang, Kuanlin; Bertelsen, Sarah; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Kim, Sungeun; Saykin, Andrew J.; De Jager, Philip L.; Albert, Marilyn; Moghekar, Abhay; O’Brien, Richard; Riemenschneider, Matthias; Petersen, Ronald C.; Blennow, Kaj; Zetterberg, Henrik; Minthon, Lennart; Van Deerlin, Vivianna M.; Lee, Virginia Man-Yee; Shaw, Leslie M.; Trojanowski, John Q.; Schellenberg, Gerard; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Peskind, Elaine R.; Li, Ge; Di Narzo, Antonio F.; Kauwe, John S. K.; Goate, Alison M.; Cruchaga, Carlos

2017-01-01

More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SER-PINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies. PMID:28247064

Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex

PubMed Central

Iafrati, Jillian; Malvache, Arnaud; Gonzalez Campo, Cecilia; Orejarena, M. Juliana; Lassalle, Olivier; Bouamrane, Lamine; Chavis, Pascale

2016-01-01

The postnatal maturation of the prefrontal cortex (PFC) represents a period of increased vulnerability to risk factors and emergence of neuropsychiatric disorders. To disambiguate the pathophysiological mechanisms contributing to these disorders, we revisited the endophenotype approach from a developmental viewpoint. The extracellular matrix protein reelin which contributes to cellular and network plasticity, is a risk factor for several psychiatric diseases. We mapped the aggregate effect of the RELN risk allele on postnatal development of PFC functions by cross-sectional synaptic and behavioral analysis of reelin-haploinsufficient mice. Multivariate analysis of bootstrapped datasets revealed subgroups of phenotypic traits specific to each maturational epoch. The preeminence of synaptic AMPA/NMDA receptor content to pre-weaning and juvenile endophenotypes shifts to long-term potentiation and memory renewal during adolescence followed by NMDA-GluN2B synaptic content in adulthood. Strikingly, multivariate analysis shows that pharmacological rehabilitation of reelin haploinsufficient dysfunctions is mediated through induction of new endophenotypes rather than reversion to wild-type traits. By delineating previously unknown developmental endophenotypic sequences, we conceived a promising general strategy to disambiguate the molecular underpinnings of complex psychiatric disorders and for the rational design of pharmacotherapies in these disorders. PMID:27765946

Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression

PubMed Central

Knorr, Ulla; Vinberg, Maj; Klose, Marianne; Feldt-Rasmussen, Ulla; Hilsted, Linda; Gade, Anders; Haastrup, Eva; Paulson, Olaf; Wetterslev, Jørn; Gluud, Christian; Gether, Ulrik; Kessing, Lars

2009-01-01

Background Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention. Methods The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group. Trial registration Local Ethics Committee: H-KF 307413 Danish Medicines Agency: 2612-3162. EudraCT: 2006-001750-28. Danish Data Agency: 2006-41-6737. ClinicalTrials.gov: NCT 00386841 PMID:19671139

Temperament and Character as Schizophrenia-Related Endophenotypes in Non-psychotic Siblings

PubMed Central

Smith, Matthew J.; Cloninger, C. Robert; Harms, Michael P.; Csernansky, John G.

2008-01-01

Background Quantitative endophenotypes are needed to better understand the pathogenesis of schizophrenia. The psychobiological model of temperament and character suggests that personality traits are heritable and regulated by brain systems influencing schizophrenia susceptibility. Thus, measures of temperament and character may serve as schizophrenia-related endophenotypes in individuals with schizophrenia and their non-psychotic siblings. Methods Individuals with schizophrenia (n=35), their non-psychotic siblings (n=34), controls (n=63), and their siblings (n=56) participated in a study of the clinical, cognitive and neuromorphological characteristics of schizophrenia. A mixed-model approach assessed group differences on the Temperament and Character Inventory (TCI). Neurocognitive deficits and psychopathology were correlated with the TCI. Configurations of TCI domains were examined using a generalized linear model. Results Individuals with schizophrenia and their siblings had higher harm avoidance than controls and their siblings. Individuals with schizophrenia had lower self-directedness and cooperativeness, and higher self-transcendence than their non-psychotic siblings, controls, and the siblings of controls. Neurocognition was not related to temperament and character in individuals with schizophrenia or either control group. In non-psychotic siblings, self-directedness and cooperativeness were correlated with working memory and crystallized IQ. Conclusion Evidence supports harm avoidance as a schizophrenia-related endophenotype. An increased risk of schizophrenia may be associated with asociality (configured as high harm avoidance and low reward dependence), schizotypy (configured as low self-directedness, low cooperativeness, and high self-transcendence), and neurocognitive deficits (poor executive functioning, working/episodic memory, attention, and low IQ). The non-psychotic siblings demonstrated features of a mature character profile including strong crystallized IQ, which may confer protection against psychopathology. PMID:18718739

L-type Ca2+ channels in mood, cognition and addiction: integrating human and rodent studies with a focus on behavioural endophenotypes.

PubMed

Kabir, Z D; Lee, A S; Rajadhyaksha, A M

2016-10-15

Brain Ca v 1.2 and Ca v 1.3 L-type Ca 2+ channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Ca v 1.2 and Ca v 1.3 Ca 2+ signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour-based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia

PubMed Central

Wagshal, Dana; Knowlton, Barbara Jean; Cohen, Jessica Rachel; Bookheimer, Susan Yost; Bilder, Robert Martin; Fernandez, Vindia Gisela; Asarnow, Robert Franklin

2015-01-01

Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia. PMID:25541139

Endophenotypes in the personality disorders

PubMed Central

Siever, Larry J.

2005-01-01

The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability impulsiwity aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychoticlike symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms. PMID:16262209

Neural markers of errors as endophenotypes in neuropsychiatric disorders

PubMed Central

Manoach, Dara S.; Agam, Yigal

2013-01-01

Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally-unaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach. PMID:23882201

Action Monitoring in boys with ADHD, their Nonaffected Siblings and Normal Controls: Evidence for an Endophenotype

PubMed Central

Albrecht, Bjoern; Brandeis, Daniel; Uebel, Henrik; Heinrich, Hartmut; Mueller, Ueli C.; Hasselhorn, Marcus; Steinhausen, Hans-Christoph; Rothenberger, Aribert; Banaschewski, Tobias

2008-01-01

Background Attention deficit/hyperactivity disorder is a very common and highly heritable child psychiatric disorder associated with dysfunctions in fronto-striatal networks that control attention and response organisation. Aim of this study was to investigate whether features of action monitoring related to dopaminergic functions represent endophenotypes which are brain functions on the pathway from genes and environmental risk factors to behaviour. Methods Action monitoring and error processing as indicated by behavioural and electrophysiological parameters during a flanker task were examined in boys with ADHD combined type according to DSM-IV (N=68), their nonaffected siblings (N=18) and healthy controls with no known family history of ADHD (N=22). Results Boys with ADHD displayed slower and more variable reaction-times. Error negativity (Ne) was smaller in boys with ADHD compared to healthy controls, while nonaffected siblings displayed intermediate amplitudes following a linear model predicted by genetic concordance. The three groups did not differ on error positivity (Pe). N2 amplitude enhancement due to conflict (incongruent flankers) was reduced in the ADHD group. Nonaffected siblings also displayed intermediate N2 enhancement. Conclusions Converging evidence from behavioural and ERP findings suggests that action monitoring and initial error processing, both related to dopaminergically modulated functions of anterior cingulate cortex, might be an endophenotype related to ADHD. PMID:18339358

Neural markers of errors as endophenotypes in neuropsychiatric disorders.

PubMed

Manoach, Dara S; Agam, Yigal

2013-01-01

Learning from errors is fundamental to adaptive human behavior. It requires detecting errors, evaluating what went wrong, and adjusting behavior accordingly. These dynamic adjustments are at the heart of behavioral flexibility and accumulating evidence suggests that deficient error processing contributes to maladaptively rigid and repetitive behavior in a range of neuropsychiatric disorders. Neuroimaging and electrophysiological studies reveal highly reliable neural markers of error processing. In this review, we evaluate the evidence that abnormalities in these neural markers can serve as sensitive endophenotypes of neuropsychiatric disorders. We describe the behavioral and neural hallmarks of error processing, their mediation by common genetic polymorphisms, and impairments in schizophrenia, obsessive-compulsive disorder, and autism spectrum disorders. We conclude that neural markers of errors meet several important criteria as endophenotypes including heritability, established neuroanatomical and neurochemical substrates, association with neuropsychiatric disorders, presence in syndromally-unaffected family members, and evidence of genetic mediation. Understanding the mechanisms of error processing deficits in neuropsychiatric disorders may provide novel neural and behavioral targets for treatment and sensitive surrogate markers of treatment response. Treating error processing deficits may improve functional outcome since error signals provide crucial information for flexible adaptation to changing environments. Given the dearth of effective interventions for cognitive deficits in neuropsychiatric disorders, this represents a potentially promising approach.

Major depression in mothers predicts reduced ventral striatum activation in adolescent female offspring with and without depression.

PubMed

Sharp, Carla; Kim, Sohye; Herman, Levi; Pane, Heather; Reuter, Tyson; Strathearn, Lane

2014-05-01

Prior research has identified reduced reward-related brain activation as a promising endophenotype for the early identification of adolescents with major depressive disorder (MDD). However, it is unclear whether reduced reward-related brain activation constitutes a true vulnerability for MDD. One way of studying vulnerability is through a high-risk design. Therefore, the aim of the current study was to determine whether reward-related activation of the ventral striatum is reduced in nondepressed daughters of mothers with a history of MDD (high-risk) similarly to currently depressed adolescent girls, compared with healthy controls. By directly comparing groups with a shared risk profile during differing states, we aimed to shed light on the endophenotypic nature of reduced reward processing for adolescent depression. We compared reward-related neural activity through functional magnetic resonance imaging (fMRI) between three groups of female biological offspring (N = 52) of mothers with differential MDD status: (a) currently depressed daughters of mothers with a history of MDD (MDD group; n = 14), (b) age- and socioeconomic status (SES)-matched never-depressed daughters of mothers with a history of MDD (high-risk group; n = 19), and (c) age- and SES-matched control daughters of mothers with no past or current psychopathology in either the mother or the daughter (healthy control group; n = 19). For the outcome phase of the reward task, right-sided ventral striatum activation was reduced for both currently depressed and high-risk girls compared with healthy controls. This ventral striatal activity correlated significantly with maternal depression scores. These findings provide further evidence of aberrant functioning for the United States Department of Health & Human Services, National Institutes of Health, National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC)-defined domain of positive valence systems as a vulnerability factor for MDD and a potential endophenotype for the development of depression.

Improving Synchronization and Functional Connectivity in Autism Spectrum Disorders Through Plasticity-Induced Rehabilitation

DTIC Science & Technology

2013-08-01

Waiter GD, Gilchrist A, Perrett DI, Murray AD, Whiten A. Neural mechanisms of imitation and ‘mirror neuron’ functioning in autistic spectrum...or risk factor associated with the onset of ASD, the inherent heterogeneity of endophenotypical presentation makes clinical management challenging. In

A risk PRODH haplotype affects sensorimotor gating, memory, schizotypy, and anxiety in healthy male subjects.

PubMed

Roussos, Panos; Giakoumaki, Stella G; Bitsios, Panos

2009-06-15

Significant associations have been shown for haplotypes comprising three PRODH single nucleotide polymorphisms (SNPs; 1945T/C, 1766A/G, 1852G/A) located in the 3' region of the gene, suggesting a role of these variants in the etiopathogenesis of schizophrenia. We assessed the relationship between these high-risk PRODH polymorphisms and schizophrenia-related endophenotypes in a large and highly homogeneous cohort of healthy males. Participants (n = 217) were tested in prepulse inhibition (PPI), verbal and working memory, trait anxiety and schizotypy. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data. This procedure revealed significant phenotypic impact of the risk CGA haplotype. Subjects were then divided in two groups; levels of PPI, anxiety, and schizotypy, verbal and working memory were compared with analysis of variance. CGA carriers (n = 32) exhibited attenuated PPI (p < .001) and verbal memory (p < .001) and higher anxiety (p < .004) and schizotypy (p < .008) compared with the noncarriers (n = 185). There were no differences in baseline startle, demographics, and working memory. The main significant correlations were schizotypy x PPI [85-dB, 120-msec trials] in the carriers and schizotypy x anxiety in the entire group and the noncarriers but not the carriers group. Our results strongly support PPI as a valid schizophrenia endophenotype and highlight the importance of examining the role of risk haplotypes on multiple endophenotypes and have implications for understanding the continuum from normality to psychosis, transitional states, and the genetics of schizophrenia-related traits.

A systematic review and meta-analysis of neurological soft signs in relatives of people with schizophrenia

PubMed Central

2011-01-01

Background Neurological soft signs are subtle but observable impairments in motor and sensory functions that are not localized to a specific area of the brain. Neurological soft signs are common in schizophrenia. It has been established that soft signs meet two of five criteria for an endophenotype, namely: association with the illness, and state independence. This review investigated whether soft signs met a further criterion for an endophenotype, namely familial association. It was hypothesized that if familial association were present then neurological soft signs would be: (a) more common in first-degree relatives of people with schizophrenia than in controls; and (b) more common in people with schizophrenia than in their first-degree relatives. Method A systematic search identified potentially eligible studies in the EMBASE (1980-2011), OVID - MEDLINE (1950-2011) and PsycINFO (1806-2011) databases. Studies were included if they carried out a three-way comparison of levels of soft signs between people with schizophrenia, their first-degree relatives, and normal controls. Data were extracted independently by two reviewers and cross-checked by double entry. Results After screening 8678 abstracts, seven studies with 1553 participants were identified. Neurological soft signs were significantly more common in first-degree relatives of people with schizophrenia than in controls (pooled standardised mean difference (SMD) 1.24, 95% confidence interval (c.i) 0.59-1.89). Neurological soft signs were also significantly more common in people with schizophrenia than in their first-degree relatives (SMD 0.92, 95% c.i 0.64-1.20). Sensitivity analyses examining the effects of age and group blinding did not significantly alter the main findings. Conclusions Both hypotheses were confirmed, suggesting that the distribution of neurological soft signs in people with schizophrenia and their first-degree relatives is consistent with the endophenotype criterion of familial association. PMID:21859445

Testing the effects of adolescent alcohol use on adult conflict-related theta dynamics.

PubMed

Harper, Jeremy; Malone, Stephen M; Iacono, William G

2017-11-01

Adolescent alcohol use (AAU) is associated with brain anomalies, but less is known about long-term neurocognitive effects. Despite theoretical models linking AAU to diminished cognitive control, empirical work testing this relationship with specific cognitive control neural correlates (e.g., prefrontal theta-band EEG dynamics) remains scarce. A longitudinal twin design was used to test the hypothesis that greater AAU is associated with reduced conflict-related EEG theta-band dynamics in adulthood, and to examine the genetic/environmental etiology of this association. In a large (N=718) population-based prospective twin sample, AAU was assessed at ages 11/14/17. Twins completed a flanker task at age 29 to elicit EEG theta-band medial frontal cortex (MFC) power and medial-dorsal prefrontal cortex (MFC-dPFC) connectivity. Two complementary analytic methods (cotwin control analysis; biometric modeling) were used to disentangle the genetic/shared environmental risk towards AAU from possible alcohol exposure effects on theta dynamics. AAU was negatively associated with adult cognitive control-related theta-band MFC power and MFC-dPFC functional connectivity. Genetic influences primarily underlie these associations. Findings provide strong evidence that genetic factors underlie the comorbidity between AAU and diminished cognitive control-related theta dynamics in adulthood. Conflict-related theta-band dynamics appear to be candidate brain-based endophenotypes/mechanisms for AAU. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Underlying Manifestations of Developmental Phonological Disorders in French-Speaking Pre-Schoolers

ERIC Educational Resources Information Center

Brosseau-Lapré, Françoise; Rvachew, Susan

2017-01-01

This study examined the psycholinguistic profiles of Quebec French-speaking children with developmental phonological disorders (DPD). The purpose was to determine whether the endophenotypes that have been identified in English-speaking children with DPD are similarly associated with speech impairment in French-speaking children. Seventy-two…

Impressions of Humanness for Android Robot may Represent an Endophenotype for Autism Spectrum Disorders.

PubMed

Kumazaki, Hirokazu; Warren, Zachary; Swanson, Amy; Yoshikawa, Yuichiro; Matsumoto, Yoshio; Ishiguro, Hiroshi; Sarkar, Nilanjan; Minabe, Yoshio; Kikuchi, Mitsuru

2018-02-01

Identification of meaningful endophenotypes may be critical to unraveling the etiology and pathophysiology of autism spectrum disorders (ASD). We investigated whether impressions of "humanness" for android robot might represent a candidate characteristic of an ASD endophenotype. We used a female type of android robot with an appearance similar to that of a real person. Significant differences in overall impressions of 'humanness' for android robot were found between adolescents with ASD and typical development (TD) controls, as well as parents of children with ASD and parents of TD controls. Our current work does suggest robotic systems could potentially play an intelligent role in dissecting ASD heterogeneity.

Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.

PubMed

Deming, Yuetiva; Li, Zeran; Kapoor, Manav; Harari, Oscar; Del-Aguila, Jorge L; Black, Kathleen; Carrell, David; Cai, Yefei; Fernandez, Maria Victoria; Budde, John; Ma, Shengmei; Saef, Benjamin; Howells, Bill; Huang, Kuan-Lin; Bertelsen, Sarah; Fagan, Anne M; Holtzman, David M; Morris, John C; Kim, Sungeun; Saykin, Andrew J; De Jager, Philip L; Albert, Marilyn; Moghekar, Abhay; O'Brien, Richard; Riemenschneider, Matthias; Petersen, Ronald C; Blennow, Kaj; Zetterberg, Henrik; Minthon, Lennart; Van Deerlin, Vivianna M; Lee, Virginia Man-Yee; Shaw, Leslie M; Trojanowski, John Q; Schellenberg, Gerard; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Peskind, Elaine R; Li, Ge; Di Narzo, Antonio F; Kauwe, John S K; Goate, Alison M; Cruchaga, Carlos

2017-05-01

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ 42 ), tau, and phosphorylated tau (ptau 181 ) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau 181 , including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ 42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10 -8 ) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10 -8 ) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10 -2 ), disease progression (GLIS1: β = 0.277, P = 1.92 × 10 -2 ), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10 -3 ). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ 42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau 181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Alpha Asymmetry in Infants at Risk for Autism Spectrum Disorders

ERIC Educational Resources Information Center

Gabard-Durnam, Laurel; Tierney, Adrienne L.; Vogel-Farley, Vanessa; Tager-Flusberg, Helen; Nelson, Charles A.

2015-01-01

An emerging focus of research on autism spectrum disorder (ASD) targets the identification of early-developing ASD endophenotypes using infant siblings of affected children. One potential neural endophenotype is resting frontal electroencephalogram (EEG) alpha asymmetry, a metric of hemispheric organization. Here, we examined the development of…

Revisiting the Suitability of Antisaccade Performance as an Endophenotype in Schizophrenia

ERIC Educational Resources Information Center

Mazhari, Shahrzad; Price, Greg; Dragovic, Milan; Waters, Flavie A.; Clissa, Peter; Jablensky, Assen

2011-01-01

Poor performance on the antisaccade task has been proposed as a candidate endophenotype in schizophrenia. Caveats to this proposal, however, include inconsistent findings in first-degree relatives of individuals with schizophrenia, and substantial heterogeneity in individuals with the disorder. In this study, we examined antisaccade performance in…

A family affair: brain abnormalities in siblings of patients with schizophrenia.

PubMed

Moran, Marcel E; Hulshoff Pol, Hilleke; Gogtay, Nitin

2013-11-01

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development.

A family affair: brain abnormalities in siblings of patients with schizophrenia

PubMed Central

Hulshoff Pol, Hilleke; Gogtay, Nitin

2013-01-01

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development. PMID:23698280

Cognitive Characteristics of Children with Genetic Syndromes

PubMed Central

Simon, Tony J.

2008-01-01

The cognitive profile of several different populations of children, each with a distinct neurogenetic disorder that has been described as fitting the pattern of a “nonverbal learning disorder”, is examined. In particular, this paper presents the view that a cognitive endophenotype, specified in terms of specific cognitive processes involving the spatial, temporal and attentional domains, can be used to generate an explanation of the neurocognitive foundation of the common impairments found in these disorders. Methods for evaluating cognitive impairments are first compared and contrasted and the concept of “nonverbal learning disorders” is described. The paper then examines data from experimental tests of spatiotemporal and executive cognitive function acquired from children with one of several disorders to determine whether such a cognitive endophenotype holds promise for moving from descriptions of to explanations for the impairments observed and whether prescriptions for therapeutic interventions might flow from such an account. Synopsis This paper presents the cognitive profile observed in children with one of several common genetic syndromes associated with “nonverbal learning disorders”. It introduces the concept of a cognitive endophenotype in order to help explain the similar pattern of impairments across the syndromes. It explores the explanation of diverse impairments in higher-order visual, spatial, temporal, numerical and executive cognitive competencies deriving from origins in more basic attentional and spatial cognitive dysfunctions. The importance of a developmental approach to understanding dysfunction is stressed. PMID:17562581

Multivariate modelling of endophenotypes associated with the metabolic syndrome in Chinese twins.

PubMed

Pang, Z; Zhang, D; Li, S; Duan, H; Hjelmborg, J; Kruse, T A; Kyvik, K O; Christensen, K; Tan, Q

2010-12-01

The common genetic and environmental effects on endophenotypes related to the metabolic syndrome have been investigated using bivariate and multivariate twin models. This paper extends the pairwise analysis approach by introducing independent and common pathway models to Chinese twin data. The aim was to explore the common genetic architecture in the development of these phenotypes in the Chinese population. Three multivariate models including the full saturated Cholesky decomposition model, the common factor independent pathway model and the common factor common pathway model were fitted to 695 pairs of Chinese twins representing six phenotypes including BMI, total cholesterol, total triacylglycerol, fasting glucose, HDL and LDL. Performances of the nested models were compared with that of the full Cholesky model. Cross-phenotype correlation coefficients gave clear indication of common genetic or environmental backgrounds in the phenotypes. Decomposition of phenotypic correlation by the Cholesky model revealed that the observed phenotypic correlation among lipid phenotypes had genetic and unique environmental backgrounds. Both pathway models suggest a common genetic architecture for lipid phenotypes, which is distinct from that of the non-lipid phenotypes. The declining performance with model restriction indicates biological heterogeneity in development among some of these phenotypes. Our multivariate analyses revealed common genetic and environmental backgrounds for the studied lipid phenotypes in Chinese twins. Model performance showed that physiologically distinct endophenotypes may follow different genetic regulations.

Twin Studies and Their Implications for Molecular Genetic Studies: Endophenotypes Integrate Quantitative and Molecular Genetics in ADHD Research

ERIC Educational Resources Information Center

Wood, Alexis C.; Neale, Michael C.

2010-01-01

Objective: To describe the utility of twin studies for attention-deficit/hyperactivity disorder (ADHD) research and demonstrate their potential for the identification of alternative phenotypes suitable for genomewide association, developmental risk assessment, treatment response, and intervention targets. Method: Brief descriptions of the classic…

Polymorphisms of the oxytocin receptor gene and overeating: the intermediary role of endophenotypic risk factors

PubMed Central

Davis, C; Patte, K; Zai, C; Kennedy, J L

2017-01-01

Background/Objectives: Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. Subject/Methods: The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Results: Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. Conclusions: The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels. PMID:28530679

Polymorphisms of the oxytocin receptor gene and overeating: the intermediary role of endophenotypic risk factors.

PubMed

Davis, C; Patte, K; Zai, C; Kennedy, J L

2017-05-22

Oxytocin (OXT) is an evolutionarily ancient neuropeptide with strong links to affiliative and prosocial behaviors, and the management of stress. Increases in OXT also tend to decrease food intake, especially of sweet carbohydrates. The social correlates of low OXT levels mesh with the social deficits and stress proneness identified in interpersonal models of overeating, as well as the increased appetite for highly palatable foods typically seen in chronic overeaters. The objectives of this study were to investigate links between polymorphisms of the oxytocin receptor (OXTR) gene and overeating, and to examine OXTR links with relevant endophenotypes of overeating related to reward and stress sensitivity, and to food preferences. The sample comprised 460 adults between the ages of 25 and 50 years recruited from the community, and representing a broad range of body weights. Overeating, reward and punishment sensitivity, and food preferences, were quantified as composite variables using well-validated questionnaires. In addition, seven single-nucleotide polymorphisms (rs237878, rs237885, rs2268493, rs2268494, rs2254298, rs53576, rs2268498) of the OXTR gene were genotyped. Analyses identified a four-marker haplotype that was significantly related to food preferences. Individual genotype analyses also found that at least one of the markers was related to each of the phenotypic variables. In addition, an empirically derived structural equation model linking genetic and phenotype variables produced a good fit to the data. The results of this preliminary study have demonstrated that OXTR variation is associated with overeating, and with endophenotypic traits such as sweet and fatty food preferences, and reward and punishment sensitivity. In general, the genetic findings also favor the view that overeating may be associated with relatively low basal OXT levels.

Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation.

PubMed

Caprio, Sonia; Perry, Rachel; Kursawe, Romy

2017-05-01

As a consequence of the global rise in the prevalence of adolescent obesity, an unprecedented phenomenon of type 2 diabetes has emerged in pediatrics. At the heart of the development of type 2 diabetes lies a key metabolic derangement: insulin resistance (IR). Despite the widespread occurrence of IR affecting an unmeasurable number of youths worldwide, its pathogenesis remains elusive. IR in obese youth is a complex phenomenon that defies explanation by a single pathway. In this review we first describe recent data on the prevalence, severity, and racial/ethnic differences in pediatric obesity. We follow by elucidating the initiating events associated with the onset of IR, and describe a distinct "endophenotype" in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue, increased visceral adipose tissue, marked IR, dyslipidemia, and fatty liver. Further, we provide evidence for the cellular and molecular mechanisms associated with this peculiar endophenotype and its relations to IR in the obese adolescent. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

The nature of schizotypy among multigenerational multiplex schizophrenia families

PubMed Central

Tarbox, Sarah I.; Almasy, Laura; Gur, Raquel E.; Nimgaonkar, Vishwajit L.; Pogue-Geile, Michael F.

2012-01-01

Identification of endophenotypes (Gottesman & Gould, 2003; Gottesman & Shields, 1972) that genetically correlate with schizophrenia and are genetically homogeneous is an important strategy for detecting genes that affect schizophrenia risk. Symptoms of schizotypy may familially correlate with schizophrenia; however, there are critical limitations of the current literature concerning this association. The present study examined the genetic architecture and genetic associations between schizotypy and schizophrenia among multigenerational, multiplex schizophrenia families. Genetic schizotypy factor scales were developed that genetically correlated with schizophrenia, although some relations were unexpected in direction suggesting minimization of “psychotic-like” symptoms. These genetic schizotypy factor scales did not genetically correlate with major depressive disorder or substance dependence indicating specificity to schizophrenia. The results highlight the possibility of significant response bias in schizophrenia families, particularly among close relatives, and suggest an important consideration when acquiring self-report information. This is a topic that deserves future study as the origins of this putative bias in relatives are unclear. In addition, the results support the identification of genetic schizotypy factors as a promising technique for maximizing genetic correlation of endophenotypes with schizophrenia. PMID:22288909

Magnetic resonance imaging traits in siblings discordant for Alzheimer disease.

PubMed

Cuenco, Karen T; Green, Robert C; Zhang, J; Lunetta, Kathryn; Erlich, Porat M; Cupples, L Adrienne; Farrer, Lindsay A; DeCarli, Charles

2008-07-01

Magnetic resonance imaging (MRI) can aid clinical assessment of brain changes potentially correlated with Alzheimer disease (AD). MRI traits may improve our ability to identify genes associated with AD-outcomes. We evaluated semi-quantitative MRI measures as endophenotypes for genetic studies by assessing their association with AD in families from the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) Study. Discordant siblings from multiple ethnicities were ascertained through a single affected proband. Semi-quantitative MRI measures were obtained for each individual. The association between continuous/ordinal MRI traits and AD were analyzed using generalized estimating equations. Medical history and Apolipoprotein E (APOE)epsilon4 status were evaluated as potential confounders. Comparisons of 214 affected and 234 unaffected subjects from 229 sibships revealed that general cerebral atrophy, white matter hyperintensities (WMH), and mediotemporal atrophy differed significantly between groups (each at P < .0001) and varied by ethnicity. Age at MRI and duration of AD confounded all associations between AD and MRI traits. Among unaffected sibs, the presence of at least one APOEepsilon4 allele and MRI infarction was associated with more WMH after adjusting for age at MRI. The strong association between MRI traits and AD suggests that MRI traits may be informative endophenotypes for basic and clinical studies of AD. In particular, WMH may be a marker of vascular disease that contributes to AD pathogenesis.

Temperament and Character as Endophenotype in Adults with Autism Spectrum Disorders or Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Sizoo, Bram B.; van der Gaag, Rutger Jan; van den Brink, Wim

2015-01-01

Autism spectrum disorder and attention deficit/hyperactivity disorder overlap in several ways, raising questions about the nature of this comorbidity. Rommelse et al. published an innovative review of candidate endophenotypes for autism spectrum disorder and attention deficit/hyperactivity disorder in cognitive and brain domains. They found that…

Response Inhibition and ADHD Traits: Correlates and Heritability in a Community Sample

ERIC Educational Resources Information Center

Crosbie, J.; Arnold, P.; Paterson, A.; Swanson, J.; Dupuis, A.; Li, X.; Shan, J.; Goodale, T.; Tam, C.; Strug, L. J.; Schachar, R. J.

2013-01-01

Endophenotypes or intermediate phenotypes are of great interest in neuropsychiatric genetics because of their potential for facilitating gene discovery. We evaluated response inhibition, latency and variability measures derived from the stop task as endophenotypes of ADHD by testing whether they were related to ADHD traits in the general…

Developmental Markers of Genetic Liability to Autism in Parents: A Longitudinal, Multigenerational Study

ERIC Educational Resources Information Center

Losh, Molly; Martin, Gary E.; Lee, Michelle; Klusek, Jessica; Sideris, John; Barron, Sheila; Wassink, Thomas

2017-01-01

Genetic liability to autism spectrum disorder (ASD) can be expressed in unaffected relatives through subclinical, genetically meaningful traits, or endophenotypes. This study aimed to identify developmental endophenotypes in parents of individuals with ASD by examining parents' childhood academic development over the school-age period. A cohort of…

A Cognitive Endophenotype of Autism in Families with Multiple Incidence

ERIC Educational Resources Information Center

Nyden, Agneta; Hagberg, Bibbi; Gousse, Veronique; Rastam, Maria

2011-01-01

Twin and family studies have established that there is a strong genetic basis for autism spectrum disorders. To facilitate the identification of susceptibility genes and to study pathways from gene-brain to cognition a more refined endophenotype-based approach may be useful. The purpose of the present study was to examine the neurocognitive…

Interval Timing Deficits Assessed by Time Reproduction Dual Tasks as Cognitive Endophenotypes for Attention-Deficit/Hyperactivity Disorder

PubMed Central

Hwang-Gu, Shoou-Lian; Gau, Susan Shur-Fen

2015-01-01

The literature has suggested timing processing as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD); however, whether the subjective internal clock speed presented by verbal estimation and limited attention capacity presented by time reproduction could be endophenotypes for ADHD is still unknown. We assessed 223 youths with DSM-IV ADHD (age range: 10-17 years), 105 unaffected siblings, and 84 typically developing (TD) youths using psychiatric interviews, intelligence tests, verbal estimation and time reproduction tasks (single task and simple and difficult dual tasks) at 5-second, 12-second, and 17-second intervals. We found that youths with ADHD tended to overestimate time in verbal estimation more than their unaffected siblings and TD youths, implying that fast subjective internal clock speed might be a characteristic of ADHD, rather than an endophenotype for ADHD. Youths with ADHD and their unaffected siblings were less precise in time reproduction dual tasks than TD youths. The magnitude of estimated errors in time reproduction was greater in youths with ADHD and their unaffected siblings than in TD youths, with an increased time interval at the 17-second interval and with increased task demands on both simple and difficult dual tasks versus the single task. Increased impaired time reproduction in dual tasks with increased intervals and task demands were shown in youths with ADHD and their unaffected siblings, suggesting that time reproduction deficits explained by limited attention capacity might be a useful endophenotype of ADHD. PMID:25992899

Are Endophenotypes Based on Measures of Executive Functions Useful for Molecular Genetic Studies of ADHD?

ERIC Educational Resources Information Center

Doyle, Alysa E.; Faraone, Stephen V.; Seidman, Larry J.; Willcutt, Erik G.; Nigg, Joel T.; Waldman, Irwin D.; Pennington, Bruce F.; Peart, Joanne; Biederman, Joseph

2005-01-01

Background: Behavioral genetic studies provide strong evidence that attention-deficit/hyperactivity disorder (ADHD) has a substantial genetic component. Yet, due to the complexity of the ADHD phenotype, questions remain as to the specific genes that contribute to this condition as well as the pathways from genes to behavior. Endophenotypes, or…

Eye Movement Dysfunction in First-Degree Relatives of Patients with Schizophrenia: A Meta-Analytic Evaluation of Candidate Endophenotypes

ERIC Educational Resources Information Center

Calkins, Monica E.; Iacono, William G.; Ones, Deniz S.

2008-01-01

Several forms of eye movement dysfunction (EMD) are regarded as promising candidate endophenotypes of schizophrenia. Discrepancies in individual study results have led to inconsistent conclusions regarding particular aspects of EMD in relatives of schizophrenia patients. To quantitatively evaluate and compare the candidacy of smooth pursuit,…

Cognitive Functioning in Affected Sibling Pairs with ADHD: Familial Clustering and Dopamine Genes

ERIC Educational Resources Information Center

Loo, Sandra K.; Rich, Erika Carpenter; Ishii, Janeen; McGough, James; McCracken, James; Nelson, Stanley; Smalley, Susan L.

2008-01-01

Background: This paper examines familiality and candidate gene associations of cognitive measures as potential endophenotypes in attention-deficit/hyperactivity disorder (ADHD). Methods: The sample consists of 540 participants, aged 6 to 18, who were diagnosed with ADHD from 251 families recruited for a larger genetic study of ADHD. All members of…

Familial Clustering and DRD4 Effects on Electroencephalogram Measures in Multiplex Families with Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Loo, Sandra K.; Hale, T. Sigi; Hanada, Grant; Macion, James; Shrestha, Anshu; McGough, James J.; McCracken, James T.; Nelson, Stanley; Smalley, Susan L.

2010-01-01

Objective: The current study tests electroencephalogram (EEG) measures as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD) by examining sibling and parent-offspring similarity, familial clustering with the disorder, and association with the dopamine receptor D4 (DRD4) candidate gene. Method: The sample consists of 531…

GABAB-mediated rescue of altered excitatory-inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction.

PubMed

Gandal, M J; Sisti, J; Klook, K; Ortinski, P I; Leitman, V; Liang, Y; Thieu, T; Anderson, R; Pierce, R C; Jonak, G; Gur, R E; Carlson, G; Siegel, S J

2012-07-17

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30-80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory-inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1(neo-/-) mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABA(B)-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

Trait-level temporal lobe hypoactivation to social exclusion in unaffected siblings of children and adolescents with autism spectrum disorders

PubMed Central

Bolling, Danielle Z.; Pelphrey, Kevin A.; Vander Wyk, Brent C.

2015-01-01

Social exclusion elicits powerful feelings of negative affect associated with rejection. Additionally, experiencing social exclusion reliably recruits neural circuitry associated with emotion processing. Recent work has demonstrated abnormal neural responses to social exclusion in children and adolescents with autism spectrum disorders (ASD). However, it remains unknown to what extent these abnormalities are due to atypical social experiences versus genetic predispositions to atypical neural processing. To address this question, the current study investigated brain responses to social exclusion compared to a baseline condition of fair play in unaffected siblings of youth with ASD using functional magnetic resonance imaging. We identified common deviations between unaffected siblings and ASD probands that might represent trait-level abnormalities in processing social exclusion versus fair play, specifically in the right anterior temporoparietal junction extending into posterior superior temporal sulcus. Thus, hypoactivation to social exclusion versus fair play in this region may represent a shared genetic vulnerability to developing autism. In addition, we present evidence supporting the idea that one’s status as an unaffected sibling moderates the relationship between IQ and neural activation to social exclusion versus fair play in anterior cingulate cortex. These results are discussed in the context of previous literature on neural endophenotypes of autism. PMID:26011751

Temperament and character as endophenotype in adults with autism spectrum disorders or attention deficit/hyperactivity disorder.

PubMed

Sizoo, Bram B; van der Gaag, Rutger Jan; van den Brink, Wim

2015-05-01

Autism spectrum disorder and attention deficit/hyperactivity disorder overlap in several ways, raising questions about the nature of this comorbidity. Rommelse et al. published an innovative review of candidate endophenotypes for autism spectrum disorder and attention deficit/hyperactivity disorder in cognitive and brain domains. They found that all the endophenotypic impairments that were reviewed in attention deficit/hyperactivity disorder were also present in autism spectrum disorder, suggesting a continuity model with attention deficit/hyperactivity disorder as "a light form of autism spectrum disorder." Using existing data, 75 adults with autism spectrum disorder and 53 with attention deficit/hyperactivity disorder were directly compared on autistic symptoms with the autism spectrum quotient, and on the endophenotypic measure of temperament and character, using the Abbreviated (Dutch: Verkorte) Temperament and Character Inventory. Based on the hypothesis that attention deficit/hyperactivity disorder and autism spectrum disorder are disorders on a continuous spectrum, autism spectrum quotient scores and abbreviated Temperament and Character Inventory scores were expected to be different from normal controls in both disorders in a similar direction. In addition, the autism spectrum quotient and abbreviated Temperament and Character Inventory scores were expected to be closely correlated. These conditions applied to only two of the seven Abbreviated Temperament and Character Inventory scales (harm avoidance and self-directedness), suggesting that temperament and character as an endophenotype of autism spectrum disorder and attention deficit/hyperactivity disorder provides only partial support for the continuity hypothesis of autism spectrum disorder and attention deficit/hyperactivity disorder. © The Author(s) 2014.

Electrophysiological Endophenotypes and the Error-Related Negativity (ERN) in Autism Spectrum Disorder: A Family Study

ERIC Educational Resources Information Center

Clawson, Ann; South, Mikle; Baldwin, Scott A.; Larson, Michael J.

2017-01-01

We examined the error-related negativity (ERN) as an endophenotype of ASD by comparing the ERN in families of ASD probands to control families. We hypothesized that ASD probands and families would display reduced-amplitude ERN relative to controls. Participants included 148 individuals within 39 families consisting of a mother, father, sibling,…

ω-3 Long-Chain Polyunsaturated Fatty Acids and Fatty Acid Desaturase Activity Ratios as Eventual Endophenotypes for ADHD.

PubMed

Henríquez-Henríquez, Marcela; Solari, Sandra; Várgas, Gisela; Vásquez, Luis; Allende, Fidel; Castañón S, Carla; Tenorio, Marcela; Quiroga Gutiérrez, Teresa

2015-11-01

Epidemiological studies suggest that long-chain polyunsaturated fatty acids (LC-PUFAs) may be suitable as endophenotypes for ADHD. To be appropriated vulnerability traits, endophenotypes should be altered in unaffected relatives of index cases. Serum profiles of LC-PUFAs in unaffected relatives of ADHD patients remain understudied. The main objective of this study was to compare serum LC-PUFAs in ADHD patients, unaffected relatives of index cases, and general-population unaffected participants. LC-PUFA profiles of 72 participants (27 ADHD patients, 27 unaffected relatives, and 18 general-population participants) were obtained by gas chromatography-mass spectrometry (GC-MS). Groups were compared by parametrical statistics. Unaffected females from the general population presented lower Docosapentaenoic acid (DPA; p = .0012) and a-linolenic acid (ALA; p = .0091) levels compared with ADHD females and unaffected relatives. In addition, docosahexaenoic acid (DHA)/ALA and DHA/DPA ratios, addressing desaturase activity, were significantly lower in ADHD patients and unaffected relatives of ADHD patients in the female-subgroup (p = .022 and .04, respectively). DHA/ALA, DHA/DPA, serum DPA, and serum ALA may be suitable as endophenotypes for ADHD women. © The Author(s) 2012.

Eye movement dysfunction in first-degree relatives of patients with schizophrenia: a meta-analytic evaluation of candidate endophenotypes.

PubMed

Calkins, Monica E; Iacono, William G; Ones, Deniz S

2008-12-01

Several forms of eye movement dysfunction (EMD) are regarded as promising candidate endophenotypes of schizophrenia. Discrepancies in individual study results have led to inconsistent conclusions regarding particular aspects of EMD in relatives of schizophrenia patients. To quantitatively evaluate and compare the candidacy of smooth pursuit, saccade and fixation deficits in first-degree biological relatives, we conducted a set of meta-analytic investigations. Among 18 measures of EMD, memory-guided saccade accuracy and error rate, global smooth pursuit dysfunction, intrusive saccades during fixation, antisaccade error rate and smooth pursuit closed-loop gain emerged as best differentiating relatives from controls (standardized mean differences ranged from .46 to .66), with no significant differences among these measures. Anticipatory saccades, but no other smooth pursuit component measures were also increased in relatives. Visually-guided reflexive saccades were largely normal. Moderator analyses examining design characteristics revealed few variables affecting the magnitude of the meta-analytically observed effects. Moderate effect sizes of relatives v. controls in selective aspects of EMD supports their endophenotype potential. Future work should focus on facilitating endophenotype utility through attention to heterogeneity of EMD performance, relationships among forms of EMD, and application in molecular genetics studies.

Exome Sequence Analysis of 14 Families With High Myopia.

PubMed

Kloss, Bethany A; Tompson, Stuart W; Whisenhunt, Kristina N; Quow, Krystina L; Huang, Samuel J; Pavelec, Derek M; Rosenberg, Thomas; Young, Terri L

2017-04-01

To identify causal gene mutations in 14 families with autosomal dominant (AD) high myopia using exome sequencing. Select individuals from 14 large Caucasian families with high myopia were exome sequenced. Gene variants were filtered to identify potential pathogenic changes. Sanger sequencing was used to confirm variants in original DNA, and to test for disease cosegregation in additional family members. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were comprehensively screened. In 14 high myopia families, we identified 73 rare and 31 novel gene variants as candidates for pathogenicity. In seven of these families, two of the novel and eight of the rare variants were within known myopia loci. A total of 104 heterozygous nonsynonymous rare variants in 104 genes were identified in 10 out of 14 probands. Each variant cosegregated with affection status. No rare variants were identified in genes known to cause myopia or in genes closest to published genome-wide association study association signals for refractive error or its endophenotypes. Whole exome sequencing was performed to determine gene variants implicated in the pathogenesis of AD high myopia. This study provides new genes for consideration in the pathogenesis of high myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.

Clinical, morphological, and biochemical correlates of head circumference in autism.

PubMed

Sacco, Roberto; Militerni, Roberto; Frolli, Alessandro; Bravaccio, Carmela; Gritti, Antonella; Elia, Maurizio; Curatolo, Paolo; Manzi, Barbara; Trillo, Simona; Lenti, Carlo; Saccani, Monica; Schneider, Cindy; Melmed, Raun; Reichelt, Karl-Ludvig; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Persico, Antonio M

2007-11-01

Head growth rates are often accelerated in autism. This study is aimed at defining the clinical, morphological, and biochemical correlates of head circumference in autistic patients. Fronto-occipital head circumference was measured in 241 nonsyndromic autistic patients, 3 to 16 years old, diagnosed according to DSM-IV criteria. We assessed 1) clinical parameters using the Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, Vineland Adaptive Behavioral Scales, intelligence quotient measures, and an ad hoc clinical history questionnaire; 2) height and weight; 3) serotonin (5-HT) blood levels and peptiduria. The distribution of cranial circumference is significantly skewed toward larger head sizes (p < .00001). Macrocephaly (i.e., head circumference >97th percentile) is generally part of a broader macrosomic endophenotype, characterized by highly significant correlations between head circumference, weight, and height (p < .001). A head circumference >75th percentile is associated with more impaired adaptive behaviors and with less impairment in IQ measures and motor and verbal language development. Surprisingly, larger head sizes are significantly associated with a positive history of allergic/immune disorders both in the patient and in his/her first-degree relatives. Our study demonstrates the existence of a macrosomic endophenotype in autism and points toward pathogenetic links with immune dysfunctions that we speculate either lead to or are associated with increased cell cycle progression and/or decreased apoptosis.

Recurrent major depression and right hippocampal volume: A bivariate linkage and association study.

PubMed

Mathias, Samuel R; Knowles, Emma E M; Kent, Jack W; McKay, D Reese; Curran, Joanne E; de Almeida, Marcio A A; Dyer, Thomas D; Göring, Harald H H; Olvera, Rene L; Duggirala, Ravi; Fox, Peter T; Almasy, Laura; Blangero, John; Glahn, David C

2016-01-01

Previous work has shown that the hippocampus is smaller in the brains of individuals suffering from major depressive disorder (MDD) than those of healthy controls. Moreover, right hippocampal volume specifically has been found to predict the probability of subsequent depressive episodes. This study explored the utility of right hippocampal volume as an endophenotype of recurrent MDD (rMDD). We observed a significant genetic correlation between the two traits in a large sample of Mexican American individuals from extended pedigrees (ρg = -0.34, p = 0.013). A bivariate linkage scan revealed a significant pleiotropic quantitative trait locus on chromosome 18p11.31-32 (LOD = 3.61). Bivariate association analysis conducted under the linkage peak revealed a variant (rs574972) within an intron of the gene SMCHD1 meeting the corrected significance level (χ(2) = 19.0, p = 7.4 × 10(-5)). Univariate association analyses of each phenotype separately revealed that the same variant was significant for right hippocampal volume alone, and also revealed a suggestively significant variant (rs12455524) within the gene DLGAP1 for rMDD alone. The results implicate right-hemisphere hippocampal volume as a possible endophenotype of rMDD, and in so doing highlight a potential gene of interest for rMDD risk. © 2015 Wiley Periodicals, Inc.

Knowledge-driven binning approach for rare variant association analysis: application to neuroimaging biomarkers in Alzheimer's disease.

PubMed

Kim, Dokyoon; Basile, Anna O; Bang, Lisa; Horgusluoglu, Emrin; Lee, Seunggeun; Ritchie, Marylyn D; Saykin, Andrew J; Nho, Kwangsik

2017-05-18

Rapid advancement of next generation sequencing technologies such as whole genome sequencing (WGS) has facilitated the search for genetic factors that influence disease risk in the field of human genetics. To identify rare variants associated with human diseases or traits, an efficient genome-wide binning approach is needed. In this study we developed a novel biological knowledge-based binning approach for rare-variant association analysis and then applied the approach to structural neuroimaging endophenotypes related to late-onset Alzheimer's disease (LOAD). For rare-variant analysis, we used the knowledge-driven binning approach implemented in Bin-KAT, an automated tool, that provides 1) binning/collapsing methods for multi-level variant aggregation with a flexible, biologically informed binning strategy and 2) an option of performing unified collapsing and statistical rare variant analyses in one tool. A total of 750 non-Hispanic Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort who had both WGS data and magnetic resonance imaging (MRI) scans were used in this study. Mean bilateral cortical thickness of the entorhinal cortex extracted from MRI scans was used as an AD-related neuroimaging endophenotype. SKAT was used for a genome-wide gene- and region-based association analysis of rare variants (MAF (minor allele frequency) < 0.05) and potential confounding factors (age, gender, years of education, intracranial volume (ICV) and MRI field strength) for entorhinal cortex thickness were used as covariates. Significant associations were determined using FDR adjustment for multiple comparisons. Our knowledge-driven binning approach identified 16 functional exonic rare variants in FANCC significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In addition, the approach identified 7 evolutionary conserved regions, which were mapped to FAF1, RFX7, LYPLAL1 and GOLGA3, significantly associated with entorhinal cortex thickness (FDR-corrected p-value < 0.05). In further analysis, the functional exonic rare variants in FANCC were also significantly associated with hippocampal volume and cerebrospinal fluid (CSF) Aβ 1-42 (p-value < 0.05). Our novel binning approach identified rare variants in FANCC as well as 7 evolutionary conserved regions significantly associated with a LOAD-related neuroimaging endophenotype. FANCC (fanconi anemia complementation group C) has been shown to modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Our results warrant further investigation in a larger independent cohort and demonstrate that the biological knowledge-driven binning approach is a powerful strategy to identify rare variants associated with AD and other complex disease.

Preference on cash-choice task predicts externalizing outcomes in 17-year-olds.

PubMed

Sparks, Jordan C; Isen, Joshua D; Iacono, William G

2014-03-01

Delay-discounting, the tendency to prefer a smaller-sooner reward to a larger-later reward, has been associated with a range of externalizing behaviors. Laboratory delay-discounting tasks have emerged as a useful measure to index impulsivity and a proclivity towards externalizing pyschopathology. While many studies demonstrate the existence of a latent externalizing factor that is heritable, there have been few genetic studies of delay-discounting. Further, the increased vulnerability for risky behavior in adolescence makes adolescent samples an attractive target for future research, and expeditious, ecologically-valid delay-discounting measures are helpful in this regard. The primary goal of this study was to help validate the utility of a "cash-choice" measure for use in a sample of older adolescents. We used a sample of 17-year-old twins (n = 791) from the Minnesota Twin Family Enrichment study. Individuals who chose the smaller-sooner reward were more likely to have used a range of addictive substances, engaged in sexual intercourse, and earned lower GPAs. Best fitting biometric models from univariate analyses supported the heritability of cash-choice and externalizing, but bivariate modeling results indicated that the correlation between cash-choice and externalizing was determined largely by shared environmental influences, thus failing to support cash-choice as a possible endophenotype for externalizing in this age group. Our findings lend further support to the utility of cash-choice as a measure of individual differences in decision making and suggest that, by late adolescence, this task indexes shared environmental risk for externalizing behavior.

Neurobiology of suicidal behaviour.

PubMed

Pjevac, Milica; Pregelj, Peter

2012-10-01

It is known that suicidal behaviour has multiple causes. If triggers could be mainly attributed to environmental factors, predisposition could be associated with early stressors on one side such as childhood adversities and genetic predisposition. No convincing animal model of suicide has been produced to date. The study of endophenotypes has been proposed as a good strategy to overcome the methodological difficulties. However, research in suicidal behaviours using endophenotypes entrails important methodological problems. Further, serotoninergic system was studied in patients with suicidal behaviour primary due to its involvement of serotonin in impulsive-aggressive behaviour, which has been shown to be a major risk factor in suicidal behaviour. Not only on the level of neurotransmitters but also the regulation of neurotropic factors could be impaired in suicide victims. Multiple lines of evidence including studies of levels of BDNF in blood cells and plasma of suicidal patients, postmortem brain studies in suicidal subjects with or without depression, and genetic association studies linking BDNF to suicide suggest that suicidal behaviour may be associated with a decrease in BDNF functioning. It seems that especially specific gene variants regulating the serotoninergic system and other neuronal systems involved in stress response are associated with suicidal behaviour. Most genetic studies on suicidal behaviour have considered a small set of functional polymorphisms relevant mostly to monoaminergic neurotransmission. However, genes and epigenetic mechanisms involved in regulation of other factors such as BDNF seem to be even more relevant for further research.

The Role of Double Dissociation Studies in the Search for Candidate Endophenotypes for the Comorbidity of Attention Deficit Hyperactivity Disorder and Reading Disability

ERIC Educational Resources Information Center

de Jong, Christien G. W.; Oosterlaan, Jaap; Sergeant, Joseph A.

2006-01-01

The neuropsychological underpinnings of Attention Deficit Hyperactivity Disorder (ADHD) and Reading Disability (RD) and their comorbidity may be studied usefully with the double dissociation design. The results of studies using the double dissociation method may be linked to the search for an endophenotype of ADHD and RD and their comorbidity.…

Endophenotypes of Dementia Associated with Traumatic Brain Injury in Retired Military Personnel

DTIC Science & Technology

2013-10-01

20 o No history of TBI or concussion (defined as no head injury resulting in being dazed, having a memory gap, loss of consciousness, or medical...yes, were you ever knocked out or have a TKO? ☐ Yes ☐ No 18. Have you ever played football ? ☐ Yes ☐ No If yes, for how many years? ____________ 13

A Genome-Wide Association Study of Autism Incorporating Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and Social Responsiveness Scale

ERIC Educational Resources Information Center

Connolly, John J.; Glessner, Joseph T.; Hakonarson, Hakon

2013-01-01

Efforts to understand the causes of autism spectrum disorders (ASDs) have been hampered by genetic complexity and heterogeneity among individuals. One strategy for reducing complexity is to target endophenotypes, simpler biologically based measures that may involve fewer genes and constitute a more homogenous sample. A genome-wide association…

Social and emotional processing as a behavioural endophenotype in eating disorders: a pilot investigation in twins.

PubMed

Kanakam, Natalie; Krug, Isabel; Raoult, Charlotte; Collier, David; Treasure, Janet

2013-07-01

Emotional processing difficulties are potential risk markers for eating disorders that are also present after recovery. The aim of this study was to examine these traits in twins with eating disorders. The Reading the Mind in the Eyes test, Emotional Stroop task and the Difficulties in Emotion Regulation Scale were administered to 112 twins with and without eating disorders (DSM IV-TR eating disorder criteria). Generalised estimating equations compared twins with eating disorders against unaffected co-twins and control twins, and within-pair correlations were calculated for clinical monozygotic (n = 50) and dizygotic twins (n = 20). Emotion recognition difficulties, attentional biases to social threat and difficulties in emotion regulation were greater in twins with eating disorders, and some were present in their unaffected twin siblings. Evidence for a possible genetic basis was highest for emotion recognition and attentional biases to social stimuli. Emotion recognition difficulties and sensitivity to social threat appear to be endophenotypes associated with eating disorders. However, the limited statistical power means that these findings are tentative and require further replication. Copyright © 2013 John Wiley & Sons, Ltd and Eating Disorders Association.

Navigating the complex path between the oxytocin receptor gene (OXTR) and cooperation: an endophenotype approach.

PubMed

Haas, Brian W; Anderson, Ian W; Smith, Jessica M

2013-11-28

Although cooperation represents a core facet of human social behavior there exists considerable variability across people in terms of the tendency to cooperate. One factor that may contribute to individual differences in cooperation is a key gene within the oxytocin (OT) system, the OT reception gene (OXTR). In this article, we aim to bridge the gap between the OXTR gene and cooperation by using an endophenotype approach. We present evidence that the association between the OXTR gene and cooperation may in part be due to how the OXTR gene affects brain systems involved in emotion recognition, empathy/theory of mind, social communication and social reward seeking. There is evidence that the OXTR gene is associated with the functional anatomy of the amygdala, visual cortex (VC), anterior cingulate and superior temporal gyrus (STG). However, it is currently unknown how the OXTR gene may be linked to the functional anatomy of other relevant brain regions that include the fusiform gyrus (FG), superior temporal sulcus (STS), ventromedial prefrontal cortex (VMPFC), temporoparietal junction (TPJ) and nucleus accumbens (NAcc). We conclude by highlighting potential future research directions that may elucidate the path between OXTR and complex behaviors such as cooperation.

Navigating the complex path between the oxytocin receptor gene (OXTR) and cooperation: an endophenotype approach

PubMed Central

Haas, Brian W.; Anderson, Ian W.; Smith, Jessica M.

2013-01-01

Although cooperation represents a core facet of human social behavior there exists considerable variability across people in terms of the tendency to cooperate. One factor that may contribute to individual differences in cooperation is a key gene within the oxytocin (OT) system, the OT reception gene (OXTR). In this article, we aim to bridge the gap between the OXTR gene and cooperation by using an endophenotype approach. We present evidence that the association between the OXTR gene and cooperation may in part be due to how the OXTR gene affects brain systems involved in emotion recognition, empathy/theory of mind, social communication and social reward seeking. There is evidence that the OXTR gene is associated with the functional anatomy of the amygdala, visual cortex (VC), anterior cingulate and superior temporal gyrus (STG). However, it is currently unknown how the OXTR gene may be linked to the functional anatomy of other relevant brain regions that include the fusiform gyrus (FG), superior temporal sulcus (STS), ventromedial prefrontal cortex (VMPFC), temporoparietal junction (TPJ) and nucleus accumbens (NAcc). We conclude by highlighting potential future research directions that may elucidate the path between OXTR and complex behaviors such as cooperation. PMID:24348360

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms.

PubMed

Woodcock, K A; Oliver, C; Humphreys, G W

2009-06-01

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes. Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics. The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage. We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Delta-beta correlation as a candidate endophenotype of social anxiety: A two-generation family study.

PubMed

Harrewijn, Anita; van der Molen, Melle J W; van Vliet, Irene M; Houwing-Duistermaat, Jeanine J; Westenberg, P Michiel

2018-02-01

Social anxiety disorder (SAD) is characterized by an extreme and intense fear and avoidance of social situations. In this two-generation family study we examined delta-beta correlation during a social performance task as candidate endophenotype of SAD. Nine families with a target participant (diagnosed with SAD), their spouse and children, as well as target's siblings with spouse and children performed a social performance task in which they gave a speech in front of a camera. EEG was measured during resting state, anticipation, and recovery. Our analyses focused on two criteria for endophenotypes: co-segregation within families and heritability. Co-segregation analyses revealed increased negative delta-low beta correlation during anticipation in participants with (sub)clinical SAD compared to participants without (sub)clinical SAD. Heritability analyses revealed that delta-low beta and delta-high beta correlation during anticipation were heritable. Delta-beta correlation did not differ between participants with and without (sub)clinical SAD during resting state or recovery, nor between participants with and without SAD during all phases of the task. It should be noted that participants were seen only once, they all performed the EEG tasks in the same order, and some participants were too anxious to give a speech. Delta-low beta correlation during anticipation of giving a speech might be a candidate endophenotype of SAD, possibly reflecting increased crosstalk between cortical and subcortical regions. If validated as endophenotype, delta-beta correlation during anticipation could be useful in studying the genetic basis, as well as improving treatment and early detection of persons at risk for developing SAD. Copyright © 2017 Elsevier B.V. All rights reserved.

Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase α to schizophrenia

PubMed Central

Takahashi, Nagahide; Nielsen, Karin Sandager; Aleksic, Branko; Petersen, Steffen; Ikeda, Masashi; Kushima, Itaru; Vacaresse, Nathalie; Ujike, Hiroshi; Iwata, Nakao; Dubreuil, Véronique; Mirza, Naheed; Sakurai, Takeshi; Ozaki, Norio; Buxbaum, Joseph D.; Sap, Jan

2011-01-01

Background Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness. Methods We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (2 independent cohorts; total of 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases) Results We find that Ptpra−/− mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to metamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in post mortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in post mortem dorsolateral prefrontal cortex of subjects with SZ. Conclusion The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease. PMID:21831360

ASSOCIATION BETWEEN GAB2 HAPLOTYPE AND HIGHER GLUCOSE METABOLISM IN ALZHEIMER'S DISEASE-AFFECTED BRAIN REGIONS IN COGNITIVELY NORMAL APOEε4 CARRIERS

PubMed Central

Liang, Winnie S.; Chen, Kewei; Lee, Wendy; Sidhar, Kunal; Corneveaux, Jason J.; Allen, April N.; Myers, Amanda; Villa, Stephen; Meechoovet, Bessie; Pruzin, Jeremy; Bandy, Daniel; Fleisher, Adam S.; Langbaum, Jessica B.S.; Huentelman, Matthew J.; Jensen, Kendall; Dunckley, Travis; Caselli, Richard J.; Kaib, Susan; Reiman, Eric M.

2010-01-01

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920

Executive functions as endophenotypes in ADHD: evidence from the Cambridge Neuropsychological Test Battery (CANTAB).

PubMed

Gau, Susan Shur-Fen; Shang, Chi-Yung

2010-07-01

Little is known about executive functions among unaffected siblings of children with attention deficit/hyperactivity disorder (ADHD), and there is lack of such information from non-Western countries. We examined verbal and nonverbal executive functions in adolescents with ADHD, unaffected siblings and controls to test whether executive functions could be potential endophenotypes for ADHD. We assessed 279 adolescents (age range: 11-17 years) with a childhood diagnosis of DSM-IV ADHD, 136 biological siblings (108 unaffected, 79.4%), and 173 unaffected controls by using psychiatric interviews, the Wechsler Intelligence Scale for Children - 3rd edition (WISC-III), including digit spans, and the tasks involving executive functions of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Intra-dimensional/Extra-dimensional Shifts (IED), Spatial Span (SSP), Spatial Working Memory (SWM), and Stockings of Cambridge (SOC). Compared with the controls, adolescents with ADHD and unaffected siblings had a significantly shorter backward digit span, more extra-dimensional shift errors in the IED, shorter spatial span length in the SSP, more total errors and poorer strategy use in the SWM, and fewer problems solved in the minimum number of moves and shorter initial thinking time in the SOC. The magnitudes of the differences in the SWM and SOC increased with increased task difficulties. In general, neither persistent ADHD nor comorbidity was associated with increased deficits in executive functions among adolescents with ADHD. The lack of much difference in executive dysfunctions between unaffected siblings and ADHD adolescents suggests that executive dysfunctions may be useful cognitive endophenotypes for ADHD genetic studies.

Moderators of neuropsychological mechanism in attention-deficit hyperactivity disorder.

PubMed

Nikolas, Molly A; Nigg, Joel T

2015-02-01

Neuropsychological measures have been proposed as both a way to tap mechanisms and as endophenotypes for child ADHD. However, substantial evidence supporting heterogeneity in neuropsychological performance among youth with ADHD as well as apparent effect differences by sex, age, and comorbidity have slowed progress. To address this, it is important to understand sibling effects in relation to these moderators. 461 youth ages 6-17 years (54.8 % male, including 251 youth with ADHD, 107 of their unaffected biological siblings, and 103 non-ADHD controls) completed diagnostic interviews and a theoretically informed battery of neuropsychological functioning. A structural equation model was used to consolidate neuropsychological domains. Group differences between unaffected siblings of youth with ADHD and controls across each domain were first examined as the primary endophenotype test for ADHD. Moderation of these effects was evaluated via investigation of interactions between diagnostic group and both proband and individual level characteristics, including sex, age, and comorbidity status. Unaffected siblings performed worse than control youth in the domains of inhibition, response time variability, and temporal information processing. Individual age moderated these effects, such that differences between controls and unaffected siblings were pronounced among younger children (ages 6-10 years) but absent among older youth (ages 11-17 years). Evidence for moderation of effects by proband sex and comorbidity status produced more variable and smaller effects. Results support the utility of inhibition, response time variability, and temporal processing as useful endophenotypes for ADHD in future genetic associations studies of the disorder, but suggest this value will vary by age among unaffected family members.

[Attention deficit hyperactivity disorder: its aetiological factors and endophenotypes].

PubMed

Ferrando-Lucas, M T

2006-02-13

Attention deficit hyperactivity disorder (ADHD) is one of the most frequent reasons for patients' visits in everyday practice. The academic and social distortion it produces in those affected by this condition have turned it into a subject that is receiving growing attention from researchers and the progress being made in the neurosciences means that it is being investigated from a wide range of approaches. Genetic aspects, as well as anatomical and neurobiological markers, are some of the new lines of research that are being used together with a more precise neuropsychological approach to obtain a more comprehensive understanding of ADHD. Such knowledge now involves genetic factors, centres of cognitive disorder and the search for endophenotypes that account for the complexity of its semiology. The primary cognitive deficits in ADHD appear to be the underlying problem in the disorder, special attention also being given to both the executive functions and the distortion of the capacity to inhibit responses. Furthermore, anatomical factors have been related to the type and severity of the symptomatology of the disorder, although the dispersion of the results and the genetic findings that focus their attention on anomalous alleles for dopamine transporting and receptor genes suggest that the disorder is more complex. The different aetiological factors that have been associated to the disorder and the variability in the semiology of ADHD place us before a situation in disarray; the determination of endophenotypes, however, could enable us carry out a better systematisation of a disorder that is currently still a long way from being fully understood.

Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

ERIC Educational Resources Information Center

Gornick, M. C.; Addington, A. M.; Sporn, A.; Gogtay, N.; Greenstein, D.; Lenane, M.; Gochman, P.; Ordonez, A.; Balkissoon, R.; Vakkalanka, R.; Weinberger, D. R.; Rapoport, J. L.; Straub, R. E.

2005-01-01

Straub "et al." ("2002") recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid…

Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism

PubMed Central

2013-01-01

Background Autism spectrum conditions (ASC) are associated with deficits in social interaction and communication, alongside repetitive, restricted, and stereotyped behavior. ASC is highly heritable. The gamma-aminobutyric acid (GABA)-ergic system has been associated consistently with atypicalities in autism, in both genetic association and expression studies. A key component of the GABA-ergic system is encoded by the GABRB3 gene, which has been previously implicated both in ASC and in individual differences in empathy. Methods In this study, 45 genotyped single nucleotide polymorphisms (SNPs) within GABRB3 were tested for association with Asperger syndrome (AS), and related quantitative traits measured through the following tests: the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ), the Systemizing Quotient-Revised (SQ-R), the Embedded Figures Test (EFT), the Reading the Mind in the Eyes Test (RMET), and the Mental Rotation Test (MRT). Two-loci, three-loci, four-loci haplotype analyses, and one seven-loci haplotype analysis were also performed in the AS case–control sample. Results Three SNPs (rs7180158, rs7165604, rs12593579) were significantly associated with AS, and two SNPs (rs9806546, rs11636966) were significantly associated with EQ. Two SNP-SNP pairs, rs12438141-rs1035751 and rs12438141-rs7179514, showed significant association with variation in the EFT scores. One SNP-SNP pair, rs7174437-rs1863455, was significantly associated with variation in the MRT scores. Additionally, a few haplotypes, including a 19 kb genomic region that formed a linkage disequilibrium (LD) block in our sample and contained several nominally significant SNPs, were found to be significantly associated with AS. Conclusion The current study confirms the role of GABRB3 as an important candidate gene in both ASC and normative variation in related endophenotypes. PMID:24321478

Minor Allele Frequency Changes the Nature of Genotype by Environment Interactions.

PubMed

Verhulst, Brad; Neale, Michael C

2016-09-01

In the classical twin study, phenotypic variation is often partitioned into additive genetic (A), common (C) and specific environment (E) components. From genetical theory, the outcome of genotype by environment interaction is expected to inflate A when the interacting factor is shared (i.e., C) between the members of a twin pair. We show that estimates of both A and C can be inflated. When the shared interacting factor changes the size of the difference between homozygotes' means, the expected sibling or DZ twin correlation is .5 if and only if the minor allele frequency (MAF) is .5; otherwise the expected DZ correlation is greater than this value, consistent (and confounded) with some additional effect of C. This result is considered in the light of the distribution of minor allele frequencies for polygenic traits. Also discussed is whether such interactions take place at the locus level or affect an aggregated biological structure or system. Interactions with structures or endophenotypes that result from the aggregated effects of many loci will generally emerge as part of the A estimate.

Developmental Markers of Genetic Liability to Autism in Parents: A Longitudinal, Multigenerational Study.

PubMed

Losh, Molly; Martin, Gary E; Lee, Michelle; Klusek, Jessica; Sideris, John; Barron, Sheila; Wassink, Thomas

2017-03-01

Genetic liability to autism spectrum disorder (ASD) can be expressed in unaffected relatives through subclinical, genetically meaningful traits, or endophenotypes. This study aimed to identify developmental endophenotypes in parents of individuals with ASD by examining parents' childhood academic development over the school-age period. A cohort of 139 parents of individuals with ASD were studied, along with their children with ASD and 28 controls. Parents' childhood records in the domains of language, reading, and math were studied from grades K-12. Results indicated that relatively lower performance and slower development of skills (particularly language related skills), and an uneven rate of development across domains predicted ASD endophenotypes in adulthood for parents, and the severity of clinical symptoms in children with ASD. These findings may mark childhood indicators of genetic liability to ASD in parents, that could inform understanding of the subclinical expression of ASD genetic liability.

Evidence of an association between 10/10 genotype of DAT1 and endophenotypes of attention deficit/hyperactivity disorder.

PubMed

Agudelo, J A; Gálvez, J M; Fonseca, D J; Mateus, H E; Talero-Gutiérrez, C; Velez-Van-Meerbeke, A

2015-04-01

Genetic variance of attention deficit-hyperactivity disorder (ADHD) is a strong determinant of this disorder. The 40 base pairs (bp) variable number tandem repeat (VNTR) located in the 3' untranslated region (UTR) of DAT1 gene increases the expression of the dopamine transporter. Therefore, DAT1 has been associated with susceptibility to ADHD. To determine the association between the VNTR of DAT1 and the phenotype of ADHD or its endophenotypes in a sample of children aged between 6 and 15 years from Bogotá. We selected 73 patients with ADHD and 54 controls. WISC test was applied in all subjects and executive functions were assessed. The VNTR of DAT1 was polymerase chain reaction-amplified. Data regarding population genetics and statistical analysis were obtained. Correlation and association tests between genotype and neuropsychological testing were performed. The DAT1 polymorphism was not associated with ADHD (P=.85). Nevertheless, the 10/10 genotype was found to be correlated with the processing speed index (P<.05). In the hyperactivity subtype, there was a genotypic correlation with some subtests of executive function (cognitive flexibility) (P≤.01). In the combined subtype, the 10/10 genotype was associated with verbal comprehension index of WISC (P<.05). A correlation was found between DAT1 VNTR and the subtest "processing speed index" of WISC and the subtest "cognitive flexibility" of executive functions. To our knowledge, this is the first report to assess DAT1 gene in a Colombian population. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Autism Spectrum and Obsessive–Compulsive Disorders: OC Behaviors, Phenotypes and Genetics

PubMed Central

Jacob, Suma; Landeros-Weisenberger, Angeli; Leckman, James F.

2014-01-01

Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive–compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive–compulsive disorder (OCD). The OCB seen in ASD vary depending on the individual’s mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family-genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions. PMID:20029829

Trait-level temporal lobe hypoactivation to social exclusion in unaffected siblings of children and adolescents with autism spectrum disorders.

PubMed

Bolling, Danielle Z; Pelphrey, Kevin A; Vander Wyk, Brent C

2015-06-01

Social exclusion elicits powerful feelings of negative affect associated with rejection. Additionally, experiencing social exclusion reliably recruits neural circuitry associated with emotion processing. Recent work has demonstrated abnormal neural responses to social exclusion in children and adolescents with autism spectrum disorders (ASD). However, it remains unknown to what extent these abnormalities are due to atypical social experiences versus genetic predispositions to atypical neural processing. To address this question, the current study investigated brain responses to social exclusion compared to a baseline condition of fair play in unaffected siblings of youth with ASD using functional magnetic resonance imaging. We identified common deviations between unaffected siblings and ASD probands that might represent trait-level abnormalities in processing Social Exclusion vs. Fair Play, specifically in the right anterior temporoparietal junction extending into posterior superior temporal sulcus. Thus, hypoactivation to Social Exclusion vs. Fair Play in this region may represent a shared genetic vulnerability to developing autism. In addition, we present evidence supporting the idea that one's status as an unaffected sibling moderates the relationship between IQ and neural activation to Social Exclusion vs. Fair Play in anterior cingulate cortex. These results are discussed in the context of previous literature on neural endophenotypes of autism. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Atypical patterns of respiratory sinus arrhythmia index an endophenotype for depression

PubMed Central

Yaroslavsky, Ilya; Rottenberg, Jonathan; Kovacs, Maria

2015-01-01

Can atypical patterns of parasympathetic nervous system activity serve as endophenotypes for depression? Using respiratory sinus arrhythmia (RSA) as an index of parasympathetic nervous system function, we examined this question in two studies: one involving mothers with and without depression histories and their offspring (at high and low risk for depression, respectively), and a further study of adolescent sibling pairs concordant and discordant for major depression. In both studies, subjects were exposed to sad mood induction; subjects’ RSA was monitored during rest periods and in response to the mood induction. We used Gottesman and Gould’s (2003) criteria for an endophenotype and a priori defined “atypical” and “normative” RSA patterns (combinations of resting RSA and RSA reactivity). We found that atypical RSA patterns (a) predicted current depressive episodes and remission status among women with histories of juvenile onset depression and healthy controls, (b) predicted longitudinal trajectories of depressive symptoms among high- and low-risk young offspring, (c) were concordant across mothers and their juvenile offspring, (d) were more prevalent among never-depressed youth at high risk for depression than their low-risk peers, and (e) were more concordant across adolescent sibling pairs in which both versus only one had a history of major depression. Thus, the results support atypical RSA patterns as an endophenotype for depression. Possible mechanisms by which RSA patterns increase depression risk and their genetic contributors are discussed. PMID:25422965

Visual processing as a potential endophenotype in youths with attention-deficit/hyperactivity disorder: A sibling study design using the counting Stroop functional MRI.

PubMed

Fan, Li-Ying; Shang, Chi-Yung; Tseng, Wen-Yih Isaac; Gau, Susan Shur-Fen; Chou, Tai-Li

2018-05-10

Deficits in inhibitory control and visual processing are common in youths with attention-deficit/hyperactivity disorder (ADHD), but little is known about endophenotypes for unaffected siblings of youths with ADHD. This study aimed to investigate the potential endophenotypes of brain activation and performance in inhibitory control and visual processing among ADHD probands, their unaffected siblings, and neurotypical youths. We assessed 27 ADHD probands, 27 unaffected siblings, and 27 age-, gender-, and IQ-matched neurotypical youths using the counting Stroop functional magnetic resonance imaging and two tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB): rapid visual information processing (RVP) for inhibitory control and spatial span (SSP) for visual processing. ADHD probands showed greater activation than their unaffected siblings and neurotypical youths in the right inferior frontal gyrus (IFG) and anterior cingulate cortex. Increased activation in the right IFG was positively correlated with the mean latency of the RVP in ADHD probands. Moreover, ADHD probands and their unaffected siblings showed less activation in the left superior parietal lobule (SPL) than neurotypical youths. Increased activation in the left SPL was positively correlated with the spatial length of the SSP in neurotypical youths. Our findings suggest that less activation in the left SPL might be considered as a candidate imaging endophenotype for visual processing in ADHD. © 2018 Wiley Periodicals, Inc.

Intra-individual reaction time variability based on ex-Gaussian distribution as a potential endophenotype for attention-deficit/hyperactivity disorder.

PubMed

Lin, H-Y; Hwang-Gu, S-L; Gau, S S-F

2015-07-01

Intra-individual variability in reaction time (IIV-RT), defined by standard deviation of RT (RTSD), is considered as an endophenotype for attention-deficit/hyperactivity disorder (ADHD). Ex-Gaussian distributions of RT, rather than RTSD, could better characterize moment-to-moment fluctuations in neuropsychological performance. However, data of response variability based on ex-Gaussian parameters as an endophenotypic candidate for ADHD are lacking. We assessed 411 adolescents with clinically diagnosed ADHD based on the DSM-IV-TR criteria as probands, 138 unaffected siblings, and 138 healthy controls. The output parameters, mu, sigma, and tau, of an ex-Gaussian RT distribution were derived from the Conners' continuous performance test. Multi-level models controlling for sex, age, comorbidity, and use of methylphenidate were applied. Compared with unaffected siblings and controls, ADHD probands had elevated sigma value, omissions, commissions, and mean RT. Unaffected siblings formed an intermediate group in-between probands and controls in terms of tau value and RTSD. There was no between-group difference in mu value. Conforming to a context-dependent nature, unaffected siblings still had an intermediate tau value in-between probands and controls across different interstimulus intervals. Our findings suggest IIV-RT represented by tau may be a potential endophenotype for inquiry into genetic underpinnings of ADHD in the context of heterogeneity. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Familiarity and recollection processes in patients with recent-onset schizophrenia and their unaffected parents.

PubMed

Lefèbvre, Andrée-Anne; Cellard, Caroline; Tremblay, Sébastien; Achim, Amélie; Rouleau, Nancie; Maziade, Michel; Roy, Marc-André

2010-01-30

Episodic memory deficits are present in patients with schizophrenia (SZ) and their unaffected relatives and could be considered as a cognitive indicator of genetic vulnerability to SZ. The present study, involving patients with SZ as well as their parents, used experimental tasks specifically designed to disentangle the contribution of familiarity and recollection processes to episodic memory. The performance of patients with SZ (n=26) and their unaffected parents (n=35) was compared with that of healthy control groups matched on socio-demographic variables (controls of patients, n=26; controls of parents, n=35) on two memory tasks assessing recollection and familiarity. The first task was designed to investigate item recognition and memory for item-spatial context associations whereas the second targeted item-item associations. The results revealed an overall episodic memory deficit in patients with SZ, encompassing both familiarity and recollection, while unaffected parents showed a dysfunction restricted to the recollection process. Our study highlights differences and similarities in the source of the episodic memory deficit found in patients with SZ and their unaffected parents, and it suggests that recollection could act as a cognitive endophenotype of SZ. The results also suggest that use of experimental tasks represents a promising method in the search of cognitive endophenotypes in SZ.

Structural brain network analysis in families multiply affected with bipolar I disorder.

PubMed

Forde, Natalie J; O'Donoghue, Stefani; Scanlon, Cathy; Emsell, Louise; Chaddock, Chris; Leemans, Alexander; Jeurissen, Ben; Barker, Gareth J; Cannon, Dara M; Murray, Robin M; McDonald, Colm

2015-10-30

Disrupted structural connectivity is associated with psychiatric illnesses including bipolar disorder (BP). Here we use structural brain network analysis to investigate connectivity abnormalities in multiply affected BP type I families, to assess the utility of dysconnectivity as a biomarker and its endophenotypic potential. Magnetic resonance diffusion images for 19 BP type I patients in remission, 21 of their first degree unaffected relatives, and 18 unrelated healthy controls underwent tractography. With the automated anatomical labelling atlas being used to define nodes, a connectivity matrix was generated for each subject. Network metrics were extracted with the Brain Connectivity Toolbox and then analysed for group differences, accounting for potential confounding effects of age, gender and familial association. Whole brain analysis revealed no differences between groups. Analysis of specific mainly frontal regions, previously implicated as potentially endophenotypic by functional magnetic resonance imaging analysis of the same cohort, revealed a significant effect of group in the right medial superior frontal gyrus and left middle frontal gyrus driven by reduced organisation in patients compared with controls. The organisation of whole brain networks of those affected with BP I does not differ from their unaffected relatives or healthy controls. In discreet frontal regions, however, anatomical connectivity is disrupted in patients but not in their unaffected relatives. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Intra-Individual Response Variability Assessed by Ex-Gaussian Analysis may be a New Endophenotype for Attention-Deficit/Hyperactivity Disorder.

PubMed

Henríquez-Henríquez, Marcela Patricia; Billeke, Pablo; Henríquez, Hugo; Zamorano, Francisco Javier; Rothhammer, Francisco; Aboitiz, Francisco

2014-01-01

Intra-individual variability of response times (RTisv) is considered as potential endophenotype for attentional deficit/hyperactivity disorder (ADHD). Traditional methods for estimating RTisv lose information regarding response times (RTs) distribution along the task, with eventual effects on statistical power. Ex-Gaussian analysis captures the dynamic nature of RTisv, estimating normal and exponential components for RT distribution, with specific phenomenological correlates. Here, we applied ex-Gaussian analysis to explore whether intra-individual variability of RTs agrees with criteria proposed by Gottesman and Gould for endophenotypes. Specifically, we evaluated if normal and/or exponential components of RTs may (a) present the stair-like distribution expected for endophenotypes (ADHD > siblings > typically developing children (TD) without familiar history of ADHD) and (b) represent a phenotypic correlate for previously described genetic risk variants. This is a pilot study including 55 subjects (20 ADHD-discordant sibling-pairs and 15 TD children), all aged between 8 and 13 years. Participants resolved a visual Go/Nogo with 10% Nogo probability. Ex-Gaussian distributions were fitted to individual RT data and compared among the three samples. In order to test whether intra-individual variability may represent a correlate for previously described genetic risk variants, VNTRs at DRD4 and SLC6A3 were identified in all sibling-pairs following standard protocols. Groups were compared adjusting independent general linear models for the exponential and normal components from the ex-Gaussian analysis. Identified trends were confirmed by the non-parametric Jonckheere-Terpstra test. Stair-like distributions were observed for μ (p = 0.036) and σ (p = 0.009). An additional "DRD4-genotype" × "clinical status" interaction was present for τ (p = 0.014) reflecting a possible severity factor. Thus, normal and exponential RTisv components are suitable as ADHD endophenotypes.

Infant social attention: an endophenotype of ASD-related traits?

PubMed Central

Jones, Emily J.H.; Venema, Kaitlin; Earl, Rachel K.; Lowy, Rachel; Webb, Sara J.

2018-01-01

Background As a neurodevelopmental disorder, symptoms of ASD likely emerge from a complex interaction between preexisting genetic vulnerabilities and the child’s environment. One way to understand causal paths to ASD is to identify dimensional ASD-related traits that vary in the general population and that predispose individuals with other risk factors toward ASD. Moving beyond behavioral traits to explore underlying neurocognitive processes may further constrain the underlying genetics. Endophenotypes are quantitative, heritable, trait-related differences that are generally assessed with laboratory-based methods, can be identified in the general population, and may be more closely tied to particular causal chains that have a more restricted set of genetic roots. The most fruitful endophenotypes may be those observed in infancy, prior to the emergence of behavioral symptoms that they are hypothesized to cause. Social motivation is an ASD-related trait that is highly heritable. In this study, we investigate whether infant endophenotypes of social attention relate to familial risk for lower social motivation in the general population. Methods We examined whether infant social attention (measured using habituation, EEG power, and event-related potential tasks previously used in infants/toddlers with ASD) varies quantitatively with parental social motivation in 117 six-month-old and 106 twelve-month-old typically developing infants assessed cross-sectionally. To assess heritable aspects of social motivation, primary caregiver biological parents completed two self-report measures of social avoidance and discomfort that have shown high heritability in previous work. Results Parents with higher social discomfort and avoidance had infants who showed shorter looks to faces but not objects; reduced theta power during naturalistic social attention; and smaller P400 responses to faces versus objects. Conclusions Early reductions in social attention are continuously related to lower parental social motivation. Alterations in social attention may be infant endophenotypes of social motivation traits related to ASD. PMID:27861851

High interleukin-6 and impulsivity: determining the role of endophenotypes in attempted suicide

PubMed Central

Isung, J; Aeinehband, S; Mobarrez, F; Nordström, P; Runeson, B; Åsberg, M; Piehl, F; Jokinen, J

2014-01-01

The dysregulation of inflammation has been associated with depression and, more recently, with suicidal behaviors. The reports regarding the relationship between interleukin-6 (IL-6) and suicide attempts are inconsistent. Personality traits such as impulsivity and aggression are considered endophenotypes and important factors that underlie suicidal behaviors. The aim of the current study was to assess whether plasma and cerebrospinal fluid (CSF) levels of IL-6 are associated with personality traits among suicide attempters. We assessed the relationships among personality traits, IL-6 and violent suicide attempts. The plasma and CSF levels of IL-6 were measured in suicide attempters (plasma=58, CSF=39) using antibody-based immunoassay systems. Personality domains were assessed using the Karolinska Scale of Personality (KSP). IL-6 levels in plasma and CSF were used to predict personality domains via regression models. Plasma IL-6 was significantly and positively correlated with extraversion as well as the KSP subscales impulsivity and monotony avoidance. CSF IL-6 was positively correlated with monotony avoidance. Violent suicide attempts tended to be associated with high plasma IL-6 levels. Plasma and CSF levels of IL-6 were not significantly associated with each other. These results indicate that impulsivity and the choice of a violent suicide attempt method might be related to higher levels of IL-6 in individuals who attempt suicide. The neuroinflammation hypothesis of suicidal behavior on the basis of elevated IL-6 levels might be partly explained by the positive association between IL-6 and impulsivity, which is a key element of the suicidal phenotype. PMID:25335166

High interleukin-6 and impulsivity: determining the role of endophenotypes in attempted suicide.

PubMed

Isung, J; Aeinehband, S; Mobarrez, F; Nordström, P; Runeson, B; Asberg, M; Piehl, F; Jokinen, J

2014-10-21

The dysregulation of inflammation has been associated with depression and, more recently, with suicidal behaviors. The reports regarding the relationship between interleukin-6 (IL-6) and suicide attempts are inconsistent. Personality traits such as impulsivity and aggression are considered endophenotypes and important factors that underlie suicidal behaviors. The aim of the current study was to assess whether plasma and cerebrospinal fluid (CSF) levels of IL-6 are associated with personality traits among suicide attempters. We assessed the relationships among personality traits, IL-6 and violent suicide attempts. The plasma and CSF levels of IL-6 were measured in suicide attempters (plasma=58, CSF=39) using antibody-based immunoassay systems. Personality domains were assessed using the Karolinska Scale of Personality (KSP). IL-6 levels in plasma and CSF were used to predict personality domains via regression models. Plasma IL-6 was significantly and positively correlated with extraversion as well as the KSP subscales impulsivity and monotony avoidance. CSF IL-6 was positively correlated with monotony avoidance. Violent suicide attempts tended to be associated with high plasma IL-6 levels. Plasma and CSF levels of IL-6 were not significantly associated with each other. These results indicate that impulsivity and the choice of a violent suicide attempt method might be related to higher levels of IL-6 in individuals who attempt suicide. The neuroinflammation hypothesis of suicidal behavior on the basis of elevated IL-6 levels might be partly explained by the positive association between IL-6 and impulsivity, which is a key element of the suicidal phenotype.

Genome-wide significant localization for working and spatial memory: Identifying genes for psychosis using models of cognition.

PubMed

Knowles, Emma E M; Carless, Melanie A; de Almeida, Marcio A A; Curran, Joanne E; McKay, D Reese; Sprooten, Emma; Dyer, Thomas D; Göring, Harald H; Olvera, Rene; Fox, Peter; Almasy, Laura; Duggirala, Ravi; Kent, Jack W; Blangero, John; Glahn, David C

2014-01-01

It is well established that risk for developing psychosis is largely mediated by the influence of genes, but identifying precisely which genes underlie that risk has been problematic. Focusing on endophenotypes, rather than illness risk, is one solution to this problem. Impaired cognition is a well-established endophenotype of psychosis. Here we aimed to characterize the genetic architecture of cognition using phenotypically detailed models as opposed to relying on general IQ or individual neuropsychological measures. In so doing we hoped to identify genes that mediate cognitive ability, which might also contribute to psychosis risk. Hierarchical factor models of genetically clustered cognitive traits were subjected to linkage analysis followed by QTL region-specific association analyses in a sample of 1,269 Mexican American individuals from extended pedigrees. We identified four genome wide significant QTLs, two for working and two for spatial memory, and a number of plausible and interesting candidate genes. The creation of detailed models of cognition seemingly enhanced the power to detect genetic effects on cognition and provided a number of possible candidate genes for psychosis. © 2013 Wiley Periodicals, Inc.

Cognitive disorganisation in schizotypy is associated with deterioration in visual backward masking.

PubMed

Cappe, Céline; Herzog, Michael H; Herzig, Daniela A; Brand, Andreas; Mohr, Christine

2012-12-30

To understand the causes of schizophrenia, a search for stable markers (endophenotypes) is ongoing. In previous years, we have shown that the shine-through visual backward masking paradigm meets the most important characteristics of an endophenotype. Here, we tested masking performance differences between healthy students with low and high schizotypy scores as determined by the self-report O-Life questionnaire assessing schizotypy along three dimensions, i.e. positive schizotypy (unusual experiences), cognitive disorganisation, and negative schizotypy (introvertive anhedonia). Forty participants performed the shine-through backward masking task and a classical cognitive test, the Wisconsin Card Sorting Task (WCST). We found that visual backward masking was impaired for students scoring high as compared to low on the cognitive disorganisation dimension, whereas the positive and negative schizotypy dimensions showed no link to masking performance. We also found group differences for students scoring high and low on the cognitive disorganisation factor for the WCST. These findings indicate that the shine-through paradigm is sensitive to differences in schizotypy which are closely linked with the pathological expression in schizophrenia. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Theory of mind and verbal working memory deficits in parents of autistic children.

PubMed

Gokcen, Sezen; Bora, Emre; Erermis, Serpil; Kesikci, Hande; Aydin, Cahide

2009-03-31

The objective of this study was to investigate the potential values of executive function and social cognition deficits as endophenotypes of autism. While theory of mind (ToM) is generally accepted as a unitary concept, some have suggested that ToM may be separated into two components (mental state reasoning and decoding). In this study, both aspects of ToM and verbal working memory abilities were investigated with relatively demanding tasks. The authors used a neurocognitive battery to compare the executive function and social cognition skills of 76 parents of autistic probands with 41 parents of healthy children. Both groups were matched for IQ, age and gender. Index parents had verbal working memory deficits. They had also low performance on a mental state reasoning task. Index parents had difficulties in reasoning about others' emotions. In contrast to findings in the control group, low performance of mental state reasoning ability was not associated with working memory deficit in index parents. Social cognition and working memory impairments may represent potential endophenotypes, related to an underlying vulnerability for autistic spectrum disorders.

Autistic traits are linked to reduced adaptive coding of face identity and selectively poorer face recognition in men but not women.

PubMed

Rhodes, Gillian; Jeffery, Linda; Taylor, Libby; Ewing, Louise

2013-11-01

Our ability to discriminate and recognize thousands of faces despite their similarity as visual patterns relies on adaptive, norm-based, coding mechanisms that are continuously updated by experience. Reduced adaptive coding of face identity has been proposed as a neurocognitive endophenotype for autism, because it is found in autism and in relatives of individuals with autism. Autistic traits can also extend continuously into the general population, raising the possibility that reduced adaptive coding of face identity may be more generally associated with autistic traits. In the present study, we investigated whether adaptive coding of face identity decreases as autistic traits increase in an undergraduate population. Adaptive coding was measured using face identity aftereffects, and autistic traits were measured using the Autism-Spectrum Quotient (AQ) and its subscales. We also measured face and car recognition ability to determine whether autistic traits are selectively related to face recognition difficulties. We found that men who scored higher on levels of autistic traits related to social interaction had reduced adaptive coding of face identity. This result is consistent with the idea that atypical adaptive face-coding mechanisms are an endophenotype for autism. Autistic traits were also linked with face-selective recognition difficulties in men. However, there were some unexpected sex differences. In women, autistic traits were linked positively, rather than negatively, with adaptive coding of identity, and were unrelated to face-selective recognition difficulties. These sex differences indicate that autistic traits can have different neurocognitive correlates in men and women and raise the intriguing possibility that endophenotypes of autism can differ in males and females. © 2013 Elsevier Ltd. All rights reserved.

Recognition of facial emotion and affective prosody in children with ASD (+ADHD) and their unaffected siblings.

PubMed

Oerlemans, Anoek M; van der Meer, Jolanda M J; van Steijn, Daphne J; de Ruiter, Saskia W; de Bruijn, Yvette G E; de Sonneville, Leo M J; Buitelaar, Jan K; Rommelse, Nanda N J

2014-05-01

Autism is a highly heritable and clinically heterogeneous neuropsychiatric disorder that frequently co-occurs with other psychopathologies, such as attention-deficit/hyperactivity disorder (ADHD). An approach to parse heterogeneity is by forming more homogeneous subgroups of autism spectrum disorder (ASD) patients based on their underlying, heritable cognitive vulnerabilities (endophenotypes). Emotion recognition is a likely endophenotypic candidate for ASD and possibly for ADHD. Therefore, this study aimed to examine whether emotion recognition is a viable endophenotypic candidate for ASD and to assess the impact of comorbid ADHD in this context. A total of 90 children with ASD (43 with and 47 without ADHD), 79 ASD unaffected siblings, and 139 controls aged 6-13 years, were included to test recognition of facial emotion and affective prosody. Our results revealed that the recognition of both facial emotion and affective prosody was impaired in children with ASD and aggravated by the presence of ADHD. The latter could only be partly explained by typical ADHD cognitive deficits, such as inhibitory and attentional problems. The performance of unaffected siblings could overall be considered at an intermediate level, performing somewhat worse than the controls and better than the ASD probands. Our findings suggest that emotion recognition might be a viable endophenotype in ASD and a fruitful target in future family studies of the genetic contribution to ASD and comorbid ADHD. Furthermore, our results suggest that children with comorbid ASD and ADHD are at highest risk for emotion recognition problems.

Motor sequencing deficit as an endophenotype of speech sound disorder: a genome-wide linkage analysis in a multigenerational family.

PubMed

Peter, Beate; Matsushita, Mark; Raskind, Wendy H

2012-10-01

The aim of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were carried out using a genome-wide panel of 404 microsatellites. In seven of the 10 family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect the component traits of language impairment. The results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification.

Motor sequencing deficit as an endophenotype of speech sound disorder: A genome-wide linkage analysis in a multigenerational family

PubMed Central

Peter, Beate; Matsushita, Mark; Raskind, Wendy H.

2012-01-01

Objectives The purpose of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. Methods In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were conducted using a genome-wide panel of 404 microsatellites. Results In seven of the ten family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect component traits of language impairment. Conclusions Results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification. PMID:22517379

Attentional network task in schizophrenic patients and theirs unaffected first degree relatives: a potential endofenotype.

PubMed

López, S Guerra; Fuster, J Iglesias; Reyes, M Martín; Collazo, T M Bravo; Quiñones, R Mendoza; Berazain, A Reyes; Rodríguez, M A Pedroso; Días de Villarvilla, T; Bobés, M Antonieta; Valdés-Sosa, M

2011-01-01

In recent years, reports of attentional deficits in schizophrenic patients and in their biological relatives have rapidly increased, including an important effort to search for the endophenotypes in order to link specific genes to this illness. Posner et al. developed a test, the Attention Network Test (ANT), to study the neural networks. This test provides a separate measure for each one of the three anatomically-defined attention networks (alerting, orienting and executive control). In this paper, we investigate the attentional performance in 32 schizophrenic patients, 29 unaffected first degree relatives and 29 healthy controls using the ANT through a study of family association. We have studied the efficiency of the segregated executive control, alerting and orienting networks by measuring how response latencies (reaction time) were modified by the cue position and the flanking stimuli. We also studied the familial association of these attentional alterations. The ANOVA revealed main effects of flanker and cue condition and a significant interaction effect between flanker and groups studied. The schizophrenic patients and their relatives had a longer median reaction time than the control group. The probands and their relatives significantly differed from the healthy controls in terms of their conflict resolution; however, the alerting network appeared to be conserved. Our results support the thesis of a specific attentional deficit in schizophrenia and show the segregation of the three attentional networks. The family association of these reported alterations supports the idea of a potential endophenotype in schizophrenia.

A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study.

PubMed

Thomaes, Tom; Thomis, Martine; Onkelinx, Steven; Fagard, Robert; Matthijs, Gert; Buys, Roselien; Schepers, Dirk; Cornelissen, Véronique; Vanhees, Luc

2011-10-03

It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training. 935 Coronary artery disease patients (CAD) who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS) were constructed based on literature and own data and were related to baseline and response VO(2) scores. Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (GR) and the ciliary neurotrophic factor gene (CNTF) had a significantly higher increase in peakVO(2) after training (p < 0.05). Carriers of the minor allele (C34T) in the adenosine monophosphate deaminase (AMPD1) gene had a significantly lower relative increase (p < 0.05) in peakVO(2). GPS of data driven models were significantly associated with the increase in peakVO(2) after training. In CAD patients, suggestive associations were found in the GR, CNTF and the AMPD1 gene with an improved change in aerobic capacity after three months of training. Additionally data driven models with a genetic predisposition score (GPS) showed a significant predictive value for the increase in peakVO(2).

A genetic predisposition score for muscular endophenotypes predicts the increase in aerobic power after training: the CAREGENE study

PubMed Central

2011-01-01

Background It is widely accepted that genetic variability might explain a large part of the observed heterogeneity in aerobic capacity and its response to training. Significant associations between polymorphisms of different genes with muscular strength, anaerobic phenotypes and body composition have been reported. Muscular endophenotypes are positively correlated with aerobic capacity, therefore, we tested the association of polymorphisms in twelve muscular related genes on aerobic capacity and its response to endurance training. Methods 935 Coronary artery disease patients (CAD) who performed an incremental exercise test until exhaustion at baseline and after three months of training were included. Polymorphisms of the genes were detected using the invader assay. Genotype-phenotype association analyses were performed using ANCOVA. Different models for a genetic predisposition score (GPS) were constructed based on literature and own data and were related to baseline and response VO2 scores. Results Carriers of the minor allele in the R23K polymorphism of the glucocorticoid receptor gene (GR) and the ciliary neurotrophic factor gene (CNTF) had a significantly higher increase in peakVO2 after training (p < 0.05). Carriers of the minor allele (C34T) in the adenosine monophosphate deaminase (AMPD1) gene had a significantly lower relative increase (p < 0.05) in peakVO2. GPS of data driven models were significantly associated with the increase in peakVO2 after training. Conclusions In CAD patients, suggestive associations were found in the GR, CNTF and the AMPD1 gene with an improved change in aerobic capacity after three months of training. Additionally data driven models with a genetic predisposition score (GPS) showed a significant predictive value for the increase in peakVO2. PMID:21967077

Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families.

PubMed

Glahn, David C; Almasy, Laura; Barguil, Marcela; Hare, Elizabeth; Peralta, Juan Manuel; Kent, Jack W; Dassori, Albana; Contreras, Javier; Pacheco, Adriana; Lanzagorta, Nuria; Nicolini, Humberto; Raventós, Henriette; Escamilla, Michael A

2010-02-01

Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. To adjudicate neurocognitive endophenotypes for bipolar disorder. All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. Neurocognitive test performance. Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

Corticostriatal circuitry in regulating diseases characterized by intrusive thinking

PubMed Central

Kalivas, Benjamin C.; Kalivas, Peter W.

2016-01-01

Intrusive thinking triggers clinical symptoms in many neuropsychiatric disorders. Using drug addiction as an exemplar disorder sustained in part by intrusive thinking, we explore studies demonstrating that impairments in corticostriatal circuitry strongly contribute to intrusive thinking. Neuroimaging studies have long implicated this projection in cue-induced craving to use drugs, and preclinical models show that marked changes are produced at corticostriatal synapses in the nucleus accumbens during a relapse episode. We delineate an accumbens microcircuit that mediates cue-induced drug seeking becoming an intrusive event. This microcircuit harbors many potential therapeutic targets. We focus on preclinical and clinical studies, showing that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. We posit that because intrusive thinking is a shared endophenotype in many disorders, N-acetylcysteine has positive effects in clinical trials for a variety of neuropsychiatric disorders, including drug addiction, gambling, trichotillomania, and depression. PMID:27069381

Corticostriatal circuitry in regulating diseases characterized by intrusive thinking.

PubMed

Kalivas, Benjamin C; Kalivas, Peter W

2016-03-01

Intrusive thinking triggers clinical symptoms in many neuropsychiatric disorders. Using drug addiction as an exemplar disorder sustained in part by intrusive thinking, we explore studies demonstrating that impairments in corticostriatal circuitry strongly contribute to intrusive thinking. Neuroimaging studies have long implicated this projection in cue-induced craving to use drugs, and preclinical models show that marked changes are produced at corticostriatal synapses in the nucleus accumbens during a relapse episode. We delineate an accumbens microcircuit that mediates cue-induced drug seeking becoming an intrusive event. This microcircuit harbors many potential therapeutic targets. We focus on preclinical and clinical studies, showing that administering N-acetylcysteine restores uptake of synaptic glutamate by astroglial glutamate transporters and thereby inhibits intrusive thinking. We posit that because intrusive thinking is a shared endophenotype in many disorders, N-acetylcysteine has positive effects in clinical trials for a variety of neuropsychiatric disorders, including drug addiction, gambling, trichotillomania, and depression.

Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

PubMed Central

Zordan, Mauro Agostino; Sandrelli, Federica

2015-01-01

There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness. We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors. We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease. PMID:25941512

An Autistic Endophenotype and Testosterone Are Involved in an Atypical Decline in Selective Attention and Visuospatial Processing in Middle-Aged Women.

PubMed

Ángel, Romero-Martínez; Luis, Moya-Albiol

2015-12-15

Mothers of offspring with autism spectrum disorders (ASD) could present mild forms of their children's cognitive characteristics, resulting from prenatal brain exposure and sensitivity to testosterone (T). Indeed, their cognition is frequently characterized by hyper-systemizing, outperforming in tests that assess cognitive domains such as selective attention, and fine motor and visuospatial skills. In the general population, all these start to decline around the mid-forties. This study aimed to characterize whether middle-aged women who are biological mothers of individuals with ASD had better performance in the aforementioned cognitive skills than mothers of normative children (in both groups n = 22; mean age = 45), using the standardized Stroop and mirror-drawing tests. We also examined the role of T in their performance in the aforementioned tests. ASD mothers outperformed controls in both tests, giving more correct answers and making fewer mistakes. In addition, they presented higher T levels, which have been associated with better cognitive performance. Cognitive decline in specific skills with aging could be delayed in these middle-aged women, corresponding to a cognitive endophenotype, T playing an important role in this process.

An Autistic Endophenotype and Testosterone Are Involved in an Atypical Decline in Selective Attention and Visuospatial Processing in Middle-Aged Women

PubMed Central

Ángel, Romero-Martínez; Luis, Moya-Albiol

2015-01-01

Mothers of offspring with autism spectrum disorders (ASD) could present mild forms of their children’s cognitive characteristics, resulting from prenatal brain exposure and sensitivity to testosterone (T). Indeed, their cognition is frequently characterized by hyper-systemizing, outperforming in tests that assess cognitive domains such as selective attention, and fine motor and visuospatial skills. In the general population, all these start to decline around the mid-forties. This study aimed to characterize whether middle-aged women who are biological mothers of individuals with ASD had better performance in the aforementioned cognitive skills than mothers of normative children (in both groups n = 22; mean age = 45), using the standardized Stroop and mirror-drawing tests. We also examined the role of T in their performance in the aforementioned tests. ASD mothers outperformed controls in both tests, giving more correct answers and making fewer mistakes. In addition, they presented higher T levels, which have been associated with better cognitive performance. Cognitive decline in specific skills with aging could be delayed in these middle-aged women, corresponding to a cognitive endophenotype, T playing an important role in this process. PMID:26694433

Risk Factors for Addiction and Their Association with Model-Based Behavioral Control.

PubMed

Reiter, Andrea M F; Deserno, Lorenz; Wilbertz, Tilmann; Heinze, Hans-Jochen; Schlagenhauf, Florian

2016-01-01

Addiction shows familial aggregation and previous endophenotype research suggests that healthy relatives of addicted individuals share altered behavioral and cognitive characteristics with individuals suffering from addiction. In this study we asked whether impairments in behavioral control proposed for addiction, namely a shift from goal-directed, model-based toward habitual, model-free control, extends toward an unaffected sample (n = 20) of adult children of alcohol-dependent fathers as compared to a sample without any personal or family history of alcohol addiction (n = 17). Using a sequential decision-making task designed to investigate model-free and model-based control combined with a computational modeling analysis, we did not find any evidence for altered behavioral control in individuals with a positive family history of alcohol addiction. Independent of family history of alcohol dependence, we however observed that the interaction of two different risk factors of addiction, namely impulsivity and cognitive capacities, predicts the balance of model-free and model-based behavioral control. Post-hoc tests showed a positive association of model-based behavior with cognitive capacity in the lower, but not in the higher impulsive group of the original sample. In an independent sample of particularly high- vs. low-impulsive individuals, we confirmed the interaction effect of cognitive capacities and high vs. low impulsivity on model-based control. In the confirmation sample, a positive association of omega with cognitive capacity was observed in highly impulsive individuals, but not in low impulsive individuals. Due to the moderate sample size of the study, further investigation of the association of risk factors for addiction with model-based behavior in larger sample sizes is warranted.

Association of Polyaminergic Loci With Anxiety, Mood Disorders, and Attempted Suicide

PubMed Central

Fiori, Laura M.; Wanner, Brigitte; Jomphe, Valérie; Croteau, Jordie; Vitaro, Frank

2010-01-01

Background The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression. Methodology/Principal Findings We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes. Conclusions/Significance These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders. PMID:21152090

Association of polyaminergic loci with anxiety, mood disorders, and attempted suicide.

PubMed

Fiori, Laura M; Wanner, Brigitte; Jomphe, Valérie; Croteau, Jordie; Vitaro, Frank; Tremblay, Richard E; Bureau, Alexandre; Turecki, Gustavo

2010-11-30

The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression. We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes. These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.

Endophenotypes of Dementia Associated with Traumatic Brain Injury in Retired Military Personnel

DTIC Science & Technology

2015-06-01

Physical Activity; GDS= Geriatric Depression Scale; PCL-C=PTSD Checklist-Civilian; PTSD=Post- Traumatic Stress Disorder *adjusted for age, gender...depression (p = 0.047) and PTSD symptoms (p = 0.02), although both are far below clinical criteria for diagnosis. Sleep quality, physical activity...Intellectual/Leisure Activities Scale 29.5 (8.5) 25.4 (9.6) 0.02 RAPA 1 ( physical activity) 3.6 (1.3) 3.3 (1.4) 0.61 RAPA 2 (strength/flexibility) 1.2

Association of single nucleotide polymorphisms in a glutamate receptor gene (GRM8) with theta power of event-related oscillations and alcohol dependence.

PubMed

Chen, Andrew C H; Tang, Yongqiang; Rangaswamy, Madhavi; Wang, Jen C; Almasy, Laura; Foroud, Tatiana; Edenberg, Howard J; Hesselbrock, Victor; Nurnberger, John; Kuperman, Samuel; O'Connor, Sean J; Schuckit, Marc A; Bauer, Lance O; Tischfield, Jay; Rice, John P; Bierut, Laura; Goate, Alison; Porjesz, Bernice

2009-04-05

Evidence suggests the P3 amplitude of the event-related potential and its underlying superimposed event-related oscillations (EROs), primarily in the theta (4-5 Hz) and delta (1-3 Hz) frequencies, as endophenotypes for the risk of alcoholism and other disinhibitory disorders. Major neurochemical substrates contributing to theta and delta rhythms and P3 involve strong GABAergic, cholinergic and glutamatergic system interactions. The aim of this study was to test the potential associations between single nucleotide polymorphisms (SNPs) in glutamate receptor genes and ERO quantitative traits. GRM8 was selected because it maps at chromosome 7q31.3-q32.1 under the peak region where we previously identified significant linkage (peak LOD = 3.5) using a genome-wide linkage scan of the same phenotype (event-related theta band for the target visual stimuli). Neural activities recorded from scalp electrodes during a visual oddball task in which rare target elicited P3s were analyzed in a subset of the Collaborative Study on the Genetics of Alcoholism (COGA) sample comprising 1,049 Caucasian subjects from 209 families (with 472 DSM-IV alcohol dependent individuals). The family-based association test (FBAT) detected significant association (P < 0.05) with multiple SNPs in the GRM8 gene and event-related theta power to target visual stimuli, and also with alcohol dependence, even after correction for multiple comparisons by false discovery rate (FDR). Our results suggest that variation in GRM8 may be involved in modulating event-related theta oscillations during information processing and also in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. (c) 2008 Wiley-Liss, Inc.

Neurocognitive Endophenotypes for Bipolar Disorder Identified in Multiplex Multigenerational Families

PubMed Central

Glahn, David C.; Almasy, Laura; Barguil, Marcela; Hare, Elizabeth; Peralta, Juan Manuel; Kent, Jack W.; Dassori, Alabana; Contreras, Javier; Pacheco, Adriana; Lanzagorta, Nuria; Nicolini, Humberto; Raventós, Henriette; Escamilla, Michael A.

2012-01-01

Context Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, one strategy for identifying risk genes is the use of quantitative endophenotypes. Objective The goal of the current study is to adjudicate neurocognitive endophenotypes for bipolar disorder. Design, Setting, and Participants 709 Latino individuals from the central valley of Costa Rica, Mexico City, Mexico, or San Antonio, Texas participated in the study. 660 of these persons were members of extended pedigrees with at least two siblings diagnosed with bipolar disorder (n=230). The remaining subjects were community controls drawn from each site and without personal or family history of bipolar disorder or schizophrenia. All subjects received psychodiagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which tests are impaired in affected individuals, sensitive to genetic liability for the illness and genetically correlated with affection status. Main Outcome Measures The main outcome measure was neurocognitive test performance. Results Two of the 21 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 of these cognitive measures compared to non-related healthy subjects. Non-bipolar first-degree relatives were impaired on five of these and three tests were genetically correlated with affection status: digit symbol coding, object delayed response, and immediate facial memory. Conclusions This large-scale extended pedigree study of cognitive functioning in bipolar disorder identified measures of processing speed, working memory and declarative (facial) memory as candidate endophenotypes for bipolar disorder. PMID:20124116

Establishing the resting state default mode network derived from functional magnetic resonance imaging tasks as an endophenotype: A twins study.

PubMed

Korgaonkar, Mayuresh S; Ram, Kaushik; Williams, Leanne M; Gatt, Justine M; Grieve, Stuart M

2014-08-01

The resting state default mode network (DMN) has been shown to characterize a number of neurological and psychiatric disorders. Evidence suggests an underlying genetic basis for this network and hence could serve as potential endophenotype for these disorders. Heritability is a defining criterion for endophenotypes. The DMN is measured either using a resting-state functional magnetic resonance imaging (fMRI) scan or by extracting resting state activity from task-based fMRI. The current study is the first to evaluate heritability of this task-derived resting activity. 250 healthy adult twins (79 monozygotic and 46 dizygotic same sex twin pairs) completed five cognitive and emotion processing fMRI tasks. Resting state DMN functional connectivity was derived from these five fMRI tasks. We validated this approach by comparing connectivity estimates from task-derived resting activity for all five fMRI tasks, with those obtained using a dedicated task-free resting state scan in an independent cohort of 27 healthy individuals. Structural equation modeling using the classic twin design was used to estimate the genetic and environmental contributions to variance for the resting-state DMN functional connectivity. About 9-41% of the variance in functional connectivity between the DMN nodes was attributed to genetic contribution with the greatest heritability found for functional connectivity between the posterior cingulate and right inferior parietal nodes (P<0.001). Our data provide new evidence that functional connectivity measures from the intrinsic DMN derived from task-based fMRI datasets are under genetic control and have the potential to serve as endophenotypes for genetically predisposed psychiatric and neurological disorders. Copyright © 2014 Wiley Periodicals, Inc.

Pheno-phenotypes: a holistic approach to the psychopathology of schizophrenia.

PubMed

Stanghellini, Giovanni; Rossi, Rodolfo

2014-05-01

Mental disorders are mainly characterized via symptom assessment. Symptoms are state-like macroscopic anomalies of behaviour, experience, and expression that are deemed relevant for diagnostic purposes. An alternative approach is based on the concept of endophenotypes, which are physiological or behavioural measures occupying the terrain between symptoms and risk genotypes. We will critically discuss these two approaches, and later focus on the concept of pheno-phenotype as it is revealed by recent phenomenological research on schizophrenia. Several studies have been recently published on the schizophrenic pheno-phenotype mainly addressing self-disorders, as well as disorders of time and bodily experience. The mainstream approach to psychopathological phenotypes is focussed on easy-to-assess operationalizable symptoms. Thinness of phenotypes and simplification of clinical constructs are the consequences of this. Also, this approach has not been successful in investigating the biological causes of mental disorders. An integrative approach is based on the concept of 'endophenotype'. Endophenotypes were conceptualized as a supportive tool for the genetic dissection of psychiatric disorders. The underlying rationale states that disease-specific phenotypes should be the upstream phenotypic manifestation of a smaller genotype than the whole disease-related genotype. Psychopathological phenotypes can also be characterized in terms of pheno-phenotypes. This approach aims at delineating the manifold phenomena experienced by patients in all of their concrete and distinctive features, so that the features of a pathological condition emerge, while preserving their peculiar feel, meaning, and value for the patient. Systematic explorations of anomalies in the patients' experience, for example, of time, space, body, self, and otherness, may provide a useful integration to the symptom-based and endophenotype-based approaches. These abnormal phenomena can be used as pointers to the fundamental alterations of the structure of subjectivity characterizing each mental disorder.

Heart rate variability as candidate endophenotype of social anxiety: A two-generation family study.

PubMed

Harrewijn, A; Van der Molen, M J W; Verkuil, B; Sweijen, S W; Houwing-Duistermaat, J J; Westenberg, P M

2018-09-01

Social anxiety disorder (SAD) is the extreme fear and avoidance of one or more social situations. The goal of the current study was to investigate whether heart rate variability (HRV) during resting state and a social performance task (SPT) is a candidate endophenotype of SAD. In this two-generation family study, patients with SAD with their partner and children, and their siblings with partner and children took part in a SPT (total n = 121, 9 families, 3-30 persons per family, age range: 8-61 years, 17 patients with SAD). In this task, participants had to watch and evaluate the speech of a female peer, and had to give a similar speech. HRV was measured during two resting state phases, and during anticipation, speech and recovery phases of the SPT. We tested two criteria for endophenotypes: co-segregation with SAD within families and heritability. HRV did not co-segregate with SAD within families. Root mean square of successive differences during the first resting phase and recovery, and high frequency power during all phases of the task were heritable. It should be noted that few participants were diagnosed with SAD. Results during the speech should be interpreted with caution, because the duration was short and there was a lot of movement. HRV during resting state and the SPT is a possible endophenotype, but not of SAD. As other studies have shown that HRV is related to different internalizing disorders, HRV might reflect a transdiagnostic genetic vulnerability for internalizing disorders. Future research should investigate which factors influence the development of psychopathology in persons with decreased HRV. Copyright © 2018 Elsevier B.V. All rights reserved.

Temporal discrimination, a cervical dystonia endophenotype: penetrance and functional correlates.

PubMed

Kimmich, Okka; Molloy, Anna; Whelan, Robert; Williams, Laura; Bradley, David; Balsters, Joshua; Molloy, Fiona; Lynch, Tim; Healy, Daniel G; Walsh, Cathal; O'Riordan, Seán; Reilly, Richard B; Hutchinson, Michael

2014-05-01

The pathogenesis of adult-onset primary dystonia remains poorly understood. There is variable age-related and gender-related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)-the shortest time interval at which two separate stimuli can be detected as being asynchronous-is abnormal both in patients with cervical dystonia and in their unaffected first-degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activation positively correlates with the ease of temporal discrimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age-related and gender-related penetrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first-degree relatives of 84 patients with cervical dystonia. In 24 unaffected first-degree relatives, fMRI scanning was performed during a temporal discrimination task. The prevalence of abnormal TDTs in unaffected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endophenotype was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits. © 2014 International Parkinson and Movement Disorder Society.

Evidence for the Late MMN as a Neurophysiological Endophenotype for Dyslexia

PubMed Central

Neuhoff, Nina; Bruder, Jennifer; Bartling, Jürgen; Warnke, Andreas; Remschmidt, Helmut; Müller-Myhsok, Bertram; Schulte-Körne, Gerd

2012-01-01

Dyslexia affects 5–10% of school-aged children and is therefore one of the most common learning disorders. Research on auditory event related potentials (AERP), particularly the mismatch negativity (MMN) component, has revealed anomalies in individuals with dyslexia to speech stimuli. Furthermore, candidate genes for this disorder were found through molecular genetic studies. A current challenge for dyslexia research is to understand the interaction between molecular genetics and brain function, and to promote the identification of relevant endophenotypes for dyslexia. The present study examines MMN, a neurophysiological correlate of speech perception, and its potential as an endophenotype for dyslexia in three groups of children. The first group of children was clinically diagnosed with dyslexia, whereas the second group of children was comprised of their siblings who had average reading and spelling skills and were therefore “unaffected” despite having a genetic risk for dyslexia. The third group consisted of control children who were not related to the other groups and were also unaffected. In total, 225 children were included in the study. All children showed clear MMN activity to/da/−/ba/contrasts that could be separated into three distinct MMN components. Whilst the first two MMN components did not differentiate the groups, the late MMN component (300–700 ms) revealed significant group differences. The mean area of the late MMN was attenuated in both the dyslexic children and their unaffected siblings in comparison to the control children. This finding is indicative of analogous alterations of neurophysiological processes in children with dyslexia and those with a genetic risk for dyslexia, without a manifestation of the disorder. The present results therefore further suggest that the late MMN might be a potential endophenotype for dyslexia. PMID:22606227

The persistence of cognitive deficits in remitted and unremitted ADHD: a case for the state-independence of response inhibition

PubMed Central

McAuley, Tara; Crosbie, Jennifer; Charach, Alice; Schachar, Russell

2014-01-01

Background Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the disorder, a criterion known as state-independence. This study examined whether these aspects of cognition exhibit state-independence in ADHD. Methods One hundred and seventy-nine children diagnosed with ADHD in a rigorous baseline assessment were contacted for follow-up assessment in adolescence. Of this sample, 130 (73%) were reascertained. At follow-up, children previously diagnosed with ADHD were identified as remittent (n = 24), persistent (n = 64), or in partial remission (n = 42) based on symptoms and impairment of the disorder. Response inhibition, working memory, and response variability were assessed both in childhood (baseline) and adolescence (follow-up) and were compared with age-matched controls (40 children and 28 adolescents) seen at either time point. Results Relative to controls, ADHD children showed baseline deficits in response inhibition, working memory, and response variability. Only the group difference in response inhibition remained significant in adolescence. In general, cognitive performance among ADHD participants improved with age and did so regardless of changes in ADHD symptoms and impairment. Within the ADHD group, however, cognitive performance in childhood and in adolescence did not differ amongst those with persistent, remittent, and partially remittent forms of the disorder. Conclusions Results demonstrate that response inhibition not only distinguishes ADHD children from their unaffected peers but is also state-independent, such that deficits remain present irrespective of changes in the disease phenotype. In other words, inhibitory deficits measured in childhood persist into adolescence even when the ADHD phenotype remits. These findings provide further evidence that the ability to stop prepotent actions is an endophenotype of ADHD. PMID:24261515

Quantitative genetic analysis of anxiety trait in bipolar disorder.

PubMed

Contreras, J; Hare, E; Chavarría, G; Raventós, H

2018-01-01

Bipolar disorder type I (BPI) affects approximately 1% of the world population. Although genetic influences on bipolar disorder are well established, identification of genes that predispose to the illness has been difficult. Most genetic studies are based on categorical diagnosis. One strategy to overcome this obstacle is the use of quantitative endophenotypes, as has been done for other medical disorders. We studied 619 individuals, 568 participants from 61 extended families and 51 unrelated healthy controls. The sample was 55% female and had a mean age of 43.25 (SD 13.90; range 18-78). Heritability and genetic correlation of the trait scale from the Anxiety State and Trait Inventory (STAI) was computed by using the general linear model (SOLAR package software). we observed that anxiety trait meets the following criteria for an endophenotype of bipolar disorder type I (BPI): 1) association with BPI (individuals with BPI showed the highest trait score (F = 15.20 [5,24], p = 0.009), 2) state-independence confirmed after conducting a test-retest in 321 subjects, 3) co-segregation within families 4) heritability of 0.70 (SE: 0.060), p = 2.33 × 10 -14 and 5) genetic correlation with BPI was 0.20, (SE = 0.17, p = 3.12 × 10 -5 ). Confounding factors such as comorbid disorders and pharmacological treatment could affect the clinical relationship between BPI and anxiety trait. Further research is needed to evaluate if anxiety traits are specially related to BPI in comparison with other traits such as anger, attention or response inhibition deficit, pathological impulsivity or low self-directedness. Anxiety trait is a heritable phenotype that follows a normal distribution when measured not only in subjects with BPI but also in unrelated healthy controls. It could be used as an endophenotype in BPI for the identification of genomic regions with susceptibility genes for this disorder. Published by Elsevier B.V.

A New Approach of Personality and Psychiatric Disorders: A Short Version of the Affective Neuroscience Personality Scales

PubMed Central

Pingault, Jean-Baptiste; Falissard, Bruno; Côté, Sylvana; Berthoz, Sylvie

2012-01-01

Background The Affective Neuroscience Personality Scales (ANPS) is an instrument designed to assess endophenotypes related to activity in the core emotional systems that have emerged from affective neuroscience research. It operationalizes six emotional endophenotypes with empirical evidence derived from ethology, neural analyses and pharmacology: PLAYFULNESS/joy, SEEKING/interest, CARING/nurturance, ANGER/rage, FEAR/anxiety, and SADNESS/separation distress. We aimed to provide a short version of this questionnaire (ANPS-S). Methodology/Principal Findings We used a sample of 830 young French adults which was randomly split into two subsamples. The first subsample was used to select the items for the short scales. The second subsample and an additional sample of 431 Canadian adults served to evaluate the psychometric properties of the short instrument. The ANPS-S was similar to the long version regarding intercorrelations between the scales and gender differences. The ANPS-S had satisfactory psychometric properties, including factorial structure, unidimensionality of all scales, and internal consistency. The scores from the short version were highly correlated with the scores from the long version. Conclusions/Significance The short ANPS proves to be a promising instrument to assess endophenotypes for psychiatrically relevant science. PMID:22848510

Cognitive endophenotypes of attention deficit/hyperactivity disorder and intra-subject variability in patients with autism spectrum disorder.

PubMed

Biscaldi, M; Bednorz, N; Weissbrodt, K; Saville, C W N; Feige, B; Bender, S; Klein, C

2016-07-01

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have previously been studied mainly in isolation from each other. However the two conditions may be aetiologically related and thus show overlap in aetiologically relevant functions. In order to address this question of potential aetiological overlap between ADHD and ASD, the present study set out to investigate putative endophenotypes of ADHD in N=33 typically developing (TD) children and N=28 patients with ASD that were (ASD+) or were not (ASD-) co-morbid for ADHD. With regard to both the cognitive endophenotype candidates (working memory, inhibition, temporal processing) and intra-subject variability (ISV) the pattern of abnormalities was inconsistent. Furthermore, the overall profile of ASD-TD differences was extremely similar to the pattern of differences between the ASD+ and ASD- sub-groups, suggesting that any abnormalities found were due to the comorbid ASD subgroup. This held in particular for ISV, which did not show in patients with ASD the task-general increase that is common in ADHD samples. Altogether, the present results do not support the hypothesis of aetiological overlap between ASD and ADHD. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuropsychological characteristics of child and adolescent offspring of patients with schizophrenia or bipolar disorder.

PubMed

de la Serna, Elena; Sugranyes, Gisela; Sanchez-Gistau, Vanessa; Rodriguez-Toscano, Elisa; Baeza, Immaculada; Vila, Montserrat; Romero, Soledad; Sanchez-Gutierrez, Teresa; Penzol, Mª José; Moreno, Dolores; Castro-Fornieles, Josefina

2017-05-01

Schizophrenia (SZ) and bipolar disorder (BD) are considered neurobiological disorders which share some clinical, cognitive and neuroimaging characteristics. Studying child and adolescent offspring of patients diagnosed with bipolar disorder (BDoff) or schizophrenia (SZoff) is regarded as a reliable method for investigating early alterations and vulnerability factors for these disorders. This study compares the neuropsychological characteristics of SZoff, BDoff and a community control offspring group (CC) with the aim of examining shared and differential cognitive characteristics among groups. 41 SZoff, 90 BDoff and 107 CC were recruited. They were all assessed with a complete neuropsychological battery which included intelligence quotient, working memory (WM), processing speed, verbal memory and learning, visual memory, executive functions and sustained attention. SZoff and BDoff showed worse performance in some cognitive areas compared with CC. Some of these difficulties (visual memory) were common to both offspring groups, whereas others, such as verbal learning and WM in SZoff or PSI in BDoff, were group-specific. The cognitive difficulties in visual memory shown by both the SZoff and BDoff groups might point to a common endophenotype in the two disorders. Difficulties in other cognitive functions would be specific depending on the family diagnosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.

PubMed

Chen, Rui; Davis, Lea K; Guter, Stephen; Wei, Qiang; Jacob, Suma; Potter, Melissa H; Cox, Nancy J; Cook, Edwin H; Sutcliffe, James S; Li, Bingshan

2017-01-01

Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs ( FOXP1 and KDM5B ). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes.

Heritability of the melatonin synthesis variability in autism spectrum disorders.

PubMed

Benabou, Marion; Rolland, Thomas; Leblond, Claire S; Millot, Gaël A; Huguet, Guillaume; Delorme, Richard; Leboyer, Marion; Pagan, Cécile; Callebert, Jacques; Maronde, Erik; Bourgeron, Thomas

2017-12-18

Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders with a complex genetic architecture. They are characterized by impaired social communication, stereotyped behaviors and restricted interests and are frequently associated with comorbidities such as intellectual disability, epilepsy and severe sleep disorders. Hyperserotonemia and low melatonin levels are among the most replicated endophenotypes reported in ASD, but their genetic causes remain largely unknown. Based on the biochemical profile of 717 individuals including 213 children with ASD, 128 unaffected siblings and 376 parents and other relatives, we estimated the heritability of whole-blood serotonin, platelet N-acetylserotonin (NAS) and plasma melatonin levels, as well as the two enzymes arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT) activities measured in platelets. Overall, heritability was higher for NAS (0.72 ± 0.091) and ASMT (0.59 ± 0.097) compared with serotonin (0.31 ± 0.078), AANAT (0.34 ± 0.077) and melatonin (0.22 ± 0.071). Bivariate analyses showed high phenotypic and genetic correlations between traits of the second step of the metabolic pathway (NAS, ASMT and melatonin) indicating the contribution of shared genetic factors. A better knowledge of the heritability of the melatonin synthesis variability constitutes an important step to identify the factors that perturb this pathway in individuals with ASD.

Genetic Deletion of Akt3 Induces an Endophenotype Reminiscent of Psychiatric Manifestations in Mice

PubMed Central

Bergeron, Yan; Bureau, Geneviève; Laurier-Laurin, Marie-Élaine; Asselin, Eric; Massicotte, Guy; Cyr, Michel

2017-01-01

The protein kinase B (PKB/Akt), found in three distinctive isoforms (PKBα/Akt1, PKBβ/Akt2, PKBγ/Akt3), is implicated in a variety of cellular processes such as cell development, growth and survival. Although Akt3 is the most expressed isoform in the brain, its role in cerebral functions is still unclear. In the present study, we investigated the behavioral, electrophysiological and biochemical consequences of Akt3 deletion in mice. Motor abilities, spatial navigation, recognition memory and LTP are intact in the Akt3 knockout (KO) mice. However, the prepulse inhibition, three-chamber social, forced swim, tail suspension, open field, elevated plus maze and light-dark transition tests revealed an endophenotype reminiscent of psychiatric manifestations such as schizophrenia, anxiety and depression. Biochemical investigations revealed that Akt3 deletion was associated with reduced levels of phosphorylated GSK3α/β at serine 21/9 in several brain regions, although Akt1 and Akt2 levels were unaffected. Notably, chronic administration of lithium, a mood stabilizer, restored the decreased phosphorylated GSK3α/β levels and rescued the depressive and anxiety-like behaviors in the Akt3 KO mice. Collectively, our data suggest that Akt3 might be a critical molecule underlying psychiatric-related behaviors in mice. PMID:28442992

Cortical asymmetries in unaffected siblings of patients with obsessive-compulsive disorder.

PubMed

Peng, Ziwen; Li, Gang; Shi, Feng; Shi, Changzheng; Yang, Qiong; Chan, Raymond C K; Shen, Dinggang

2015-12-30

Obsessive-compulsive disorder (OCD) is considered to be associated with atypical brain asymmetry. However, no study has examined the asymmetry in OCD from the perspective of cortical morphometry. This study is aimed to describe the characteristics of cortical asymmetry in OCD patients, and to investigate whether these features exist in their unaffected siblings - a vital step in identifying putative endophenotypes for OCD. A total of 48 subjects (16 OCD patients, 16 unaffected siblings, and 16 matched controls) were recruited who had complete magnetic resonance imaging scans. Left-right hemispheric asymmetries of cortical thickness were measured using a surface-based threshold-free cluster enhancement method. OCD patients and siblings both showed leftward asymmetries of cortical thickness in the anterior cingulate cortex (ACC), which showed a significant positive correlation with compulsive subscale scores. In addition, siblings and healthy controls showed significantly decreased leftward asymmetries in the orbitofrontal cortex (OFC), and the decreased leftward bias in the OFC was accompanied by lower scales on the Yale-Brown Obsessive-Compulsive Scale. To sum up, leftward asymmetries of cortical thickness in the ACC may represent an endophenotype of increased hereditary risk for OCD, while decreased leftward asymmetries of cortical thickness in the OFC may represent a protective factor. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.

PubMed

Kauwe, John S K; Bailey, Matthew H; Ridge, Perry G; Perry, Rachel; Wadsworth, Mark E; Hoyt, Kaitlyn L; Staley, Lyndsay A; Karch, Celeste M; Harari, Oscar; Cruchaga, Carlos; Ainscough, Benjamin J; Bales, Kelly; Pickering, Eve H; Bertelsen, Sarah; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2014-10-01

Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.

Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes

PubMed Central

2014-01-01

Background We previously performed systematic association studies of glutamate receptor gene family members with schizophrenia, and found positive associations of polymorphisms in the GRM3 (a gene of metabotropic glutamate receptor 3: mGluR3) with the disorder. Physiological roles of GRM3 in brain functions and its functional roles in the pathogenesis of schizophrenia remain to be resolved. Results We generated mGluR3 knockout (KO) mice and conducted comprehensive behavioral analyses. KO mice showed hyperactivity in the open field, light/dark transition, and 24-hour home cage monitoring tests, impaired reference memory for stressful events in the Porsolt forced swim test, impaired contextual memory in cued and contextual fear conditioning test, and impaired working memory in the T-Maze forced alternation task test. Hyperactivity and impaired working memory are known as endophenotypes of schizophrenia. We examined long-term synaptic plasticity by assessing long-term potentiation (LTP) in the CA1 region in the hippocampi of KO and wild-type (WT) mice. We observed no differences in the amplitude of LTP between the two genotypes, suggesting that mGluR3 is not essential for LTP in the CA1 region of the mouse hippocampus. As hyperactivity is typically associated with increased dopaminergic transmission, we performed in vivo microdialysis measurements of extracellular dopamine in the nucleus accumbens of KO and WT mice. We observed enhancements in the methamphetamine (MAP)-induced release of dopamine in KO mice. Conclusions These results demonstrate that a disturbance in the glutamate-dopamine interaction may be involved in the pathophysiology of schizophrenia-like behavior, such as hyperactivity in mGluR3 KO mice. PMID:24758191

Increased reaction time variability in attention-deficit hyperactivity disorder as a response-related phenomenon: evidence from single-trial event-related potentials.

PubMed

Saville, Christopher W N; Feige, Bernd; Kluckert, Christian; Bender, Stephan; Biscaldi, Monica; Berger, Andrea; Fleischhaker, Christian; Henighausen, Klaus; Klein, Christoph

2015-07-01

Increased intra-subject variability (ISV) in reaction times (RTs) is a promising endophenotype for attention-deficit hyperactivity disorder (ADHD) and among the most robust hallmarks of the disorder. ISV has been assumed to represent an attentional deficit, either reflecting lapses in attention or increased neural noise. Here, we use an innovative single-trial event-related potential approach to assess whether the increased ISV associated with ADHD is indeed attributable to attention, or whether it is related to response-related processing. We measured electroencephalographic responses to working memory oddball tasks in patients with ADHD (N = 20, aged 11.3 ± 1.1) and healthy controls (N = 25, aged 11.7 ± 1.1), and analysed these data with a recently developed method of single-trial event-related potential analysis. Estimates of component latency variability were computed for the stimulus-locked and response-locked forms of the P3b and the lateralised readiness potential (LRP). ADHD patients showed significantly increased ISV in behavioural ISV. This increased ISV was paralleled by an increase in variability in response-locked event-related potential latencies, while variability in stimulus-locked latencies was equivalent between groups. This result held across the P3b and LRP. Latency of all components predicted RTs on a single-trial basis, confirming that all were relevant for speed of processing. These data suggest that the increased ISV found in ADHD could be associated with response-end, rather than stimulus-end processes, in contrast to prevailing conceptions about the endophenotype. This mental chronometric approach may also be useful for exploring whether the existing lack of specificity of ISV to particular psychiatric conditions can be improved upon. © 2014 Association for Child and Adolescent Mental Health.

Schizophrenia and Depression Co-Morbidity: What We have Learned from Animal Models

PubMed Central

Samsom, James N.; Wong, Albert H. C.

2015-01-01

Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of CUB and SUSHI multiple domains 1, PDZ and LIM domain 5, glutamate Delta 1 receptor, diabetic db/db mice, neuropeptide Y, disrupted in schizophrenia 1, and its interacting partners, reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia. PMID:25762938

Obsessive-compulsive disorder: Insights from animal models☆

PubMed Central

Szechtman, Henry; Ahmari, Susanne E.; Beninger, Richard J.; Eilam, David; Harvey, Brian H.; Edemann-Callesen, Henriette; Winter, Christine

2017-01-01

Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests. PMID:27168347

[Association of kynurenine-3-monooxygenase gene with schizophrenia].

PubMed

Golimbet, V E; Lezheiko, T V; Alfimova, M V; Abramova, L I; Kondrat'ev, N V

2014-06-01

Neurotoxic products produced during tryptophan metabolism via the kynurenine pathway could be involved in schizophrenia pathogenesis. It has been shown that kynurenine-3-monooxygenase (KMO) is indirectly involved in these products' formation. KMO polymorphic loci rs2275163 (C/T) and rs1053230 (A/G) were examined in 187 schizophrenia patients and 229 healthy subjects. A genetic combination of allele T and genotype GG was observed more often in a patient group compared with healthy controls (p = 0.003, OR 2.0 (95% CI 1.2-2.9). In the latter group, this combination was associated with schizophrenia endophenotype (p = 0.04), which manifested in a higher expression of schizotypal personality traits assessed using the MMPI test.

Group and site differences on the California Verbal Learning Test in persons with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia (COGS).

PubMed

Stone, William S; Giuliano, Anthony J; Tsuang, Ming T; Braff, David L; Cadenhead, Kristin S; Calkins, Monica E; Dobie, Dorcas J; Faraone, Stephen V; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Mintz, Jim; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Roe, Andrea H; Schork, Nicholas J; Siever, Larry J; Silverman, Jeremy M; Swerdlow, Neal R; Thomas, Alison R; Tsuang, Debby W; Turetsky, Bruce I; Seidman, Larry J

2011-05-01

Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

[Posttraumatic stress disorder endophenotypes: several clinical dimensions for specific treatments].

PubMed

Auxéméry, Y

2012-01-01

Posttraumatic stress disorder is a syndrome with a very complex clinical that it is useful to describe according to a multidimensional approach. Following a critical review of the international literature, we have been able to highlight the genetic supports of posttraumatic stress disorder in the perspective of returning to the source of the clinical of this syndrome in order to steer its treatment better. We consider in succession the neuromodulation pathways involving dopamine, serotonine and noradrenaline to describe the hyperdomaminergic, hyposerotoninergic and hypernoradrenergic endophenotypes of posttraumatic stress disorder. Neurogenetic studies have affirmed two essential proposals. On the one hand, the pharmacological treatment of psychotraumatic disorders can be very closely adjusted to the different endophenotypes. On the other hand, the psychotherapeutic approach retains all its importance in the sense that it is the subjective implication that generated the trauma, subjectivity interacting with a genetic heritage and environmental factors integrating a social context. The changing definition of posttraumatic stress disorder over time comes from scientific exploration in part determined by a sociocultural context and, reciprocally, the psychic trauma is caused by the collapse of reassuring social values which were considered as immutable. The clinical is not developed according to fixed references: the evolution of neurogenetic techniques changes our perception of psychic traumas and the therapeutic possibilities.

Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

PubMed

Schulze-Rauschenbach, Svenja; Lennertz, Leonhard; Ruhrmann, Stephan; Petrovsky, Nadine; Ettinger, Ulrich; Pukrop, Ralf; Dreher, Jan; Klosterkötter, Joachim; Maier, Wolfgang; Wagner, Michael

2015-12-30

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Disentangling the adult attention-deficit hyperactivity disorder endophenotype: parametric measurement of attention.

PubMed

Finke, Kathrin; Schwarzkopf, Wolfgang; Müller, Ulrich; Frodl, Thomas; Müller, Hermann J; Schneider, Werner X; Engel, Rolf R; Riedel, Michael; Möller, Hans-Jürgen; Hennig-Fast, Kristina

2011-11-01

Attention deficit hyperactivity disorder (ADHD) persists frequently into adulthood. The decomposition of endophenotypes by means of experimental neuro-cognitive assessment has the potential to improve diagnostic assessment, evaluation of treatment response, and disentanglement of genetic and environmental influences. We assessed four parameters of attentional capacity and selectivity derived from simple psychophysical tasks (verbal report of briefly presented letter displays) and based on a "theory of visual attention." These parameters are mathematically independent, quantitative measures, and previous studies have shown that they are highly sensitive for subtle attention deficits. Potential reductions of attentional capacity, that is, of perceptual processing speed and working memory storage capacity, were assessed with a whole report paradigm. Furthermore, possible pathologies of attentional selectivity, that is, selection of task-relevant information and bias in the spatial distribution of attention, were measured with a partial report paradigm. A group of 30 unmedicated adult ADHD patients and a group of 30 demographically matched healthy controls were tested. ADHD patients showed significant reductions of working memory storage capacity of a moderate to large effect size. Perceptual processing speed, task-based, and spatial selection were unaffected. The results imply a working memory deficit as an important source of behavioral impairments. The theory of visual attention parameter working memory storage capacity might constitute a quantifiable and testable endophenotype of ADHD.

Is attention to detail a similarly strong candidate endophenotype for anorexia nervosa and bulimia nervosa?

PubMed

Roberts, Marion E; Tchanturia, Kate; Treasure, Janet L

2013-08-01

To investigate whether attention to detail is a similarly strong candidate endophenotype of anorexia (AN) and bulimia nervosa (BN), and to explore the incidence and clinical correlates of attention to detail. A total of 266 women (including AN, BN, recovered AN, unaffected sisters of AN/BN & control women) undertook a thorough clinical assessment and were administered two neuropsychological measures of attention to detail (Group Embedded Figure Test; Rey-Osterrieth Complex Figure). Superior attention to detail was found across all AN groups including recovered AN and unaffected AN sisters. Those with BN and their unaffected sisters showed a profile more consistent with poor global integration. The combined effect of superior attention to detail and poor global integration ("weak coherence") was present in 42.3% of active cases and corresponded with a more severe illness, elevated obsessive-compulsive symptoms, and a higher likelihood of comorbid clinical anxiety and self-harm. Attention to detail is a stronger candidate endophenotype of AN compared to BN, where poor global integration may be more relevant. The unique contribution of both aspects of weak coherence (superior attention to detail/poor global integration) requires further exploration and understanding in both eating disorders. Integrating cognitive remediation of these traits into treatment for the subset of patients it is relevant for may improve outcome.

Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease.

PubMed

Nho, Kwangsik; Kim, Sungeun; Horgusluoglu, Emrin; Risacher, Shannon L; Shen, Li; Kim, Dokyoon; Lee, Seunggeun; Foroud, Tatiana; Shaw, Leslie M; Trojanowski, John Q; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2017-05-24

The APOE ε4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non-Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Aβ 1-42 (p < 1.0 × 10 -3 ). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Aβ 1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases.

Polygenic Risk for Schizophrenia Influences Cortical Gyrification in 2 Independent General Populations.

PubMed

Liu, Bing; Zhang, Xiaolong; Cui, Yue; Qin, Wen; Tao, Yan; Li, Jin; Yu, Chunshui; Jiang, Tianzi

2017-05-01

Schizophrenia is highly heritable, whereas the effect of each genetic variant is very weak. Since clinical heterogeneity and complexity of schizophrenia is high, considerable effort has been made to relate genetic variants to underlying neurobiological aspects of schizophrenia (endophenotypes). Given the polygenic nature of schizophrenia, our goal was to form a measure of additive genetic risk and explore its relationship to cortical morphology. Utilizing the data from a recent genome-wide association study that included nearly 37 000 cases of schizophrenia, we computed a polygenic risk score (PGRS) for each subject in 2 independent and healthy general populations. We then investigated the effect of polygenic risk for schizophrenia on cortical gyrification calculated from 3.0T structural imaging data in the discovery dataset (N = 315) and replication dataset (N = 357). We found a consistent effect of the polygenic risk for schizophrenia on cortical gyrification in the inferior parietal lobules in 2 independent general-population samples. A higher PGRS was significantly associated with a lower local gyrification index in the bilateral inferior parietal lobles, where case-control differences have been reported in previous studies on schizophrenia. Our findings strongly support the effectiveness of both PGRSs and endophenotypes in establishing the genetic architecture of psychiatry. Our findings may provide some implications regarding individual differences in the genetic risk for schizophrenia to cortical morphology and brain development. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk.

PubMed

Knowles, E E M; Huynh, K; Meikle, P J; Göring, H H H; Olvera, R L; Mathias, S R; Duggirala, R; Almasy, L; Blangero, J; Curran, J E; Glahn, D C

2017-06-01

The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated. In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range=3-80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD. We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD. This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chronic Pain and Chronic Stress: Two Sides of the Same Coin?

PubMed

Abdallah, Chadi G; Geha, Paul

2017-02-01

Pain and stress share significant conceptual and physiological overlaps. Both phenomena challenge the body's homeostasis and necessitate decision-making to help animals adapt to their environment. In addition, chronic stress and chronic pain share a common behavioral model of failure to extinguish negative memories. Yet, they also have discrepancies such that the final brain endophenotype of posttraumatic stress disorder, depression, and chronic pain appears to be different among the three conditions, and the role of the hypothalamic-pituitary-adrenal axis remains unclear in the physiology of pain. Persistence of either stress or pain is maladaptive and could lead to compromised well-being. In this brief review, we highlight the commonalities and differences between chronic stress and chronic pain, while focusing particularly on the central role of the limbic brain. We assess the current attempts in the field to conceptualize and understand chronic pain, within the context of knowledge gained from the stress literature. The limbic brain-including hippocampus, amygdala, and ventromedial pre-frontal cortex-plays a critical role in learning. These brain areas integrate incoming nociceptive or stress signals with internal state, and generate learning signals necessary for decision-making. Therefore, the physiological and structural remodeling of this learning circuitry is observed in conditions such as chronic pain, depression, and posttraumatic stress disorder, and is also linked to the risk of onset of these conditions.

Increased Cerebellar Functional Connectivity With the Default-Mode Network in Unaffected Siblings of Schizophrenia Patients at Rest

PubMed Central

Guo, Wenbin; Liu, Feng; Zhang, Zhikun; Liu, Guiying; Liu, Jianrong; Yu, Liuyu; Xiao, Changqing; Zhao, Jingping

2015-01-01

The default-mode network (DMN) is vital in the neurobiology of schizophrenia, and the cerebellum participates in the high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities remains unclear in unaffected siblings of schizophrenia patients. Forty-six unaffected siblings of schizophrenia patients and 46 healthy controls were recruited for a resting-state scan. The images were analyzed using the functional connectivity (FC) method. The siblings showed significantly increased FCs between the left Crus I and the left superior medial prefrontal cortex (MPFC), as well as between the lobule IX and the bilateral MPFC (orbital part) and right superior MPFC compared with the controls. No significantly decreased FC was observed in the siblings relative to the controls. The analyses were replicated in 49 first-episode, drug-naive patients with schizophrenia, and the results showed that the siblings and the patients shared increased FCs between the left Crus I and the left superior MPFC, as well as between the lobule IX and the left MPFC (orbital part) compared with the controls. These findings suggest that increased cerebellar-DMN connectivities emerge earlier than illness onset, which highlight the contribution of the cerebellum to the DMN alterations in unaffected siblings. The shared increased cerebellar-DMN connectivities between the patients and the siblings may be used as candidate endophenotypes for schizophrenia. PMID:25956897

Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample.

PubMed

Ojeda, Diego A; Forero, Diego A

2014-10-01

Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations.

Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.

PubMed

Carlisle, Holly J; Luong, Tinh N; Medina-Marino, Andrew; Schenker, Leslie; Khorosheva, Eugenia; Indersmitten, Tim; Gunapala, Keith M; Steele, Andrew D; O'Dell, Thomas J; Patterson, Paul H; Kennedy, Mary B

2011-11-09

Densin is an abundant scaffold protein in the postsynaptic density (PSD) that forms a high-affinity complex with αCaMKII and α-actinin. To assess the function of densin, we created a mouse line with a null mutation in the gene encoding it (LRRC7). Homozygous knock-out mice display a wide variety of abnormal behaviors that are often considered endophenotypes of schizophrenia and autism spectrum disorders. At the cellular level, loss of densin results in reduced levels of α-actinin in the brain and selective reduction in the localization of mGluR5 and DISC1 in the PSD fraction, whereas the amounts of ionotropic glutamate receptors and other prominent PSD proteins are unchanged. In addition, deletion of densin results in impairment of mGluR- and NMDA receptor-dependent forms of long-term depression, alters the early dynamics of regulation of CaMKII by NMDA-type glutamate receptors, and produces a change in spine morphology. These results indicate that densin influences the function of mGluRs and CaMKII at synapses and contributes to localization of mGluR5 and DISC1 in the PSD fraction. They are consistent with the hypothesis that mutations that disrupt the organization and/or dynamics of postsynaptic signaling complexes in excitatory synapses can cause behavioral endophenotypes of mental illness.

Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

PubMed Central

Watanabe, Akiko; Toyota, Tomoko; Owada, Yuji; Hayashi, Takeshi; Iwayama, Yoshimi; Matsumata, Miho; Ishitsuka, Yuichi; Nakaya, Akihiro; Maekawa, Motoko; Ohnishi, Tetsuo; Arai, Ryoichi; Sakurai, Katsuyasu; Yamada, Kazuo; Kondo, Hisatake; Hashimoto, Kenji; Osumi, Noriko; Yoshikawa, Takeo

2007-01-01

Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming. PMID:18001149

Mice Lacking the Circadian Modulators SHARP1 and SHARP2 Display Altered Sleep and Mixed State Endophenotypes of Psychiatric Disorders

PubMed Central

Shahmoradi, Ali; Reinecke, Lisa; Kroos, Christina; Wichert, Sven P.; Oster, Henrik; Wehr, Michael C.; Taneja, Reshma; Hirrlinger, Johannes; Rossner, Moritz J.

2014-01-01

Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2. PMID:25340473

Profiles of executive function in parents and siblings of individuals with autism spectrum disorders.

PubMed

Wong, D; Maybery, M; Bishop, D V M; Maley, A; Hallmayer, J

2006-11-01

Delineation of a cognitive endophenotype for autism is useful both for exploring the genetic mechanisms underlying the disorder and for identifying which cognitive traits may be primary to it. This study investigated whether first-degree relatives of individuals with autism spectrum disorders (ASDs) demonstrate a specific profile of performance on a range of components of executive function (EF), to determine whether EF deficits represent possible endophenotypes for autism. Parents and siblings of ASD and control probands were tested on EF tasks measuring planning, set-shifting, inhibition and generativity. ASD parents showed poorer performance than control parents on a test of ideational fluency or generativity, and ASD fathers demonstrated a weakness in set-shifting to a previously irrelevant dimension. ASD siblings revealed a mild reduction in ideational fluency and a weakness in non-verbal generativity when compared with control siblings. Neither ASD parents nor siblings displayed significant difficulties with planning or inhibition. These results indicated that the broad autism phenotype may not be characterized primarily by impairments in planning and cognitive flexibility, as had been previously proposed. Weaknesses in generativity emerged as stronger potential endophenotypes in this study, suggesting that this aspect of EF should play a central role in cognitive theories of autism. However, discrepancies in the EF profile demonstrated by parents and siblings suggest that factors related to age or parental responsibility may affect the precise pattern of deficits observed.

Grey matter, an endophenotype for schizophrenia? A voxel-based morphometry study in siblings of patients with schizophrenia.

PubMed

van der Velde, Jorien; Gromann, Paula M; Swart, Marte; de Haan, Lieuwe; Wiersma, Durk; Bruggeman, Richard; Krabbendam, Lydia; Aleman, André

2015-05-01

Grey matter, both volume and concentration, has been proposed as an endophenotype for schizophrenia given a number of reports of grey matter abnormalities in relatives of patients with schizophrenia. However, previous studies on grey matter abnormalities in relatives have produced inconsistent results. The aim of the present study was to examine grey matter differences between controls and siblings of patients with schizophrenia and to examine whether the age, genetic loading or subclinical psychotic symptoms of selected individuals could explain the previously reported inconsistencies. We compared the grey matter volume and grey matter concentration of healthy siblings of patients with schizophrenia and healthy controls matched for age, sex and education using voxel-based morphometry (VBM). Furthermore, we selected subsamples based on age (< 30 yr), genetic loading and subclinical psychotic symptoms to examine whether this would lead to different results. We included 89 siblings and 69 controls in our study. The results showed that siblings and controls did not differ significantly on grey matter volume or concentration. Furthermore, specifically selecting participants based on age, genetic loading or subclinical psychotic symptoms did not alter these findings. The main limitation was that subdividing the sample resulted in smaller samples for the subanalyses. Furthermore, we used MRI data from 2 different scanner sites. These results indicate that grey matter measured through VBM might not be a suitable endophenotype for schizophrenia.

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

PubMed

Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

2005-12-30

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

Recent considerations in the use of recombinant interferon gamma for biological therapy of atopic dermatitis.

PubMed

Brar, Kanwaljit; Leung, Donald Y M

2016-01-01

Atopic dermatitis (AD) is the most common inflammatory skin disease in the general population. There are different endophenotypes of AD that likely have a unique immune and molecular basis, such as those who are predisposed to eczema herpeticum, or Staphylococcus aureus infections. In this review, we highlight the endophenotypes of AD where reduced interferon gamma expression may be playing a role. Additionally, we review the potential role of recombinant interferon gamma therapy in the treatment of atopic dermatitis and the particular phenotypes that may benefit from this treatment. Recombinant interferon gamma treatment will likely benefit the pediatric population with AD, as well as those with susceptibilities for skin infections. Future studies are needed to elucidate whether IFN-γ may reduce the prevalence of skin infection in AD.

Differences in Neural Correlates of Speech Perception in 3 Month Olds at High and Low Risk for Autism Spectrum Disorder.

PubMed

Edwards, Laura A; Wagner, Jennifer B; Tager-Flusberg, Helen; Nelson, Charles A

2017-10-01

In this study, we investigated neural precursors of language acquisition as potential endophenotypes of autism spectrum disorder (ASD) in 3-month-old infants at high and low familial ASD risk. Infants were imaged using functional near-infrared spectroscopy while they listened to auditory stimuli containing syllable repetitions; their neural responses were analyzed over left and right temporal regions. While female low risk infants showed initial neural activation that decreased over exposure to repetition-based stimuli, potentially indicating a habituation response to repetition in speech, female high risk infants showed no changes in neural activity over exposure. This finding may indicate a potential neural endophenotype of language development or ASD specific to females at risk for the disorder.

Attention/Vigilance in Schizophrenia: Performance Results from a Large Multi-Site Study of the Consortium on the Genetics of Schizophrenia (COGS)

PubMed Central

Nuechterlein, Keith H.; Green, Michael F.; Calkins, Monica E.; Greenwood, Tiffany A.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Light, Gregory A.; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Sprock, Joyce; Stone, William S.; Sugar, Catherine A.; Swerdlow, Neal R.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Braff, David L.

2015-01-01

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from Phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT - Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d’) in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d’. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity. PMID:25749017

Attention/vigilance in schizophrenia: performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS).

PubMed

Nuechterlein, Keith H; Green, Michael F; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2015-04-01

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity. Copyright © 2015 Elsevier B.V. All rights reserved.

Personality traits as an endophenotype in genetic studies on suicidality in bipolar disorder.

PubMed

Pawlak, J; Dmitrzak-Węglarz, M; Maciukiewicz, M; Kapelski, P; Czerski, P; Leszczyńska-Rodziewicz, A; Zaremba, D; Hauser, J

2017-04-01

Introduction The influence of personality traits on suicidal behaviour risk has been well documented. Personality traits and suicidal behaviour are partially genetically determined and personality has been described as an endophenotype of suicidal behaviour. The aim of this study was to investigate a possible association between personality traits with suicidal behaviour and selected serotonergic gene polymorphisms. In the study we included 156 patients meeting DSM-IV criteria for bipolar disorder (BP) and 93 healthy controls. The personality dimensions were assessed using the Temperament and Character Inventory (TCI). We genotyped two selected polymorphisms of the tryptophan hydroxylase 1 (TPH1) gene (rs1800532 218A>C and rs1799913 779A>C) and polymorphism in the promoter region of serotonin transporter gene (5-HTTLPR, rs25531) related to serotoninergic neurotransmission. Multiple poisson regression, logistic regression and Kruskal-Wallis tests were applied. We found numerous differences between the BP patients and the control group in terms of their TCI dimensions/subdimensions. Significant differences were found between patients with, and without, suicidal attempts in fatigability and asthenia (Ha4), as well as in harm avoidance (Ha). We also found that the interactions between TCI subdimensions (the interaction of disordiness (Ns4) and spiritual acceptance (St3), disordiness (Ns4) and integrated conscience (C5), extravagance (Ns3) and resourcefulness (Sd3)) were significantly contributing for suicidal behaviour risk. We found association between all studied genetic polymorphisms and several TCI dimensions and subdimensions. Our results confirm that personality traits are partially determined by genes. Both personality traits and the interactions between temperament and character traits, may be helpful in predicting suicidal behaviour.

Why Some People Discount More than Others: Baseline Activation in the Dorsal PFC Mediates the Link between COMT Genotype and Impatient Choice

PubMed Central

Gianotti, Lorena R. R.; Figner, Bernd; Ebstein, Richard P.; Knoch, Daria

2012-01-01

Individuals differ widely in how steeply they discount future rewards. The sources of these stable individual differences in delay discounting (DD) are largely unknown. One candidate is the COMT Val158Met polymorphism, known to modulate prefrontal dopamine levels and affect DD. To identify possible neural mechanisms by which this polymorphism may contribute to stable individual DD differences, we measured 73 participants’ neural baseline activation using resting electroencephalogram (EEG). Such neural baseline activation measures are highly heritable and stable over time, thus an ideal endophenotype candidate to explain how genes may influence behavior via individual differences in neural function. After EEG-recording, participants made a series of incentive-compatible intertemporal choices to determine the steepness of their DD. We found that COMT significantly affected DD and that this effect was mediated by baseline activation level in the left dorsal prefrontal cortex (DPFC): (i) COMT had a significant effect on DD such that the number of Val alleles was positively correlated with steeper DD (higher numbers of Val alleles means greater COMT activity and thus lower dopamine levels). (ii) A whole-brain search identified a cluster in left DPFC where baseline activation was correlated with DD; lower activation was associated with steeper DD. (iii) COMT had a significant effect on the baseline activation level in this left DPFC cluster such that a higher number of Val alleles was associated with lower baseline activation. (iv) The effect of COMT on DD was explained by the mediating effect of neural baseline activation in the left DPFC cluster. Our study thus establishes baseline activation level in left DPFC as salient neural signature in the form of an endophenotype that mediates the link between COMT and DD. PMID:22586360

maLPA1-null mice as an endophenotype of anxious depression

PubMed Central

Moreno-Fernández, R D; Pérez-Martín, M; Castilla-Ortega, E; Rosell del Valle, C; García-Fernández, M I; Chun, J; Estivill-Torrús, G; Rodríguez de Fonseca, F; Santín, L J; Pedraza, C

2017-01-01

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1–6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression. PMID:28375206

maLPA1-null mice as an endophenotype of anxious depression.

PubMed

Moreno-Fernández, R D; Pérez-Martín, M; Castilla-Ortega, E; Rosell Del Valle, C; García-Fernández, M I; Chun, J; Estivill-Torrús, G; Rodríguez de Fonseca, F; Santín, L J; Pedraza, C

2017-04-04

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.

Understanding alcohol use disorders with neuroelectrophysiology

PubMed Central

RANGASWAMY, MADHAVI; PORJESZ, BERNICE

2015-01-01

Neurocognitive deficits associated with impairments in various brain regions and neural circuitries, particularly involving frontal lobes, have been associated with chronic alcoholism, as well as with a predisposition to develop alcohol use and related disorders (AUDs). AUD is a multifactorial disorder caused by complex interactions between behavioral, genetic, and environmental liabilities. Neuroelectrophysiological techniques are instrumental in understanding brain and behavior relationships and have also proved very useful in evaluating the genetic diathesis of alcoholism. This chapter describes findings from neuroelectrophysiological measures (electroencephalogram, event-related potentials, and event-related oscillations) related to acute and chronic effects of alcohol on the brain and those that reflect underlying deficits related to a predisposition to develop AUDs and related disorders. The utility of these measures as effective endophenotypes to identify and understand genes associated with brain electrophysiology, cognitive networks, and AUDs has also been discussed. PMID:25307587

Variants in Adjacent Oxytocin/Vasopressin Gene Region and Associations with ASD Diagnosis and Other Autism Related Endophenotypes.

PubMed

Francis, Sunday M; Kistner-Griffin, Emily; Yan, Zhongyu; Guter, Stephen; Cook, Edwin H; Jacob, Suma

2016-01-01

There has been increasing interest in oxytocin (peptide: OT, gene: OXT) as a treatment pathway for neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). Neurodevelopmental disorders affect functional, social, and intellectual abilities. With advances in molecular biology, research has connected multiple gene regions to the clinical presentation of ASD. Studies have also shown that the neuropeptide hormones OT and arginine vasopressin (AVP) influence mammalian social and territorial behaviors and may have treatment potential for neurodevelopmental disorders. Published data examining molecular and phenotypic variation in ASD, such as cognitive abilities, are limited. Since most studies have focused on the receptors in the OT-AVP system, we investigated genetic variation within peptide genes for association with phenotypic ASD features that help identify subgroups within the spectrum. In this study, TDT analysis was carried out utilizing FBAT in 207 probands (156 trios) and a European Ancestry (EA) subsample (108 trios).The evolutionarily related and adjacent genes of OXT and AVP were studied for associations between the tagged single nucleotide polymorphisms and ASD diagnosis, social abilities, restrictive and repetitive behaviors, and IQ for cognitive abilities. Additionally, relationships with whole blood serotonin (WB5HT) were explored because of the developmental relationships connecting plasma levels of OT and WB5HT within ASD. RESULTS indicate significant association between OXT rs6084258 (p = 0.001) and ASD. Associations with several endophenotypes were also noted: OXT rs6133010 was associated with IQ (full scale IQ, p = 0.008; nonverbal IQ, p = 0.010, verbal IQ, p = 0.006); and OXT rs4813625 and OXT rs877172 were associated with WB5HT levels (EA, p = 0.027 and p = 0.033, respectively). Additionally, we measured plasma OT (pOT) levels in a subsample (N = 54). RESULTS show the three polymorphisms, OXT rs6084258, OXT rs11697250, and OXT rs877172, have significant association with pOT (EA, p = 0.011, p = 0.010, and p = 0.002, respectively). These findings suggest that SNPs near OXT and AVP are associated with diagnosis of ASD, social behaviors, restricted and repetitive behaviors, IQ, pOT, and WB5HT. Future studies need to replicate these findings and examine gene-interactions in other neurodevelopmental disorders. Mechanisms of action may influence early social and cognitive development that may or may not be limited to ASD diagnosis.

A depressive endophenotype of mild cognitive impairment and Alzheimer's disease.

PubMed

Johnson, Leigh A; Hall, James R; O'Bryant, Sid E

2013-01-01

Alzheimer's disease (AD) is a devastating public health problem that affects over 5.4 million Americans. Depression increases the risk of Mild Cognitive Impairment (MCI) and AD. By understanding the influence of depression on cognition, the potential exists to identify subgroups of depressed elders at greater risk for cognitive decline and AD. The current study sought to: 1) clinically identify a sub group of geriatric patients who suffer from depression related cognitive impairment; 2) cross validate this depressive endophenotype of MCI/AD in an independent cohort. Data was analyzed from 519 participants of Project FRONTIER. Depression was assessed with the GDS30 and cognition was assessed using the EXIT 25 and RBANS. Five GDS items were used to create the Depressive endophenotype of MCI and AD (DepE). DepE was significantly negatively related to RBANS index scores of Immediate Memory (B=-2.22, SE=.37, p<0.001), visuospatial skills (B=-1.11, SE=0.26, p<0.001), Language (B=-1.03, SE=0.21, p<0.001), Attention (B=-2.56, SE=0.49, p<0.001), and Delayed Memory (B=-1.54, SE = 037, p<0.001), and higher DepE scores were related to poorer executive functioning (EXIT25; B=0.65, SE=0.19, p=0.001). DepE scores significantly increased risk for MCI diagnosis (odds ratio [OR] = 2.04; 95% CI=1.54-2.69). Data from 235 participants in the TARCC (Texas Alzheimer's Research & Care Consortium) were analyzed for cross-validation of findings in an independent cohort. The DepE was significantly related to poorer scores on all measures, and a significantly predicted of cognitive change over 12- and 24-months. The current findings suggest that a depressive endophenotype of MCI and AD exists and can be clinically identified using the GDS-30. Higher scores increased risk for MCI and was cross-validated by predicting AD in the TARCC. A key purpose for the search for distinct subgroups of individuals at risk for AD and MCI is to identify novel treatment and preventative opportunities.

Grey matter, an endophenotype for schizophrenia? A voxel-based morphometry study in siblings of patients with schizophrenia

PubMed Central

van der Velde, Jorien; Gromann, Paula M.; Swart, Marte; de Haan, Lieuwe; Wiersma, Durk; Bruggeman, Richard; Krabbendam, Lydia; Aleman, André

2015-01-01

Background Grey matter, both volume and concentration, has been proposed as an endophenotype for schizophrenia given a number of reports of grey matter abnormalities in relatives of patients with schizophrenia. However, previous studies on grey matter abnormalities in relatives have produced inconsistent results. The aim of the present study was to examine grey matter differences between controls and siblings of patients with schizophrenia and to examine whether the age, genetic loading or subclinical psychotic symptoms of selected individuals could explain the previously reported inconsistencies. Methods We compared the grey matter volume and grey matter concentration of healthy siblings of patients with schizophrenia and healthy controls matched for age, sex and education using voxel-based morphometry (VBM). Furthermore, we selected subsamples based on age (< 30 yr), genetic loading and subclinical psychotic symptoms to examine whether this would lead to different results. Results We included 89 siblings and 69 controls in our study. The results showed that siblings and controls did not differ significantly on grey matter volume or concentration. Furthermore, specifically selecting participants based on age, genetic loading or subclinical psychotic symptoms did not alter these findings. Limitations The main limitation was that subdividing the sample resulted in smaller samples for the subanalyses. Furthermore, we used MRI data from 2 different scanner sites. Conclusion These results indicate that grey matter measured through VBM might not be a suitable endophenotype for schizophrenia. PMID:25768029

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

PubMed Central

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Del-Aguila, Jorge L.; Fernandez, Maria Victoria; Carrell, David; Black, Kathleen; Budde, John; Ma, ShengMei; Saef, Benjamin; Howells, Bill; Bertelsen, Sarah; Bailey, Matthew; Ridge, Perry G.; Hefti, Franz; Fillit, Howard; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Carrillo, Maria; Fleisher, Adam; Reeder, Stephanie; Trncic, Nadira; Burke, Anna; Tariot, Pierre; Reiman, Eric M.; Chen, Kewei; Sabbagh, Marwan N.; Beiden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Green, Robert C.; Marshall, Gad; Johnson, Keith A.; Sperling, Reisa A.; Snyder, Peter; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Bernick, Charles; Munic, Donna; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Relkin, Norman; Chaing, Gloria; Ravdin, Lisa; Paul, Steven; Flashman, Laura A.; Seltzer, Marc; Hynes, Mary L.; Santulli, Robert B.; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Friedl, Karl; Murali Doraiswamy, P.; Petrella, Jeffrey R.; Borges-Neto, Salvador; James, Olga; Wong, Terence; Coleman, Edward; Schwartz, Adam; Cellar, Janet S.; Levey, Allan L.; Lah, James J.; Behan, Kelly; Scott Turner, Raymond; Johnson, Kathleen; Reynolds, Brigid; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Obisesan, Thomas O.; Wolday, Saba; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Tatsuoka, Curtis; Fatica, Parianne; Farlow, Martin R.; Saykin, Andrew J.; Foroud, Tatiana M.; Shen, Li; Faber, Kelly; Kim, Sungeun; Nho, Kwangsik; Marie Hake, Ann; Matthews, Brandy R.; Brosch, Jared R.; Herring, Scott; Hunt, Cynthia; Albert, Marilyn; Onyike, Chiadi; D’Agostino, Daniel; Kielb, Stephanie; Graff-Radford, Neill R; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Petersen, Ronald; Jack, Clifford R.; Bernstein, Matthew; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Chertkow, Howard; Hosein, Chris; Mintzer, Jacob; Spicer, Kenneth; Bachman, David; Grossman, Hillel; Mitsis, Effie; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Potter, William; Buckholtz, Neil; Hsiao, John; Kittur, Smita; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Pogorelec, Dana M.; Rusinek, Henry; de Leon, Mony J; Glodzik, Lidia; De Santi, Susan; Johnson, Nancy; Chuang-Kuo; Kerwin, Diana; Bonakdarpour, Borna; Weintraub, Sandra; Grafman, Jordan; Lipowski, Kristine; Mesulam, Marek-Marsel; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Kaye, Jeffrey; Quinn, Joseph; Silbert, Lisa; Lind, Betty; Carter, Raina; Dolen, Sara; Borrie, Michael; Lee, T-Y; Bartha, Rob; Martinez, Walter; Villena, Teresa; Sadowsky, Carl; Khachaturian, Zaven; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Frank, Richard; Fleischman, Debra; Arfanakis, Konstantinos; Shah, Raj C.; deToledo-Morrell, Leyla; Sorensen, Greg; Finger, Elizabeth; Pasternack, Stephen; Rachinsky, Irina; Drost, Dick; Rogers, John; Kertesz, Andrew; Furst, Ansgar J.; Chad, Stevan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Robin Hsiung, Ging-Yuek; Mudge, Benita; Assaly, Michele; Fox, Nick; Schultz, Susan K.; Boles Ponto, Laura L.; Shim, Hyungsub; Ekstam Smith, Karen; Burns, Jeffrey M.; Swerdlow, Russell H.; Brooks, William M.; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Natelson Love, Marissa; DeCarli, Charles; Carmichael, Owen; Olichney, John; Maillard, Pauline; Fletcher, Evan; Nguyen, Dana; Preda, Andrian; Potkin, Steven; Mulnard, Ruth A.; Thai, Gaby; McAdams-Ortiz, Catherine; Landau, Susan; Jagust, William; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H.S.; Lu, Po H.; Bartzokis, George; Thompson, Paul; Donohue, Michael; Thomas, Ronald G.; Walter, Sarah; Gessert, Devon; Brewer, James; Vanderswag, Helen; Sather, Tamie; Jiminez, Gus; Balasubramanian, Archana B.; Mason, Jennifer; Sim, Iris; Aisen, Paul; Davis, Melissa; Morrison, Rosemary; Harvey, Danielle; Thal, Lean; Beckett, Laurel; Neylan, Thomas; Finley, Shannon; Weiner, Michael W.; Hayes, Jacqueline; Rosen, Howard J.; Miller, Bruce L.; Perry, David; Massoglia, Dino; Brawman-Mentzer, Olga; Schuff, Norbert; Smith, Charles D.; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Koeppe, Robert A.; Lord, Joanne L.; Heidebrink, Judith L.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Clark, Christopher M.; Trojanowki, John Q.; Shaw, Leslie M.; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Foster, Norm; Montine, Tom; Fruehling, J. Jay; Harding, Sandra; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Petrie, Eric C.; Peskind, Elaine; Li, Gail; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Smith, Amanda; Ashok Raj, Balebail; Fargher, Kristin; Kuller, Lew; Mathis, Chet; Ann Oakley, Mary; Lopez, Oscar L.; Simpson, Donna M.; Sink, Kaycee M.; Gordineer, Leslie; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Cairns, Nigel J.; Raichle, Marc; Morris, John C.; Householder, Erin; Taylor-Reinwald, Lisa; Holtzman, David; Ances, Beau; Carroll, Maria; Creech, Mary L.; Franklin, Erin; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Varma, Pradeep; MacAvoy, Martha G.; Carson, Richard E.; van Dyck, Christopher H.; Davies, Peter; Holtzman, David; Morris, John C.; Bales, Kelly; Pickering, Eve H.; Lee, Jin-Moo; Heitsch, Laura; Kauwe, John; Goate, Alison; Piccio, Laura; Cruchaga, Carlos

2016-01-01

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.

Autism Tendencies and Psychosis Proneness Interactively Modulate Saliency Cost

PubMed Central

Abu-Akel, Ahmad; Apperly, Ian A.; Wood, Stephen J.; Hansen, Peter C.; Mevorach, Carmel

2017-01-01

Atypical responses to salient information are a candidate endophenotype for both autism and psychosis spectrum disorders. The present study investigated the costs and benefits of such atypicalities for saliency-based selection in a large cohort of neurotypical adults in whom both autism and psychosis expressions were assessed. Two experiments found that autism tendencies and psychosis proneness interactively modulated the cost incurred in the presence of a task-irrelevant salient distractor. Specifically, expressions of autism and psychosis had opposing effects on responses to salient information such that the benefits associated with high expressions for autism offset costs associated with high expressions for psychosis. The opposing influences observed on saliency cost may be driven by distinct attentional mechanisms that are differentially affected by expressions for autism and psychosis. PMID:27217269

Advances in Electrophysiological Research

PubMed Central

Kamarajan, Chella; Porjesz, Bernice

2015-01-01

Electrophysiological measures of brain function are effective tools to understand neurocognitive phenomena and sensitive indicators of pathophysiological processes associated with various clinical conditions, including alcoholism. Individuals with alcohol use disorder (AUD) and their high-risk offspring have consistently shown dysfunction in several electrophysiological measures in resting state (i.e., electroencephalogram) and during cognitive tasks (i.e., event-related potentials and event-related oscillations). Researchers have recently developed sophisticated signal-processing techniques to characterize different aspects of brain dynamics, which can aid in identifying the neural mechanisms underlying alcoholism and other related complex disorders. These quantitative measures of brain function also have been successfully used as endophenotypes to identify and help understand genes associated with AUD and related disorders. Translational research also is examining how brain electrophysiological measures potentially can be applied to diagnosis, prevention, and treatment. PMID:26259089

Heterogeneity in brain reactivity to pleasant and food cues: evidence of sign-tracking in humans

PubMed Central

Versace, Francesco; Kypriotakis, George; Basen-Engquist, Karen

2016-01-01

Aberrant brain reward responses to food-related cues are an implied characteristic of human obesity; yet, findings are inconsistent. To explain these inconsistencies, we aimed to uncover endophenotypes associated with heterogeneity in attributing incentive salience to food cues in the context of other emotionally salient cues; a phenomenon described as sign- vs goal tracking in preclinical models. Data from 64 lean and 88 obese adults who were 35.5 ± 9.4 years old and predominantly women (79%) were analyzed. Participants viewed food-related, pleasant, neutral and unpleasant images while recording electroencephalograph. Late positive potentials were used to assess incentive salience attributed to the visual stimuli. Eating and affective traits were also assessed. Findings demonstrated that obese individuals, in general, do not demonstrate aberrant brain reward responses to food-related cues. As hypothesized, latent profile analysis of the late positive potential uncovered two distinct groups. ‘Sign-trackers’ showed greater responses to food-related cues (P < 0.001) but lower responses to pleasant stimuli (P < 0.001) compared with ‘goal-trackers’. There were proportionally more obese than lean ‘sign-trackers’ (P = 0.03). Obese ‘sign-trackers’ reported significantly higher levels of emotional eating and food craving (P < 0.001). By examining the heterogeneity in brain reactivity to various emotional stimuli, this translational study highlights the need to consider important neurobehavioral endophenotypes of obesity. PMID:26609106

Risk for bipolar disorder is associated with face-processing deficits across emotions.

PubMed

Brotman, Melissa A; Skup, Martha; Rich, Brendan A; Blair, Karina S; Pine, Daniel S; Blair, James R; Leibenluft, Ellen

2008-12-01

Youths with euthymic bipolar disorder (BD) have a deficit in face-emotion labeling that is present across multiple emotions. Recent research indicates that youths at familial risk for BD, but without a history of mood disorder, also have a deficit in face-emotion labeling, suggesting that such impairments may be an endophenotype for BD. It is unclear whether this deficit in at-risk youths is present across all emotions or if the impairment presents initially as an emotion-specific dysfunction that then generalizes to other emotions as the symptoms of BD become manifest. Thirty-seven patients with pediatric BD, 25 unaffected children with a first-degree relative with BD, and 36 typically developing youths were administered the Emotional Expression Multimorph Task, a computerized behavioral task, which presents gradations of facial emotions from 100% neutrality to 100% emotional expression (happiness, surprise, fear, sadness, anger, and disgust). Repeated-measures analysis of covariance revealed that, compared with the control youths, the patients and the at-risk youths required significantly more intense emotional information to identify and correctly label face emotions. The patients with BD and the at-risk youths did not differ from each other. Group-by-emotion interactions were not significant, indicating that the group effects did not differ based on the facial emotion. The youths at risk for BD demonstrate nonspecific deficits in face-emotion recognition, similar to patients with the illness. Further research is needed to determine whether such deficits meet all the criteria for an endophenotype.

Differences in saccadic eye movements in subjects at high and low risk for panic disorder.

PubMed

Zwanzger, Peter; Bradwejn, Jacques; Diemer, Julia; Marshall, Roger W; Koszycki, Diana

2012-01-01

Panic disorder (PD) has a strong genetic component showing high heritability rates and familial aggregation. Moreover, there is evidence for associations between parental PD and patterns of psychopathology. So far, little is known about possible endophenotypes representing premorbid vulnerability markers in high-risk subjects for PD. In the present study, we investigated saccadic eye movement (SEM) as an index of CNS inhibitory function in subjects at high risk for PD. 132 healthy children at high and low familial risk for PD were included in the study. Basal SEM parameters were obtained using an electro-oculography (EOG) based system measuring peak saccadic eye velocity (pSEV), latency and accuracy. Moreover, with regard to self rating scales, state-trait-anxiety (STAI-C), childhood behavioral inhibition (CSRI), and anxiety sensitivity (CASI) were assessed. There was a significant overall difference for basal SEM parameters across groups as revealed by MANCOVA (F7,118=2.184, p=.040). A significant influence was found for the covariate age, while gender and puberty status had no influence on SEM. High-risk (HR) subjects showed significantly lower pSEV. Moreover, levels of state and trait anxiety were higher in HR children (F1=5.429, p=.021). In our sample, measurement of pSEV allowed discrimination between children at high and low risk for PD. Since these results argue for possible alterations of saccadic function in high risk subjects, differences in underlying neurobiological mechanisms might be discussed as a possible endophenotype of PD.

Genetics of impulsive behaviour

PubMed Central

Bevilacqua, Laura; Goldman, David

2013-01-01

Impulsivity, defined as the tendency to act without foresight, comprises a multitude of constructs and is associated with a variety of psychiatric disorders. Dissecting different aspects of impulsive behaviour and relating these to specific neurobiological circuits would improve our understanding of the etiology of complex behaviours for which impulsivity is key, and advance genetic studies in this behavioural domain. In this review, we will discuss the heritability of some impulsivity constructs and their possible use as endophenotypes (heritable, disease-associated intermediate phenotypes). Several functional genetic variants associated with impulsive behaviour have been identified by the candidate gene approach and re-sequencing, and whole genome strategies can be implemented for discovery of novel rare and common alleles influencing impulsivity. Via deep sequencing an uncommon HTR2B stop codon, common in one population, was discovered, with implications for understanding impulsive behaviour in both humans and rodents and for future gene discovery. PMID:23440466

Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

PubMed Central

Gogtay, Nitin; Hua, Xue; Stidd, Reva; Boyle, Christina P.; Lee, Suh; Weisinger, Brian; Chavez, Alex; Giedd, Jay N.; Clasen, Liv; Toga, Arthur W.; Rapoport, Judith L.; Thompson, Paul M.

2013-01-01

Context Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. Objective To study WM growth differences in non-psychotic siblings of patients with COS. Design Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. Setting National Institutes of Health Clinical Center, Bethesda, Maryland. Participants Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1[5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9[5.3] years; 29 male, 28 female). Intervention Magnetic resonance imaging. Main Outcome Measure White matter growth rates. Results We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P =.004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. Conclusions In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age. PMID:22945617

Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder.

PubMed

Kim, Bung-Nyun; Kim, Jae-Won; Cummins, Tarrant D R; Bellgrove, Mark A; Hawi, Ziarih; Hong, Soon-Beom; Yang, Young-Hui; Kim, Hyo-Jin; Shin, Min-Sup; Cho, Soo-Churl; Kim, Ji-Hoon; Son, Jung-Woo; Shin, Yun-Mi; Chung, Un-Sun; Han, Doug-Hyun

2013-06-01

Noradrenergic dysfunction may be associated with cognitive impairments in attention-deficit/hyperactivity disorder (ADHD), including increased response time variability, which has been proposed as a leading endophenotype for ADHD. The aim of this study was to examine the relationship between polymorphisms in the α-2A-adrenergic receptor (ADRA2A) and norepinephrine transporter (SLC6A2) genes and attentional performance in ADHD children before and after pharmacological treatment.One hundred one medication-naive ADHD children were included. All subjects were administered methylphenidate (MPH)-OROS for 12 weeks. The subjects underwent a computerized comprehensive attention test to measure the response time variability at baseline before MPH treatment and after 12 weeks. Additive regression analyses controlling for ADHD symptom severity, age, sex, IQ, and final dose of MPH examined the association between response time variability on the comprehensive attention test measures and allelic variations in single-nucleotide polymorphisms of the ADRA2A and SLC6A2 before and after MPH treatment.Increasing possession of an A allele at the G1287A polymorphism of SLC6A2 was significantly related to heightened response time variability at baseline in the sustained (P = 2.0 × 10) and auditory selective attention (P = 1.0 × 10) tasks. Response time variability at baseline increased additively with possession of the T allele at the DraI polymorphism of the ADRA2A gene in the auditory selective attention task (P = 2.0 × 10). After medication, increasing possession of a G allele at the MspI polymorphism of the ADRA2A gene was associated with increased MPH-related change in response time variability in the flanker task (P = 1.0 × 10).Our study suggested an association between norepinephrine gene variants and response time variability measured at baseline and after MPH treatment in children with ADHD. Our results add to a growing body of evidence, suggesting that response time variability is a viable endophenotype for ADHD and suggesting its utility as a surrogate end point for measuring stimulant response in pharmacogenetic studies.

Prefrontal cortex, dopamine, and jealousy endophenotype.

PubMed

Marazziti, Donatella; Poletti, Michele; Dell'Osso, Liliana; Baroni, Stefano; Bonuccelli, Ubaldo

2013-02-01

Jealousy is a complex emotion characterized by the perception of a threat of loss of something that the person values,particularly in reference to a relationship with a loved one, which includes affective, cognitive, and behavioral components. Neural systems and cognitive processes underlying jealousy are relatively unclear, and only a few neuroimaging studies have investigated them. The current article discusses recent empirical findings on delusional jealousy, which is the most severe form of this feeling, in neurodegenerative diseases. After reviewing empirical findings on neurological and psychiatric disorders with delusional jealousy, and after considering its high prevalence in patients with Parkinson's disease under dopamine agonist treatment, we propose a core neural network and core cognitive processes at the basis of (delusional) jealousy, characterizing this symptom as possible endophenotype. In any case,empirical investigation of the neural bases of jealousy is just beginning, and further studies are strongly needed to elucidate the biological roots of this complex emotion.

A watershed model of individual differences in fluid intelligence.

PubMed

Kievit, Rogier A; Davis, Simon W; Griffiths, John; Correia, Marta M; Cam-Can; Henson, Richard N

2016-10-01

Fluid intelligence is a crucial cognitive ability that predicts key life outcomes across the lifespan. Strong empirical links exist between fluid intelligence and processing speed on the one hand, and white matter integrity and processing speed on the other. We propose a watershed model that integrates these three explanatory levels in a principled manner in a single statistical model, with processing speed and white matter figuring as intermediate endophenotypes. We fit this model in a large (N=555) adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) using multiple measures of processing speed, white matter health and fluid intelligence. The model fit the data well, outperforming competing models and providing evidence for a many-to-one mapping between white matter integrity, processing speed and fluid intelligence. The model can be naturally extended to integrate other cognitive domains, endophenotypes and genotypes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model

PubMed Central

Pizzagalli, Diego A.

2014-01-01

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (1) anhedonia, (2) dopamine, and (3) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affect mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research. PMID:24471371

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

PubMed Central

Hagihara, Hideo; Catts, Vibeke S; Katayama, Yuta; Shoji, Hirotaka; Takagi, Tsuyoshi; Huang, Freesia L; Nakao, Akito; Mori, Yasuo; Huang, Kuo-Ping; Ishii, Shunsuke; Graef, Isabella A; Nakayama, Keiichi I; Shannon Weickert, Cynthia; Miyakawa, Tsuyoshi

2018-01-01

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder. PMID:28776581

Parkinson disease: α-synuclein mutational screening and new clinical insight into the p.E46K mutation.

PubMed

Pimentel, Márcia M G; Rodrigues, Fabíola C; Leite, Marco Antônio A; Campos Júnior, Mário; Rosso, Ana Lucia; Nicaretta, Denise H; Pereira, João S; Silva, Delson José; Della Coletta, Marcus V; Vasconcellos, Luiz Felipe R; Abreu, Gabriella M; Dos Santos, Jussara M; Santos-Rebouças, Cíntia B

2015-06-01

Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding α-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. In this study, we conducted a molecular screening of α-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real-time PCR. The only alteration identified was the p.E46K mutation in a 60-year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. Our findings add new insight into the preexisting information about α-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in α-synuclein are uncommon among Brazilian patients with Parkinson's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency.

PubMed

Bortolato, Marco; Floris, Gabriele; Shih, Jean C

2018-05-10

The two monoamine oxidase (MAO) enzymes, A and B, catalyze the metabolism of monoamine neurotransmitters, such as serotonin, norepinephrine, and dopamine. The phenotypic outcomes of MAO congenital deficiency have been studied in humans and animal models, to explore the role of these enzymes in behavioral regulation. The clinical condition caused by MAOA deficiency, Brunner syndrome, was first described as a disorder characterized by overt antisocial and aggressive conduct. Building on this discovery, subsequent studies were focused on the characterization of the role of MAOA in the neurobiology of antisocial conduct. MAO A knockout mice were found to display high levels of intermale aggression; however, further analyses of these mutants unveiled additional behavioral abnormalities mimicking the core symptoms of autism-spectrum disorder. These findings were strikingly confirmed in newly reported cases of Brunner syndrome. The role of MAOB in behavioral regulation remains less well-understood, even though Maob-deficient mice have been found to exhibit greater behavioral disinhibition and risk-taking responses, supporting previous clinical studies showing associations between low MAO B activity and impulsivity. Furthermore, lack of MAOB was found to exacerbate the severity of psychopathological deficits induced by concurrent MAOA deficiency. Here, we summarize how the convergence of clinical reports and behavioral phenotyping in mutant mice has helped frame a complex picture of psychopathological features in MAO-deficient individuals, which encompass a broad spectrum of neurodevelopmental problems. This emerging knowledge poses novel conceptual challenges towards the identification of the endophenotypes shared by autism-spectrum disorder, antisocial behavior and impulse-control problems, as well as their monoaminergic underpinnings.

Integration of bioinformatics and imaging informatics for identifying rare PSEN1 variants in Alzheimer's disease.

PubMed

Nho, Kwangsik; Horgusluoglu, Emrin; Kim, Sungeun; Risacher, Shannon L; Kim, Dokyoon; Foroud, Tatiana; Aisen, Paul S; Petersen, Ronald C; Jack, Clifford R; Shaw, Leslie M; Trojanowski, John Q; Weiner, Michael W; Green, Robert C; Toga, Arthur W; Saykin, Andrew J

2016-08-12

Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics. A WGS data set (N = 815) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was used in this analysis. 757 non-Hispanic Caucasian participants underwent WGS from a blood sample and high resolution T1-weighted structural MRI at baseline. An automated MRI analysis technique (FreeSurfer) was used to measure cortical thickness and volume of neuroanatomical structures. We assessed imaging and cerebrospinal fluid (CSF) biomarkers as LOAD-related quantitative endophenotypes. Single variant analyses were performed using PLINK and gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). A total of 839 rare variants (MAF < 1/√(2 N) = 0.0257) were found within a region of ±10 kb from PSEN1. Among them, six exonic (three non-synonymous) variants were observed. A single variant association analysis showed that the PSEN1 p. E318G variant increases the risk of LOAD only in participants carrying APOE ε4 allele where individuals carrying the minor allele of this PSEN1 risk variant have lower CSF Aβ1-42 and higher CSF tau. A gene-based analysis resulted in a significant association of rare but not common (MAF ≥ 0.0257) PSEN1 variants with bilateral entorhinal cortical thickness. This is the first study to show that PSEN1 rare variants collectively show a significant association with the brain atrophy in regions preferentially affected by LOAD, providing further support for a role of PSEN1 in LOAD. The PSEN1 p. E318G variant increases the risk of LOAD only in APOE ε4 carriers. Integrating bioinformatics with imaging informatics for identification of rare variants could help explain the missing heritability in LOAD.

Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder.

PubMed

Bey, Katharina; Meyhöfer, Inga; Lennertz, Leonhard; Grützmann, Rosa; Heinzel, Stephan; Kaufmann, Christian; Klawohn, Julia; Riesel, Anja; Ettinger, Ulrich; Kathmann, Norbert; Wagner, Michael

2018-05-02

Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.

EEG correlates of visual short-term memory as neuro-cognitive endophenotypes of ADHD.

PubMed

Wiegand, Iris; Hennig-Fast, Kristina; Kilian, Beate; Müller, Hermann J; Töllner, Thomas; Möller, Hans-Jürgen; Engel, Rolf R; Finke, Kathrin

2016-05-01

Attention deficit hyperactivity disorder (ADHD) frequently persists into adulthood. A reduction in visual short-term memory (vSTM) storage capacity was recently suggested as a potential neuro-cognitive endophenotype, i.e., a testable marker of an individual's liability for developing ADHD. This study aimed at identifying markers of the brain abnormalities underlying vSTM reductions in adult ADHD. We combined behavioral parameter-based assessment with electrophysiology in groups of adult ADHD patients and healthy age-matched controls. Amplitudes of ERP markers of vSTM storage capacity, the contralateral delay activity (CDA) and the P3b, were analyzed according to (i) differences between individuals with higher vs. lower storage capacity K and (ii) differences between ADHD patients and control participants. We replicated the finding of reduced storage capacity in adult ADHD. Across groups, individuals with higher relative to lower storage capacity showed a larger CDA and P3b. We further found differences between the patient and control groups in the ERPs: The CDA amplitude was attenuated in an early time window for ADHD patients compared to control participants, and was negatively correlated with ADHD patients' symptom severity ratings. Furthermore, the P3b was larger in ADHD patients relative to control participants. These electrophysiological findings indicate altered brain mechanisms underlying visual storage capacity in ADHD, which are characterized by deficient encoding and maintenance, and increased recruitment of control processes. Accordingly, (quantifiable) ERP markers of vSTM in adult ADHD bear candidacy as neuro-cognitive endophenotypes of the disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

Increased sensitivity to positive social stimuli in monozygotic twins at risk of bipolar vs. unipolar disorder.

PubMed

Kærsgaard, S; Meluken, I; Kessing, L V; Vinberg, M; Miskowiak, K W

2018-05-01

Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins. Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co-twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and -regulation in social scenarios and non-affective cognition. Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high-risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition. The modest sample size limited the statistical power of the study. Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder. Copyright © 2018 Elsevier B.V. All rights reserved.

Cognitive deficits as an endophenotype for anorexia nervosa: an accepted fact or a need for re-examination?

PubMed

Talbot, Amy; Hay, Phillipa; Buckett, Geoffrey; Touyz, Stephen

2015-01-01

To investigate whether impaired set shifting and weak central coherence represent state or trait characteristics and, therefore, candidate endophenotypes of anorexia nervosa (AN). Forty-nine individuals with lifetime AN (24 acutely unwell, 10 weight recovered, and 15 fully recovered) and 43 healthy controls completed the Wisconsin Card Sorting Test (WCST), the Matching Familiar Figures Test, and the Rey Complex Figure Task measuring cognitive flexibility, local processing, and global processing, respectively. Participants also completed questionnaires assessing eating disorder, anxiety and depressive symptoms, obsessional traits, interpersonal functioning, and quality of life. Body mass index was calculated from height and weight measurements. Participants with lifetime AN demonstrated poorer set shifting ability than healthy controls as evidenced by a greater number of perseverative errors on the WCST. When participants were grouped according to illness status, only those in the two recovered groups demonstrated poorer set shifting ability than healthy controls while patients with acute AN performed comparably to all other groups. There were no significant differences between groups on measures of local and global processing. No relationship was found between specific clinical features of AN and cognitive performance. The results of this study are consistent with a global trend toward set shifting difficulties in patients with AN but do not support weak central coherence as a candidate endophenotype for AN. These findings have clinical implications in terms of treatment selection and planning, particularly in relation to the use of cognitive remediation therapy with patients with AN. © 2014 Wiley Periodicals, Inc.

Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.

PubMed

Mosconi, Lisa; Berti, Valentina; Quinn, Crystal; McHugh, Pauline; Petrongolo, Gabriella; Varsavsky, Isabella; Osorio, Ricardo S; Pupi, Alberto; Vallabhajosula, Shankar; Isaacson, Richard S; de Leon, Mony J; Brinton, Roberta Diaz

2017-09-26

This observational multimodality brain imaging study investigates emergence of endophenotypes of late-onset Alzheimer disease (AD) risk during endocrine transition states in a cohort of clinically and cognitively normal women and age-matched men. Forty-two 40- to 60-year-old cognitively normal women (15 asymptomatic perimenopausal by age [CNT], 13 perimenopausal [PERI], and 14 postmenopausal [MENO]) and 18 age- and education-matched men were examined. All patients had volumetric MRI, 18 F-fluoro-2-deoxyglucose (FDG)-PET (glucose metabolism), and Pittsburgh compound B-PET scans (β-amyloid [Aβ] deposition, a hallmark of AD pathology). As expected, the MENO group was older than the PERI and CNT groups. Otherwise, groups were comparable on clinical and neuropsychological measures and APOE4 distribution. Compared to CNT women and to men, and controlling for age, PERI and MENO groups exhibited increased indicators of AD endophenotype, including hypometabolism, increased Aβ deposition, and reduced gray and white matter volumes in AD-vulnerable regions ( p < 0.001). AD biomarker abnormalities were greatest in MENO, intermediate in PERI, and lowest in CNT women ( p < 0.001). Aβ deposition was exacerbated in APOE4 -positive MENO women relative to the other groups ( p < 0.001). Multimodality brain imaging indicates sex differences in development of the AD endophenotype, suggesting that the preclinical AD phase is early in the female aging process and coincides with the endocrine transition of perimenopause. These data indicate that the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process. © 2017 American Academy of Neurology.

Risk or resilience? Empathic abilities in patients with bipolar disorders and their first-degree relatives.

PubMed

Seidel, Eva-Maria; Habel, Ute; Finkelmeyer, Andreas; Hasmann, Alexander; Dobmeier, Matthias; Derntl, Birgit

2012-03-01

Endophenotypes are intermediate phenotypes which are considered a more promising marker of genetic risk than illness itself. While previous research mostly used cognitive deficits, emotional functions are of greater relevance for bipolar disorder regarding the characteristic emotional hyper-reactability and deficient social-emotional competence. Hence, the aim of the present study was to clarify whether empathic abilities can serve as a possible endophenotype of bipolar disorder by applying a newly developed task in bipolar patients and their first-degree relatives. Three components of empathy (emotion recognition, perspective taking and affective responsiveness) have been assessed in a sample of 21 bipolar patients, 21 first-degree relatives and 21 healthy controls. Data analysis indicated significant differences between controls and patients for emotion recognition and affective responsiveness but not for perspective taking. This shows that in addition to difficulties in recognizing facial emotional expressions, bipolar patients have difficulties in identifying emotions they would experience in a given situation. However, the ability to take the perspective of another person in an emotional situation was intact but decreased with increasing severity of residual hypomanic and depressive symptoms. Relatives performed comparably bad on emotion recognition but did not differ from controls or patients in affective responsiveness. This study is the first to show that deficient emotion recognition is the only component of empathy which forms a possible endophenotype of bipolar disorder. This has important implications for prevention strategies. Furthermore, changes in affective responsiveness in first-degree relatives show a potential resilience marker. Copyright © 2011 Elsevier Ltd. All rights reserved.

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16.

PubMed

Cathomas, Flurin; Sigrist, Hannes; Schmid, Luca; Seifritz, Erich; Gassmann, Martin; Bettler, Bernhard; Pryce, Christopher R

2017-01-15

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABA B receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABA B receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12 -/- ) exhibit increased auditory fear learning and that Kctd12 +/- mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABA B receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16 -/- and Kctd16 +/- mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16 -/- and Kctd16 +/- mice. When fear memory was tested on the following day, Kctd16 -/- mice exhibited less extinction of auditory fear memory relative to WT and Kctd16 +/- mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16 +/- mice. Relative to WT, both Kctd16 +/- and Kctd16 -/- mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABA B receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Early identification and high-risk strategies for bipolar disorder.

PubMed

Correll, Christoph U; Penzner, Julie B; Lencz, Todd; Auther, Andrea; Smith, Christopher W; Malhotra, Anil K; Kane, John M; Cornblatt, Barbara A

2007-06-01

To describe and compare the relative merits of different identification strategies for individuals at risk for bipolar disorder (BPD). Selective review of data that support early identification in BPD, with a particular focus on emerging clinical high-risk strategies. Early detection of individuals at risk for BPD can utilize genetic, endophenotypic and clinical methods. Most published work focuses on genetic familial endophenotypic risk markers for BPD. However, despite encouraging results, problems with specificity and sensitivity limit the application of these data to early prevention programs. In addition, offspring studies of BPD patients systematically exclude the majority of subjects without a first-degree bipolar relative. On the other hand, emerging work in the clinical-high-risk arena has already produced encouraging results. Although still preliminary, the identification of individuals in subsyndromal or attenuated symptom 'prodromal' stages of BPD seems to be an under-researched area that holds considerable promise deserving increased attention. Required next steps include the development of rating tools for attenuated and subsyndromal manic and depressive symptoms and of prodromal criteria that will allow prodromal symptomatology to be systematically studied in patients with recent-onset bipolar, as well as in prospective population-based phenomenology trials and attenuated symptom-based high-risk studies. Given the current limitations of each early identification method, combining clinical, endophenotypic and genetic strategies will increase prediction accuracy. Since reliable biological markers for BPD have not been established and since most patients with BPD lack a first-degree relative with this disorder, clinical high-risk approaches have great potential to inform early identification and intervention programs.

EEG-LORETA endophenotypes of the common idiopathic generalized epilepsy syndromes.

PubMed

Clemens, B; Puskás, S; Besenyei, M; Emri, M; Opposits, G; Kis, S A; Hollódy, K; Fogarasi, A; Kondákor, I; Füle, K; Bense, K; Fekete, I

2012-05-01

We tested the hypothesis that the cortical areas with abnormal local EEG synchronization are dissimilar in the three common idiopathic generalized epilepsy (IGE) phenotypes: IGE patients with absence seizures (ABS), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures exclusively (EGTCS). Groups of unmedicated ABS, JME and EGTCS patients were investigated. Waking EEG background activity (without any epileptiform potentials) was analyzed by a source localization method, LORETA (Low Resolution Electromagnetic Tomography). Each patient group was compared to a separate, age-matched group of healthy control persons. Voxel-based, normalized broad-band (delta, theta, alpha, and beta) and very narrow band (VNB, 1Hz bandwidth, from 1 to 25Hz) LORETA activity (=current source density, A/m(2)) were computed for each person. Group comparison included subtraction (average patient data minus average control data) and group statistics (multiple t-tests, where Bonferroni-corrected p<0.05 values were accepted as statistically significant). Statistically not significant main findings were: overall increased delta and theta broad band activity in the ABS and JME groups; decrease of alpha and beta activity in the EGTCS group. Statistically significant main findings were as follows. JME group: bilaterally increased theta activity in posterior (temporal, parietal, and occipital) cortical areas; bilaterally increased activity in the medial and basal prefrontal area in the 8Hz VNB; bilaterally decreased activity in the precuneus, posterior cingulate and superior parietal lobule in the 11Hz and 21-22Hz VNBs. ABS group: bilaterally increased theta activity emerged in the basal prefrontal and medial temporal limbic areas. Decreased activity was found at 19-21Hz in the right postcentral gyrus and parts of the right superior and medial temporal gyri. EGTCS group: decreased activity was found in the frontal cortex and the postcentral gyrus at 10-11Hz, increased activity in the right parahippocampal gyrus at 16-18Hz. Increased theta activity in the posterior parts of the cortex is the endophenotype for JME. Increased theta activity in the fronto-temporal limbic areas is the endophenotype for ABS. Statistically not significant findings might indicate diffuse biochemical abnormality of the cortex in JME and ABS. EEG-LORETA endophenotypes may correspond to the selective propensity to generate absence and myoclonic seizures in the ABS and JME syndromes. Copyright © 2011 Elsevier B.V. All rights reserved.

Endophenotypes of Dementia Associated with Traumatic Brain Injury in Retired Military Personnel

DTIC Science & Technology

2014-10-01

demographic and medical history data, various health and lifestyle  questionnaires, and a neurological examination. All the  neuropsychological  tests took...with clinical and  neuropsychological  data from over 140 veterans.  Cross‐sectional data analysis started and manuscript in preparation. Conclusion  In...ischemic encephalopathy, encephalitis or schizophrenia ) o Lack of competence to provide consent to participate in research o No verbal and oral fluency

Heritability and molecular-genetic basis of the P3 event-related brain potential: A genome-wide association study

PubMed Central

MALONE, STEPHEN M.; VAIDYANATHAN, UMA; BASU, SAONLI; MILLER, MICHAEL B.; MCGUE, MATT; IACONO, WILLIAM G.

2014-01-01

P3 amplitude is a candidate endophenotype for disinhibitory psychopathology, psychosis, and other disorders. The present study is a comprehensive analysis of the behavioral- and molecular-genetic basis of P3 amplitude and a P3 genetic factor score in a large community sample (N = 4,211) of adolescent twins and their parents, genotyped for 527,829 single nucleotide polymorphisms (SNPs). Biometric models indicated that as much as 65% of the variance in each measure was due to additive genes. All SNPs in aggregate accounted for approximately 40% to 50% of the heritable variance. However, analyses of individual SNPs did not yield any significant associations. Analyses of individual genes did not confirm previous associations between P3 amplitude and candidate genes but did yield a novel association with myelin expression factor 2 (MYEF2). Main effects of individual variants may be too small to be detected by GWAS without larger samples. PMID:25387705

Social Motor Coordination in Unaffected Relatives of Schizophrenia Patients: A Potential Intermediate Phenotype

PubMed Central

Del-Monte, Jonathan; Capdevielle, Delphine; Varlet, Manuel; Marin, Ludovic; Schmidt, Richard C.; Salesse, Robin N.; Bardy, Benoît G.; Boulenger, Jean Philippe; Gély-Nargeot, Marie Christine; Attal, Jérôme; Raffard, Stéphane

2013-01-01

Intermediate endophenotypes emerge as an important concept in the study of schizophrenia. Although research on phenotypes mainly investigated cognitive, metabolic or neurophysiological markers so far, some authors also examined the motor behavior anomalies as a potential trait-marker of the disease. However, no research has investigated social motor coordination despite the possible importance of its anomalies in schizophrenia. The aim of this study was thus to determine whether coordination modifications previously demonstrated in schizophrenia are trait-markers that might be associated with the risk for this pathology. Interpersonal motor coordination in 27 unaffected first-degree relatives of schizophrenia patients and 27 healthy controls was assessed using a hand-held pendulum task to examine the presence of interpersonal coordination impairments in individuals at risk for the disorder. Measures of neurologic soft signs, clinical variables and neurocognitive functions were collected to assess the cognitive and clinical correlates of social coordination impairments in at-risk relatives. After controlling for potential confounding variables, unaffected relatives of schizophrenia patients had impaired intentional interpersonal coordination compared to healthy controls while unintentional interpersonal coordination was preserved. More specifically, in intentional coordination, the unaffected relatives of schizophrenia patients exhibited coordination patterns that had greater variability and in which relatives did not lead the coordination. These results show that unaffected relatives of schizophrenia patients, like the patients themselves, also present deficits in intentional interpersonal coordination. For the first time, these results suggest that intentional interpersonal coordination impairments might be a potential motor intermediate endophenotype of schizophrenia opening new perspectives for early diagnosis. PMID:24106467

Knockdown of phospholipase C-β1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes

PubMed Central

Kim, Seong-Wook; Seo, Misun; Kim, Duk-Soo; Kang, Moonkyung; Kim, Yeon-Soo; Koh, Hae-Young; Shin, Hee-Sup

2015-01-01

Background Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-β1 expression and the pathogenesis of schizophrenia. Although PLC-β1-null (PLC-β1−/−) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-β1 expression in the brain contribute to specific behavioural defects. Methods We selectively knocked down PLC-β1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice. Results Silencing PLC-β1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophrenia- related behaviours observed in PLC-β1−/− mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-β1 knockdown mice. Limitations Phenotypes of PLC-β1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia. Conclusion These results indicate that PLC-β1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-β1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder. PMID:25268789

OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice.

PubMed

Brzózka, M M; Unterbarnscheidt, T; Schwab, M H; Rossner, M J

2016-02-09

Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Parkinsonian motor impairment predicts personality domains related to genetic risk and treatment outcomes in schizophrenia

PubMed Central

Molina, Juan L; Calvó, María; Padilla, Eduardo; Balda, Mara; Alemán, Gabriela González; Florenzano, Néstor V; Guerrero, Gonzalo; Kamis, Danielle; Rangeon, Beatriz Molina; Bourdieu, Mercedes; Strejilevich, Sergio A; Conesa, Horacio A; Escobar, Javier I; Zwir, Igor; Cloninger, C Robert; de Erausquin, Gabriel A

2017-01-01

Identifying endophenotypes of schizophrenia is of critical importance and has profound implications on clinical practice. Here we propose an innovative approach to clarify the mechanims through which temperament and character deviance relates to risk for schizophrenia and predict long-term treatment outcomes. We recruited 61 antipsychotic naïve subjects with chronic schizophrenia, 99 unaffected relatives, and 68 healthy controls from rural communities in the Central Andes. Diagnosis was ascertained with the Schedules of Clinical Assessment in Neuropsychiatry; parkinsonian motor impairment was measured with the Unified Parkinson’s Disease Rating Scale; mesencephalic parenchyma was evaluated with transcranial ultrasound; and personality traits were assessed using the Temperament and Character Inventory. Ten-year outcome data was available for ~40% of the index cases. Patients with schizophrenia had higher harm avoidance and self-transcendence (ST), and lower reward dependence (RD), cooperativeness (CO), and self-directedness (SD). Unaffected relatives had higher ST and lower CO and SD. Parkinsonism reliably predicted RD, CO, and SD after correcting for age and sex. The average duration of untreated psychosis (DUP) was over 5 years. Further, SD was anticorrelated with DUP and antipsychotic dosing at follow-up. Baseline DUP was related to antipsychotic dose-years. Further, ‘explosive/borderline’, ‘methodical/obsessive’, and ‘disorganized/schizotypal’ personality profiles were associated with increased risk of schizophrenia. Parkinsonism predicts core personality features and treatment outcomes in schizophrenia. Our study suggests that RD, CO, and SD are endophenotypes of the disease that may, in part, be mediated by dopaminergic function. Further, SD is an important determinant of treatment course and outcome. PMID:28127577

Parkinsonian motor impairment predicts personality domains related to genetic risk and treatment outcomes in schizophrenia.

PubMed

Molina, Juan L; Calvó, María; Padilla, Eduardo; Balda, Mara; Alemán, Gabriela González; Florenzano, Néstor V; Guerrero, Gonzalo; Kamis, Danielle; Rangeon, Beatriz Molina; Bourdieu, Mercedes; Strejilevich, Sergio A; Conesa, Horacio A; Escobar, Javier I; Zwir, Igor; Cloninger, C Robert; de Erausquin, Gabriel A

2017-01-01

Identifying endophenotypes of schizophrenia is of critical importance and has profound implications on clinical practice. Here we propose an innovative approach to clarify the mechanims through which temperament and character deviance relates to risk for schizophrenia and predict long-term treatment outcomes. We recruited 61 antipsychotic naïve subjects with chronic schizophrenia, 99 unaffected relatives, and 68 healthy controls from rural communities in the Central Andes. Diagnosis was ascertained with the Schedules of Clinical Assessment in Neuropsychiatry; parkinsonian motor impairment was measured with the Unified Parkinson's Disease Rating Scale; mesencephalic parenchyma was evaluated with transcranial ultrasound; and personality traits were assessed using the Temperament and Character Inventory. Ten-year outcome data was available for ~40% of the index cases. Patients with schizophrenia had higher harm avoidance and self-transcendence (ST), and lower reward dependence (RD), cooperativeness (CO), and self-directedness (SD). Unaffected relatives had higher ST and lower CO and SD. Parkinsonism reliably predicted RD, CO, and SD after correcting for age and sex. The average duration of untreated psychosis (DUP) was over 5 years. Further, SD was anticorrelated with DUP and antipsychotic dosing at follow-up. Baseline DUP was related to antipsychotic dose-years. Further, 'explosive/borderline', 'methodical/obsessive', and 'disorganized/schizotypal' personality profiles were associated with increased risk of schizophrenia. Parkinsonism predicts core personality features and treatment outcomes in schizophrenia. Our study suggests that RD, CO, and SD are endophenotypes of the disease that may, in part, be mediated by dopaminergic function. Further, SD is an important determinant of treatment course and outcome.

Using coordinate-based meta-analyses to explore structural imaging genetics.

PubMed

Janouschek, Hildegard; Eickhoff, Claudia R; Mühleisen, Thomas W; Eickhoff, Simon B; Nickl-Jockschat, Thomas

2018-05-05

Imaging genetics has become a highly popular approach in the field of schizophrenia research. A frequently reported finding is that effects from common genetic variation are associated with a schizophrenia-related structural endophenotype. Genetic contributions to a structural endophenotype may be easier to delineate, when referring to biological rather than diagnostic criteria. We used coordinate-based meta-analyses, namely the anatomical likelihood estimation (ALE) algorithm on 30 schizophrenia-related imaging genetics studies, representing 44 single-nucleotide polymorphisms at 26 gene loci investigated in 4682 subjects. To test whether analyses based on biological information would improve the convergence of results, gene ontology (GO) terms were used to group the findings from the published studies. We did not find any significant results for the main contrast. However, our analysis enrolling studies on genotype × diagnosis interaction yielded two clusters in the left temporal lobe and the medial orbitofrontal cortex. All other subanalyses did not yield any significant results. To gain insight into possible biological relationships between the genes implicated by these clusters, we mapped five of them to GO terms of the category "biological process" (AKT1, CNNM2, DISC1, DTNBP1, VAV3), then five to "cellular component" terms (AKT1, CNNM2, DISC1, DTNBP1, VAV3), and three to "molecular function" terms (AKT1, VAV3, ZNF804A). A subsequent cluster analysis identified representative, non-redundant subsets of semantically similar terms that aided a further interpretation. We regard this approach as a new option to systematically explore the richness of the literature in imaging genetics.

Emotional intelligence in non-psychotic first-degree relatives of people with schizophrenia.

PubMed

Albacete, Auria; Bosque, Clara; Custal, Nuria; Crespo, José M; Gilabert, Ester; Albiach, Angela; Menchón, José M; Contreras, Fernando

2016-08-01

Subtle social cognitive deficits in unaffected relatives of schizophrenia patients have received increasing attention over the last few years, supporting their potential endophenotypic role for this disorder. The current study assessed non-psychotic first-degree relatives' performance on a multidimensional measure of emotional intelligence (EI): the Mayer-Salovey-Caruso Emotional Intelligence Test 2.0 (MSCEIT). Endorsed by the National Institute of Mental Health, the MSCEIT is a valid and reliable instrument for detecting emotion-processing deficits among schizophrenia patients and people high in schizotypy. Thirty-seven first-degree relatives, 37 schizophrenia outpatients and 37 healthy controls completed the MSCEIT, which comprises eight subscales aimed to assess the four branches of EI: Identifying, Facilitating, Understanding and Managing Emotions. Potential associations with cognitive function and schizotypy levels, measured with the Schizotypal Personality Questionnaire-Brief, were further evaluated. Relatives had significantly lower MSCEIT total scores than controls and also significantly lower scores on the Identifying emotions branch. Nevertheless, schizophrenia patients still had the poorest global EI performance. The strongest positive correlations were found in relatives and controls with measures of executive function, processing speed and general intelligence. A higher level of schizotypy correlated significantly with lower MSCEIT scores among controls, but not among relatives. Contrary to expectations in the general population, the current study observed subtle EI impairment in non-psychotic first-degree relatives of schizophrenia patients. These findings support the hypothesis that these EI deficiencies may be potential endophenotypes located between the clinical phenotype and the genetic predisposition for schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

Brief monocular deprivation as an assay of short-term visual sensory plasticity in schizophrenia - "the binocular effect".

PubMed

Foxe, John J; Yeap, Sherlyn; Leavitt, Victoria M

2013-01-01

Visual sensory processing deficits are consistently observed in schizophrenia, with clear amplitude reduction of the visual evoked potential (VEP) during the initial 50-150 ms of processing. Similar deficits are seen in unaffected first-degree relatives and drug-naïve first-episode patients, pointing to these deficits as potential endophenotypic markers. Schizophrenia is also associated with deficits in neural plasticity, implicating dysfunction of both glutamatergic and GABAergic systems. Here, we sought to understand the intersection of these two domains, asking whether short-term plasticity during early visual processing is specifically affected in schizophrenia. Brief periods of monocular deprivation (MD) induce relatively rapid changes in the amplitude of the early VEP - i.e., short-term plasticity. Twenty patients and 20 non-psychiatric controls participated. VEPs were recorded during binocular viewing, and were compared to the sum of VEP responses during brief monocular viewing periods (i.e., Left-eye + Right-eye viewing). Under monocular conditions, neurotypical controls exhibited an effect that patients failed to demonstrate. That is, the amplitude of the summed monocular VEPs was robustly greater than the amplitude elicited binocularly during the initial sensory processing period. In patients, this "binocular effect" was absent. Patients were all medicated. Ideally, this study would also include first-episode unmedicated patients. These results suggest that short-term compensatory mechanisms that allow healthy individuals to generate robust VEPs in the context of MD are not effectively activated in patients with schizophrenia. This simple assay may provide a useful biomarker of short-term plasticity in the psychotic disorders and a target endophenotype for therapeutic interventions.

Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.

PubMed

Varma, Vijay R; Oommen, Anup M; Varma, Sudhir; Casanova, Ramon; An, Yang; Andrews, Ryan M; O'Brien, Richard; Pletnikova, Olga; Troncoso, Juan C; Toledo, Jon; Baillie, Rebecca; Arnold, Matthias; Kastenmueller, Gabi; Nho, Kwangsik; Doraiswamy, P Murali; Saykin, Andrew J; Kaddurah-Daouk, Rima; Legido-Quigley, Cristina; Thambisetty, Madhav

2018-01-01

The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.

Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study

PubMed Central

Oommen, Anup M.; Varma, Sudhir; Casanova, Ramon; An, Yang; O’Brien, Richard; Pletnikova, Olga; Kastenmueller, Gabi; Doraiswamy, P. Murali; Kaddurah-Daouk, Rima; Thambisetty, Madhav

2018-01-01

Background The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. Methods and findings Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and “asymptomatic Alzheimer’s disease” (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes—sphingolipids and glycerophospholipids—that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer’s Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer’s Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703–11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516–7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373–9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047–4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. Conclusions We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD. PMID:29370177

The utility of P300 as a schizophrenia endophenotype and predictive biomarker: clinical and socio-demographic modulators in COGS-2.

PubMed

Turetsky, Bruce I; Dress, Erich M; Braff, David L; Calkins, Monica E; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Light, Gregory

2015-04-01

Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results. Copyright © 2014 Elsevier B.V. All rights reserved.

The Utility of P300 as a Schizophrenia Endophenotype and Predictive Biomarker: Clinical and Socio-Demographic Modulators in COGS-2

PubMed Central

Turetsky, Bruce I.; Dress, Erich M.; Braff, David L.; Calkins, Monica E.; Green, Michael F.; Greenwood, Tiffany A.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Nuechterlein, Keith H.; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Sprock, Joyce; Stone, William S.; Sugar, Catherine A.; Swerdlow, Neal R.; Tsuang, Debby W.; Tsuang, Ming T.; Light, Gregory

2014-01-01

Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 control and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results. PMID:25306203

Effect of a syringe aspiration technique versus a mechanical suction technique and use of N-butylscopolammonium bromide on the quantity and quality of bronchoalveolar lavage fluid samples obtained from horses with the summer pasture endophenotype of equine asthma.

PubMed

Bowser, Jacquelyn E; Costa, Lais R R; Rodil, Alba U; Lopp, Christine T; Johnson, Melanie E; Wills, Robert W; Swiderski, Cyprianna E

2018-03-01

OBJECTIVE To evaluate the effect of 2 bronchoalveolar lavage (BAL) sampling techniques and the use of N-butylscopolammonium bromide (NBB) on the quantity and quality of BAL fluid (BALF) samples obtained from horses with the summer pasture endophenotype of equine asthma. ANIMALS 8 horses with the summer pasture endophenotype of equine asthma. PROCEDURES BAL was performed bilaterally (right and left lung sites) with a flexible videoendoscope passed through the left or right nasal passage. During lavage of the first lung site, a BALF sample was collected by means of either gentle syringe aspiration or mechanical suction with a pressure-regulated wall-mounted suction pump. The endoscope was then maneuvered into the contralateral lung site, and lavage was performed with the alternate fluid retrieval technique. For each horse, BAL was performed bilaterally once with and once without premedication with NBB (21-day interval). The BALF samples retrieved were evaluated for volume, total cell count, differential cell count, RBC count, and total protein concentration. RESULTS Use of syringe aspiration significantly increased total BALF volume (mean volume increase, 40 mL [approx 7.5% yield]) and decreased total RBC count (mean decrease, 142 cells/μL), compared with use of mechanical suction. The BALF nucleated cell count and differential cell count did not differ between BAL procedures. Use of NBB had no effect on BALF retrieval. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that retrieval of BALF by syringe aspiration may increase yield and reduce barotrauma in horses at increased risk of bronchoconstriction and bronchiolar collapse. Further studies to determine the usefulness of NBB and other bronchodilators during BAL procedures in horses are warranted.

Is negative self-referent bias an endophenotype for depression? An fMRI study of emotional self-referent words in twins at high vs. low risk of depression.

PubMed

Miskowiak, K W; Larsen, J E; Harmer, C J; Siebner, H R; Kessing, L V; Macoveanu, J; Vinberg, M

2018-01-15

Negative cognitive bias and aberrant neural processing of self-referent emotional words seem to be trait-marks of depression. However, it is unclear whether these neurocognitive changes are present in unaffected first-degree relatives and constitute an illness endophenotype. Fifty-three healthy, never-depressed monozygotic or dizygotic twins with a co-twin history of depression (high-risk group: n = 26) or no first-degree family history of depression (low-risk group: n = 27) underwent neurocognitive testing and functional magnetic imaging (fMRI) as part of a follow-up cohort study. Participants performed a self-referent emotional word categorisation task and free word recall task followed by a recognition task during fMRI. Participants also completed questionnaires assessing mood, personality traits and coping strategies. High-risk and low-risk twins (age, mean ± SD: 40 ± 11) were well-balanced for demographic variables, mood, coping and neuroticism. High-risk twins showed lower accuracy during self-referent categorisation of emotional words independent of valence and more false recollections of negative words than low-risk twins during free recall. Functional MRI yielded no differences between high-risk and low-risk twins in retrieval-specific neural activity for positive or negative words or during the recognition of negative versus positive words within the hippocampus or prefrontal cortex. The subtle display of negative recall bias is consistent with the hypothesis that self-referent negative memory bias is an endophenotype for depression. High-risk twins' lower categorisation accuracy adds to the evidence for valence-independent cognitive deficits in individuals at familial risk for depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of temperament on depression and anxiety symptoms and depressive disorder in a population-based birth cohort.

PubMed

Nyman, Emma; Miettunen, Jouko; Freimer, Nelson; Joukamaa, Matti; Mäki, Pirjo; Ekelund, Jesper; Peltonen, Leena; Järvelin, Marjo-Riitta; Veijola, Juha; Paunio, Tiina

2011-06-01

The aim of this study was to characterize at the population level how innate features of temperament relate to experience of depressive mood and anxiety, and whether these symptoms have separable temperamental backgrounds. The study subjects were 4773 members of the population-based Northern Finland Birth Cohort 1966, a culturally and genetically homogeneous study sample. Temperament was measured at age 31 using the temperament items of the Temperament and Character Inventory and a separate Pessimism score. Depressive mood was assessed based on a previous diagnosis of depressive disorder or symptoms of depression according to the Hopkins Symptom Check List - 25. Anxiety was assessed analogously. High levels of Harm avoidance and Pessimism were related to both depressive mood (effect sizes; d=0.84 and d=1.25, respectively) and depressive disorder (d=0.68 and d=0.68, respectively). Of the dimensions of Harm avoidance, Anticipatory worry and Fatigability had the strongest effects. Symptoms of depression and anxiety showed very similar underlying temperament patterns. Although Harm avoidance and Pessimism appear to be important endophenotype candidates for depression and anxiety, their potential usefulness as endophenotypes, and whether they meet all the suggested criteria for endophenotypes will remain to be confirmed in future studies. Personality characteristics of Pessimism and Harm avoidance, in particular its dimensions Anticipatory worry and Fatigability, are strongly related to symptoms of depression and anxiety as well as to depressive disorder in this population. These temperamental features may be used as dimensional susceptibility factors in etiological studies of depression, which may aid in the development of improved clinical practice. Copyright © 2011 Elsevier B.V. All rights reserved.

Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

PubMed

Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.

Deconstructing the “Resting” State: Exploring the Temporal Dynamics of Frontal Alpha Asymmetry as an Endophenotype for Depression

PubMed Central

Allen, John J. B.; Cohen, Michael X

2010-01-01

Asymmetry in frontal electrocortical alpha-band (8–13 Hz) activity recorded during resting situations (i.e., in absence of a specific task) has been investigated in relation to emotion and depression for over 30 years. This asymmetry reflects an aspect of endogenous cortical dynamics that is stable over repeated measurements and that may serve as an endophenotype for mood or other psychiatric disorders. In nearly all of this research, EEG activity is averaged across several minutes, obscuring transient dynamics that unfold on the scale of milliseconds to seconds. Such dynamic states may ultimately have greater value in linking brain activity to surface EEG asymmetry, thus improving its status as an endophenotype for depression. Here we introduce novel metrics for characterizing frontal alpha asymmetry that provide a more in-depth neurodynamical understanding of recurrent endogenous cortical processes during the resting-state. The metrics are based on transient “bursts” of asymmetry that occur frequently during the resting-state. In a sample of 306 young adults, 143 with a lifetime diagnosis of major depressive disorder (62 currently symptomatic), three questions were addressed: (1) How do novel peri-burst metrics of dynamic asymmetry compare to conventional fast-Fourier transform-based metrics? (2) Do peri-burst metrics adequately differentiate depressed from non-depressed participants? and, (3) what EEG dynamics surround the asymmetry bursts? Peri-burst metrics correlated with traditional measures of asymmetry, and were sensitive to both current and past episodes of major depression. Moreover, asymmetry bursts were characterized by a transient lateralized alpha suppression that is highly consistent in phase across bursts, and a concurrent contralateral transient alpha enhancement that is less tightly phase-locked across bursts. This approach opens new possibilities for investigating rapid cortical dynamics during resting-state EEG. PMID:21228910

Increased Cerebellar Functional Connectivity With the Default-Mode Network in Unaffected Siblings of Schizophrenia Patients at Rest.

PubMed

Guo, Wenbin; Liu, Feng; Zhang, Zhikun; Liu, Guiying; Liu, Jianrong; Yu, Liuyu; Xiao, Changqing; Zhao, Jingping

2015-11-01

The default-mode network (DMN) is vital in the neurobiology of schizophrenia, and the cerebellum participates in the high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN abnormalities remains unclear in unaffected siblings of schizophrenia patients. Forty-six unaffected siblings of schizophrenia patients and 46 healthy controls were recruited for a resting-state scan. The images were analyzed using the functional connectivity (FC) method. The siblings showed significantly increased FCs between the left Crus I and the left superior medial prefrontal cortex (MPFC), as well as between the lobule IX and the bilateral MPFC (orbital part) and right superior MPFC compared with the controls. No significantly decreased FC was observed in the siblings relative to the controls. The analyses were replicated in 49 first-episode, drug-naive patients with schizophrenia, and the results showed that the siblings and the patients shared increased FCs between the left Crus I and the left superior MPFC, as well as between the lobule IX and the left MPFC (orbital part) compared with the controls. These findings suggest that increased cerebellar-DMN connectivities emerge earlier than illness onset, which highlight the contribution of the cerebellum to the DMN alterations in unaffected siblings. The shared increased cerebellar-DMN connectivities between the patients and the siblings may be used as candidate endophenotypes for schizophrenia. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson’s Disease 1

PubMed Central

Stephenson, Diane; Hu, Michele T.; Romero, Klaus; Breen, Kieran; Burn, David; Ben-Shlomo, Yoav; Bhattaram, Atul; Isaac, Maria; Venuto, Charles; Kubota, Ken; Little, Max A.; Friend, Stephen; Lovestone, Simon; Morris, Huw R.; Grosset, Donald; Sutherland, Margaret; Gallacher, John; Williams-Gray, Caroline; Bain, Lisa J.; Avilés, Enrique; Marek, Ken; Toga, Arthur W.; Stark, Yafit; Forrest Gordon, Mark; Ford, Steve

2015-01-01

Abstract Parkinson’s disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson’s UK and co-organized by Critical Path Institute’s (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson’s disease. PMID:26406139

T-cell infiltration into the perilesional cortex is long-lasting and associates with poor somatomotor recovery after experimental traumatic brain injury.

PubMed

Ndode-Ekane, Xavier Ekolle; Matthiesen, Liz; Bañuelos-Cabrera, Ivette; Palminha, Cátia Alexandra Pêgas; Pitkänen, Asla

2018-06-06

T-lymphocyte (T-cell) invasion into the brain parenchyma is a major consequence of traumatic brain injury (TBI). However, the role of T-cells in the post-TBI functional outcome and secondary inflammatory processes is unknown. We explored the dynamics of T-cell infiltration into the cortex after TBI to establish whether the infiltration relates to post-injury functional impairment/recovery and progression of the secondary injury. TBI was induced in rats by lateral fluid-percussion injury, and the acute functional impairment was assessed using the neuroscore. Animals were killed between 1-90 d post-TBI for immunohistochemical analysis of T-cell infiltration (CD3), chronic macrophage/microglial reaction (CD68), blood-brain barrier (BBB) dysfunction (IgG), and endophenotype of the cortical injury. Furthermore, the occurrence of spontaneous seizures and spike-and-wave discharges were assessed using video-electroencephalography. The number of T-cells peaked at 2-d post-TBI, and then dramatically decreased by 7-d post-TBI (5% of 2-d value). Unexpectedly, chronic T-cell infiltration at 1 or 3 months post-TBI did not correlate with the severity of chronic inflammation (p >  0.05) or BBB dysfunction (p >  0.05). Multiple regression analysis indicated that inflammation and BBB dysfunction is associated with 48% of the perilesional T-cell infiltration even at the chronic time-point (r = 0.695, F = 6.54, p <  0.05). The magnitude of T-cell infiltration did not predict the pathologic endophenotype of cortical injury, but the higher the number of T-cells in the cortex, the poorer the recovery index based on the neuroscore (r = - 0.538, p <  0.05). T-cell infiltration was not associated with the number or duration of age-related spike-and-wave discharges (SWD). Nevertheless, the higher the number of SWD, the poorer the recovery index (r = - 0.767, p <  0.5). These findings suggest that acute infiltration of T-cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery.

Sustained and selective attention deficits as vulnerability markers to psychosis.

PubMed

Mulet, B; Valero, J; Gutiérrez-Zotes, A; Montserrat, C; Cortés, M J; Jariod, M; Martorell, L; Vilella, E; Labad, A

2007-04-01

The first descriptions of schizophrenia emphasized attention problems patients with schizophrenia have but recent results evidence that other psychotic disorders share them. We compared the performance in sustained and selective attention between psychotic patients (P), their healthy first degree relatives (R) and healthy volunteers (C) to prove whether these alterations could be an endophenotype of vulnerability to psychosis. We also compared the performance of schizophrenic patients (SZP) and that of patients with other functional psychoses (OP) in order to prove whether these alterations are specific of any psychotic disorder. Seventy-six P, 70 R and 39 C were included in the study. A selective attention index, comprising TMT A and B and Stroop Test, and a sustained attention index comprising the Continuous Performance Test were calculated. We conducted an univariant general linear model to compare three group performances in these indexes, with age, sex and years of education as a covariables. We found significant differences between the indexes when we compared P, R and C. No differences in performance were found between SZP and OP. Our data showed that sustained and selective attention alterations could be a vulnerability factor to psychotic disorders in general, but they were not specific of schizophrenia.

Broadening the diagnosis of bipolar disorder: benefits vs. risks

PubMed Central

STRAKOWSKI, STEPHEN M.; FLECK, DAVID E.; MAJ, MARIO

2011-01-01

There is considerable debate over whether bipolar and related disorders that share common signs and symptoms, but are currently defined as distinct clinical entities in DSM-IV and ICD-10, may be better characterized as falling within a more broadly defined “bipolar spectrum”. With a spectrum view in mind, the possibility of broadening the diagnosis of bipolar disorder has been proposed. This paper discusses some of the rationale for an expanded diagnostic scheme from both clinical and research perspectives in light of potential drawbacks. The ultimate goal of broadening the diagnosis of bipolar disorder is to help identify a common etiopathogenesis for these conditions to better guide treatment. To help achieve this goal, bipolar researchers have increasingly expanded their patient populations to identify objective biological or endophenotypic markers that transcend phenomenological observation. Although this approach has and will likely continue to produce beneficial results, the upcoming DSM-IV and ICD-10 revisions will place increasing scrutiny on psychiatry’s diagnostic classification systems and pressure to re-evaluate our conceptions of bipolar disorder. However, until research findings can provide consistent and converging evidence as to the validity of a broader diagnostic conception, clinical expansion to a dimensional bipolar spectrum should be considered with caution. PMID:21991268

Autism Tendencies and Psychosis Proneness Interactively Modulate Saliency Cost.

PubMed

Abu-Akel, Ahmad; Apperly, Ian A; Wood, Stephen J; Hansen, Peter C; Mevorach, Carmel

2017-01-01

Atypical responses to salient information are a candidate endophenotype for both autism and psychosis spectrum disorders. The present study investigated the costs and benefits of such atypicalities for saliency-based selection in a large cohort of neurotypical adults in whom both autism and psychosis expressions were assessed. Two experiments found that autism tendencies and psychosis proneness interactively modulated the cost incurred in the presence of a task-irrelevant salient distractor. Specifically, expressions of autism and psychosis had opposing effects on responses to salient information such that the benefits associated with high expressions for autism offset costs associated with high expressions for psychosis. The opposing influences observed on saliency cost may be driven by distinct attentional mechanisms that are differentially affected by expressions for autism and psychosis. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The relation among perfectionism, obsessive-compulsive personality disorder and obsessive-compulsive disorder in individuals with eating disorders.

PubMed

Halmi, Katherine A; Tozzi, Federica; Thornton, Laura M; Crow, Scott; Fichter, Manfred M; Kaplan, Allan S; Keel, Pamela; Klump, Kelly L; Lilenfeld, Lisa R; Mitchell, James E; Plotnicov, Katherine H; Pollice, Christine; Rotondo, Alessandro; Strober, Michael; Woodside, D Blake; Berrettini, Wade H; Kaye, Walter H; Bulik, Cynthia M

2005-12-01

Perfectionism and obsessionality are core features of eating disorders (ED), yet the nature of their relation remains unknown. Understanding the relation between these traits may enhance our ability to identify relevant behavioral endophenotypes for ED. Six-hundred seven individuals with anorexia and bulimia nervosa from the International Price Foundation Genetic Study were assessed for perfectionism, obsessive-compulsive personality disorder (OCPD), and obsessive-compulsive disorder (OCD). No differences were found across ED subtypes in the prevalence of OCPD and OCD, nor with the association between OCD and OCPD. Perfectionism scores were highest in individuals with OCPD whether alone or in combination with OCD. Perfectionism appears to be more closely associated with obsessive-compulsive personality symptoms rather than OCD. The pairing of perfectionism with OCPD may be a relevant core behavioral feature underlying vulnerability to ED. Copyright 2005 by Wiley Periodicals, Inc.

A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease.

PubMed

Mostafavi, Sara; Gaiteri, Chris; Sullivan, Sarah E; White, Charles C; Tasaki, Shinya; Xu, Jishu; Taga, Mariko; Klein, Hans-Ulrich; Patrick, Ellis; Komashko, Vitalina; McCabe, Cristin; Smith, Robert; Bradshaw, Elizabeth M; Root, David E; Regev, Aviv; Yu, Lei; Chibnik, Lori B; Schneider, Julie A; Young-Pearse, Tracy L; Bennett, David A; De Jager, Philip L

2018-06-01

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

Influence of sex and stress exposure across the lifespan on endophenotypes of depression: focus on behavior, glucocorticoids, and hippocampus

PubMed Central

Gobinath, Aarthi R.; Mahmoud, Rand; Galea, Liisa A.M.

2015-01-01

Sex differences exist in vulnerability, symptoms, and treatment of many neuropsychiatric disorders. In this review, we discuss both preclinical and clinical research that investigates how sex influences depression endophenotypes at the behavioral, neuroendocrine, and neural levels across the lifespan. Chronic exposure to stress is a risk factor for depression and we discuss how stress during the prenatal, postnatal, and adolescent periods differentially affects males and females depending on the method of stress and metric examined. Given that the integrity of the hippocampus is compromised in depression, we specifically focus on sex differences in how hippocampal plasticity is affected by stress and depression across the lifespan. In addition, we examine how female physiology predisposes depression in adulthood, specifically in postpartum and perimenopausal periods. Finally, we discuss the underrepresentation of women in both preclinical and clinical research and how this limits our understanding of sex differences in vulnerability, presentation, and treatment of depression. PMID:25610363

Sensory Responsiveness in Siblings of Children with Autism Spectrum Disorders

PubMed Central

Hilton, Claudia L.; Babb-Keeble, Alison; Westover, Erin Eitzmann; Zhang, Yi; Adams, Claire; Collins, Diane M.; Karmarkar, Amol; Reistetter, Timothy A.; Constantino, John N.

2017-01-01

This study examined sensory responsiveness in unaffected siblings of children with autism spectrum disorder (ASD) and associations between sensory responsiveness and social severity. Sensory Profile Caregiver Questionnaires and Social Responsiveness Scales were completed by parents of 185 children between age 4 and 10.95 years. Significant differences were found between participants with ASD and controls, and between participants with ASD and unaffected siblings for all sensory quadrants and domains, but not between controls and unaffected siblings. Social responsiveness scores were significantly correlated with scores from most sensory profile categories. Sensory responsiveness as an endophenotype of ASD is not indicated from these findings; however, studies with larger numbers of unaffected siblings and controls are needed to confirm the null hypothesis. PMID:27704293

Sensory Responsiveness in Siblings of Children with Autism Spectrum Disorders.

PubMed

Hilton, Claudia L; Babb-Keeble, Alison; Westover, Erin Eitzmann; Zhang, Yi; Adams, Claire; Collins, Diane M; Karmarkar, Amol; Reistetter, Timothy A; Constantino, John N

2016-12-01

This study examined sensory responsiveness in unaffected siblings of children with autism spectrum disorder (ASD) and associations between sensory responsiveness and social severity. Sensory Profile Caregiver Questionnaires and Social Responsiveness Scales were completed by parents of 185 children between age 4 and 10.95 years. Significant differences were found between participants with ASD and controls, and between participants with ASD and unaffected siblings for all sensory quadrants and domains, but not between controls and unaffected siblings. Social responsiveness scores were significantly correlated with scores from most sensory profile categories. Sensory responsiveness as an endophenotype of ASD is not indicated from these findings; however, studies with larger numbers of unaffected siblings and controls are needed to confirm the null hypothesis.

Genetic epidemiology of osteoarthritis: recent developments and future directions

PubMed Central

Hochberg, Marc C.; Yerges-Armstrong, Laura; Yau, Michelle; Mitchell, Braxton D.

2013-01-01

Purpose of review Despite the high prevalence of osteoarthritis and its enormous public health impact, the cause of the disease remains largely obscure. The identification of genes associated with osteoarthritis can help reveal underlying biological mechanisms that may lead to development of new therapeutic targets or biomarkers for early detection and risk stratification. The goal of this short review is to provide a brief overview of the current status of genetics of osteoarthritis with an emphasis on developments generated in the last year. Recent findings This review focuses on the following areas: identification of new genes through genetic association studies, including genome-wide association studies; family-based studies and extreme osteoarthritis phenotypes; endophenotypes and pain; and overlap of osteoarthritis with other age-related disorders. Summary Although recent genetic discoveries have produced innovative findings with respect to the pathophysiology of osteoarthritis, we have yet to realize new treatments to improve the quality of life of patients with osteoarthritis. PMID:23249833

Neurobiology of Adolescent Substance Use and Addictive Behaviors: Prevention and Treatment Implications

PubMed Central

Hammond, Christopher J.; Mayes, Linda C.; Potenza, Marc N.

2015-01-01

Psychoactive substance and nonsubstance/behavioral addictions are major public health concerns associated with significant societal cost. Adolescence is a period of dynamic biologic, psychological, and behavioral changes. Adolescence is also associated with an increased risk for substance use and addictive disorders. During adolescence, developmental changes in neural circuitry of reward processing, motivation, cognitive control, and stress may contribute to vulnerability for increased levels of engagement in substance use and nonsubstance addictive behaviors. Current biologic models of adolescent vulnerability for addictions incorporate existing data on allostatic changes in function and structure of the midbrain dopaminergic system, stress-associated neuroplasticity, and maturational imbalances between cognitive control and reward reactivity. When characterizing adolescent vulnerability, identifying subgroups of adolescents at high risk for addictive behaviors is a major goal of the addiction field. Genetics, epigenetics, and intermediate phenotypes/endophenotypes may assist in characterizing children and adolescents at risk. Improved understanding of the neurobiology of adolescence and addiction vulnerability has the potential to refine screening, enhance prevention and intervention strategies, and inform public policy. PMID:25022184

Reduced Face Identity Aftereffects in Relatives of Children with Autism

ERIC Educational Resources Information Center

Fiorentini, Chiara; Gray, Laura; Rhodes, Gillian; Jeffery, Linda; Pellicano, Elizabeth

2012-01-01

Autism is a pervasive developmental condition with complex aetiology. To aid the discovery of genetic mechanisms, researchers have turned towards identifying potential endophenotypes--subtle neurobiological or neurocognitive traits present in individuals with autism and their "unaffected" relatives. Previous research has shown that relatives of…

Cortical morphology of adolescents with bipolar disorder and with schizophrenia.

PubMed

Janssen, Joost; Alemán-Gómez, Yasser; Schnack, Hugo; Balaban, Evan; Pina-Camacho, Laura; Alfaro-Almagro, Fidel; Castro-Fornieles, Josefina; Otero, Soraya; Baeza, Inmaculada; Moreno, Dolores; Bargalló, Nuria; Parellada, Mara; Arango, Celso; Desco, Manuel

2014-09-01

Recent evidence points to overlapping decreases in cortical thickness and gyrification in the frontal lobe of patients with adult-onset schizophrenia and bipolar disorder with psychotic symptoms, but it is not clear if these findings generalize to patients with a disease onset during adolescence and what may be the mechanisms underlying a decrease in gyrification. This study analyzed cortical morphology using surface-based morphometry in 92 subjects (age range 11-18 years, 52 healthy controls and 40 adolescents with early-onset first-episode psychosis diagnosed with schizophrenia (n=20) or bipolar disorder with psychotic symptoms (n=20) based on a two year clinical follow up). Average lobar cortical thickness, surface area, gyrification index (GI) and sulcal width were compared between groups, and the relationship between the GI and sulcal width was assessed in the patient group. Both patients groups showed decreased cortical thickness and increased sulcal width in the frontal cortex when compared to healthy controls. The schizophrenia subgroup also had increased sulcal width in all other lobes. In the frontal cortex of the combined patient group sulcal width was negatively correlated (r=-0.58, p<0.001) with the GI. In adolescents with schizophrenia and bipolar disorder with psychotic symptoms there is cortical thinning, decreased GI and increased sulcal width of the frontal cortex present at the time of the first psychotic episode. Decreased frontal GI is associated with the widening of the frontal sulci which may reduce sulcal surface area. These results suggest that abnormal growth (or more pronounced shrinkage during adolescence) of the frontal cortex represents a shared endophenotype for psychosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Perinatal stress, brain inflammation and risk of autism-review and proposal.

PubMed

Angelidou, Asimenia; Asadi, Shahrzad; Alysandratos, Konstantinos-Dionysios; Karagkouni, Anna; Kourembanas, Stella; Theoharides, Theoharis C

2012-07-02

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism "susceptibility" genes have been identified, but "environmental" factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood-brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with "allergic" or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood-brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders.

PubMed

Saunders, John A; Gandal, Michael J; Roberts, Timothy P; Siegel, Steve J

2012-10-01

Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials. Copyright © 2012. Published by Elsevier B.V.

Revolution of Alzheimer Precision Neurology Passageway of Systems Biology and Neurophysiology.

PubMed

Hampel, Harald; Toschi, Nicola; Babiloni, Claudio; Baldacci, Filippo; Black, Keith L; Bokde, Arun L W; Bun, René S; Cacciola, Francesco; Cavedo, Enrica; Chiesa, Patrizia A; Colliot, Olivier; Coman, Cristina-Maria; Dubois, Bruno; Duggento, Andrea; Durrleman, Stanley; Ferretti, Maria-Teresa; George, Nathalie; Genthon, Remy; Habert, Marie-Odile; Herholz, Karl; Koronyo, Yosef; Koronyo-Hamaoui, Maya; Lamari, Foudil; Langevin, Todd; Lehéricy, Stéphane; Lorenceau, Jean; Neri, Christian; Nisticò, Robert; Nyasse-Messene, Francis; Ritchie, Craig; Rossi, Simone; Santarnecchi, Emiliano; Sporns, Olaf; Verdooner, Steven R; Vergallo, Andrea; Villain, Nicolas; Younesi, Erfan; Garaci, Francesco; Lista, Simone

2018-03-16

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

Behavioral and Neural Sustained Attention Deficits in Bipolar Disorder and Familial Risk of Bipolar Disorder.

PubMed

Pagliaccio, David; Wiggins, Jillian Lee; Adleman, Nancy E; Harkins, Elizabeth; Curhan, Alexa; Towbin, Kenneth E; Brotman, Melissa A; Pine, Daniel S; Leibenluft, Ellen

2017-11-01

Few neuroimaging studies compare individuals affected with bipolar disorder (BP), at high familial risk of BP, and at low risk to identify endophenotypes for BP. None have examined variability in attention, despite promising behavioral work in this area. We used functional magnetic resonance imaging (fMRI) methods uniquely powered to compare the neural correlates of attention variability in these three groups. The present study examined 8- to 25-year-old individuals (n = 106) who completed an fMRI attention task: 24 with BP, 29 at risk based on a first-degree relative with BP, and 53 healthy, low-risk individuals. Group differences in intrasubject variability in reaction time were examined, and a sophisticated fMRI analytic approach was used to quantify precisely trialwise associations between reaction time and brain activity. The latter has not been examined previously in BP or risk of BP. Relative to healthy individuals, those with BP or at risk for BP exhibited increased reaction time variability (F 2,102 = 4.26, p = .02, η p 2 = .08). Importantly, we identified blunted relationships between trialwise variation in reaction time and brain activity in the inferior and middle frontal gyri, precuneus, cingulate cortex, caudate, and postcentral gyrus (all regions: p < .001, η p 2 > .06) in both at-risk and BP individuals compared with healthy, low-risk individuals. This blunting partially mediated group differences in reaction time variability (β = .010, 95% confidence interval 0.002 to 0.020, Sobel Z = 2.08, p = .038). Blunting in key frontal, cingulate, and striatal areas was evident in unaffected, at-risk individuals and in euthymic BP patients. Elucidating such novel neural endophenotypes can facilitate new approaches to BP prediction, diagnosis, and prevention. Published by Elsevier Inc.

Revolution of Alzheimer Precision Neurology: Passageway of Systems Biology and Neurophysiology

PubMed Central

Hampel, Harald; Toschi, Nicola; Babiloni, Claudio; Baldacci, Filippo; Black, Keith L.; Bokde, Arun L.W.; Bun, René S.; Cacciola, Francesco; Cavedo, Enrica; Chiesa, Patrizia A.; Colliot, Olivier; Coman, Cristina-Maria; Dubois, Bruno; Duggento, Andrea; Durrleman, Stanley; Ferretti, Maria-Teresa; George, Nathalie; Genthon, Remy; Habert, Marie-Odile; Herholz, Karl; Koronyo, Yosef; Koronyo-Hamaoui, Maya; Lamari, Foudil; Langevin, Todd; Lehéricy, Stéphane; Lorenceau, Jean; Neri, Christian; Nisticò, Robert; Nyasse-Messene, Francis; Ritchie, Craig; Rossi, Simone; Santarnecchi, Emiliano; Sporns, Olaf; Verdooner, Steven R.; Vergallo, Andrea; Villain, Nicolas; Younesi, Erfan; Garaci, Francesco; Lista, Simone

2018-01-01

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an “omics”-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer’s disease (AD). The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group “Alzheimer Precision Medicine” (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development towards breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND. PMID:29562524

Auditory Vigilance and Working Memory in Youth at Familial Risk for Schizophrenia or Affective Psychosis in the Harvard Adolescent Family High Risk Study.

PubMed

Seidman, Larry J; Pousada-Casal, Andrea; Scala, Silvia; Meyer, Eric C; Stone, William S; Thermenos, Heidi W; Molokotos, Elena; Agnew-Blais, Jessica; Tsuang, Ming T; Faraone, Stephen V

2016-11-01

The degree of overlap between schizophrenia (SCZ) and affective psychosis (AFF) has been a recurring question since Kraepelin's subdivision of the major psychoses. Studying nonpsychotic relatives allows a comparison of disorder-associated phenotypes, without potential confounds that can obscure distinctive features of the disorder. Because attention and working memory have been proposed as potential endophenotypes for SCZ and AFF, we compared these cognitive features in individuals at familial high-risk (FHR) for the disorders. Young, unmedicated, first-degree relatives (ages, 13-25 years) at FHR-SCZ (n=41) and FHR-AFF (n=24) and community controls (CCs, n=54) were tested using attention and working memory versions of the Auditory Continuous Performance Test. To determine if schizotypal traits or current psychopathology accounted for cognitive deficits, we evaluated psychosis proneness using three Chapman Scales, Revised Physical Anhedonia, Perceptual Aberration, and Magical Ideation, and assessed psychopathology using the Hopkins Symptom Checklist -90 Revised. Compared to controls, the FHR-AFF sample was significantly impaired in auditory vigilance, while the FHR-SCZ sample was significantly worse in working memory. Both FHR groups showed significantly higher levels of physical anhedonia and some psychopathological dimensions than controls. Adjusting for physical anhedonia, phobic anxiety, depression, psychoticism, and obsessive-compulsive symptoms eliminated the FHR-AFF vigilance effects but not the working memory deficits in FHR-SCZ. The working memory deficit in FHR-SZ was the more robust of the cognitive impairments after accounting for psychopathological confounds and is supported as an endophenotype. Examination of larger samples of people at familial risk for different psychoses remains necessary to confirm these findings and to clarify the role of vigilance in FHR-AFF. (JINS, 2016, 22, 1026-1037).

Physiogenomic analysis of localized FMRI brain activity in schizophrenia.

PubMed

Windemuth, Andreas; Calhoun, Vince D; Pearlson, Godfrey D; Kocherla, Mohan; Jagannathan, Kanchana; Ruaño, Gualberto

2008-06-01

The search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes.

Major depression in mothers predict reduced ventral striatum activation in adolescent female offspring with and without depression

USDA-ARS?s Scientific Manuscript database

Prior research has identified reduced reward-related brain activation as a promising endophenotype for the early identification of adolescents with major depressive disorder. However, it is unclear whether reduced reward-related brain activation constitutes a true vulnerability for major depressive ...

On Using Vernier Acuity to Assess Magnocellular Sensitivity

ERIC Educational Resources Information Center

Skottun, Bernt C.; Skoyles, John R.

2010-01-01

A recent study [Keri, S., & Benedek, G. (2009). Visual pathway deficit in female fragile x premutation carriers: A potential endophenotype. "Brain and Cognition", 69, 291-295] has found Vernier acuity deficiencies together with contrast sensitivity defects consistent with a magnocellular deficit in female fragile x premutation carriers. This may…

Association of the 5′-upstream regulatory region of the α7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia

PubMed Central

Stephens, Sarah H.; Logel, Judith; Barton, Amanda; Franks, Alexis; Schultz, Jessica; Short, Margaret; Dickenson, Jane; James, Benjamin; Fingerlin, Tasha E.; Wagner, Brandie; Hodgkinson, Colin; Graw, Sharon; Ross, Randal G.; Freedman, Robert; Leonard, Sherry

2009-01-01

Background The α7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies. Methods Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5′-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia. Results The rs3087454 SNP, located at position −1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P = 0.0009, African American; P = 0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia. Conclusions The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia. PMID:19181484

Positive Emotion Specificity and Mood Symptoms in an Adolescent Outpatient Sample

PubMed Central

Gruber, June; Van Meter, Anna; Gilbert, Kirsten E.; Youngstrom, Eric A.; Youngstrom, Jennifer Kogos; Feeny, Norah C.; Findling, Robert L.

2017-01-01

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11–18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development. PMID:28529394

Gamma-band abnormalities as markers of autism spectrum disorders

PubMed Central

Rojas, Donald C.; Wilson, Lisa B.

2014-01-01

Summary Autism is a behaviorally diagnosed neurodevelopmental disorder with no current biomarkers with high specificity and sensitivity. Gamma-band abnormalities have been reported in many studies of autism spectrum disorders. Gamma-band activity is associated with perceptual and cognitive functions that are compromised in autism. Some gamma-band deficits have also been seen in unaffected first-degree relatives, suggesting heritability of these findings. This review covers the published literature on gamma abnormalities in autism, the proposed mechanisms underlying the deficits, and the potential for translation into new treatments. Although the utility of gamma-band metrics as diagnostic biomarkers is currently limited, such changes in autism are also useful as endophenotypes, for evaluating potential neural mechanisms, and for use as surrogate markers of treatment response to interventions. PMID:24712425

Executive Functions as Endophenotypes in ADHD: Evidence from the Cambridge Neuropsychological Test Battery (CANTAB)

ERIC Educational Resources Information Center

Gau, Susan Shur-Fen; Shang, Chi-Yung

2010-01-01

Background: Little is known about executive functions among unaffected siblings of children with attention deficit/hyperactivity disorder (ADHD), and there is lack of such information from non-Western countries. We examined verbal and nonverbal executive functions in adolescents with ADHD, unaffected siblings and controls to test whether executive…

Autism and 15q11-q13 Disorders: Behavioral, Genetic, and Pathophysiological Issues

ERIC Educational Resources Information Center

Dykens, Elisabeth M.; Sutcliffe, James S.; Levitt, Pat

2004-01-01

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare…

Research Review: Crossing Syndrome Boundaries in the Search for Brain Endophenotypes

ERIC Educational Resources Information Center

Levy, Yonata; Ebstein, Richard P.

2009-01-01

The inherent imprecision of behavioral phenotyping is the single most important factor contributing to the failure to discover the biological factors that are involved in psychiatric and neurodevelopmental disorders (e.g., Bearden & Freimer, 2006). In this review article we argue that in addition to an appreciation of the inherent complexity at…

Brief Report: An Autistic Spectrum Subtype Revealed through Familial Psychopathology Coupled with Cognition in ASD

ERIC Educational Resources Information Center

Lajiness-O'Neill, Renee; Menard, Philip

2008-01-01

This study identified a possible autistic spectrum subtype expressed through family psychopathology coupled with autistic probands' cognitive functioning (i.e., an endophenotypic profile). Participants included 24 children with Autism Spectrum Disorder (ASD) and 49 children with Learning Disorder (LD). There were significantly higher rates of Mood…

Visual Pathway Deficit in Female Fragile X Premutation Carriers: A Potential Endophenotype

ERIC Educational Resources Information Center

Keri, Szabolcs; Benedek, Gyorgy

2009-01-01

Previous studies indicated impaired magnocellular (M) and relatively spared parvocellular (P) visual pathway functioning in patients with fragile X syndrome. In this study, we assessed M and P pathways in 22 female fragile X premutation carriers with normal intelligence and in 20 healthy non-carrier controls. Testing procedure included visual…

Anorexia Nervosa and Autism Spectrum Disorders: Guided Investigation of Social Cognitive Endophenotypes

ERIC Educational Resources Information Center

Zucker, Nancy L.; Losh, Molly; Bulik, Cynthia M.; LaBar, Kevin S.; Piven, Joseph; Pelphrey, Kevin A.

2007-01-01

Death by suicide occurs in a disproportionate percentage of individuals with anorexia nervosa (AN), with a standardized mortality ratio indicating a 57-fold greater risk of death from suicide relative to an age-matched cohort. Longitudinal studies indicate impaired social functioning increases risk for fatal outcomes, while social impairment…

Neurocognitive Functioning in AD/HD, Predominantly Inattentive and Combined Subtypes

ERIC Educational Resources Information Center

Solanto, Mary V.; Gilbert, Sharone N.; Raj, Anu; Zhu, John; Pope-Boyd, Sa'brina; Stepak, Brenda; Vail, Lucia; Newcorn, Jeffrey H.

2007-01-01

The Predominantly Inattentive (PI) and Combined (CB) subtypes of AD/HD differ in cognitive tempo, age of onset, gender ratio, and comorbidity, yet a differentiating endophenotype has not been identified. The aim of this study was to test rigorously diagnosed PI, CB, and typical children on measures selected for their potential to reveal…

Sensation seeking and impulsive traits as personality endophenotypes for antisocial behavior: Evidence from two independent samples

PubMed Central

Mann, Frank D.; Engelhardt, Laura; Briley, Daniel A.; Grotzinger, Andrew D.; Patterson, Megan W.; Tackett, Jennifer L.; Strathan, Dixie B.; Heath, Andrew; Lynskey, Michael; Slutske, Wendy; Martin, Nicholas G.; Tucker-Drob, Elliot M.; Harden, K. Paige

2017-01-01

Sensation seeking and impulsivity are personality traits that are correlated with risk for antisocial behavior (ASB). This paper uses two independent samples of twins to (a) test the extent to which sensation seeking and impulsivity statistically mediate genetic influence on ASB, and (b) compare this to genetic influences accounted for by other personality traits. In Sample 1, delinquent behavior, as well as impulsivity, sensation seeking and Big Five personality traits, were measured in adolescent twins from the Texas Twin Project. In Sample 2, adult twins from the Australian Twin Registry responded to questionnaires that assessed individual differences in Eysenck's and Cloninger's personality dimensions, and a structured telephone interview that asked participants to retrospectively report DSM-defined symptoms of conduct disorder. Bivariate quantitative genetic models were used to identify genetic overlap between personality traits and ASB. Across both samples, novelty/sensation seeking and impulsive traits accounted for larger portions of genetic variance in ASB than other personality traits. We discuss whether sensation seeking and impulsive personality are causal endophenotypes for ASB, or merely index genetic liability for ASB. PMID:28824215

Hippocampal place cell and inhibitory neuron activity in disrupted-in-schizophrenia-1 mutant mice: implications for working memory deficits

PubMed Central

Mesbah-Oskui, Lia; Georgiou, John; Roder, John C

2015-01-01

Background: Despite the prevalence of working memory deficits in schizophrenia, the neuronal mechanisms mediating these deficits are not fully understood. Importantly, deficits in spatial working memory are identified in numerous mouse models that exhibit schizophrenia-like endophenotypes. The hippocampus is one of the major brain regions that actively encodes spatial location, possessing pyramidal neurons, commonly referred to as ‘place cells’, that fire in a location-specific manner. This study tests the hypothesis that mice with a schizophrenia-like endophenotype exhibit impaired encoding of spatial location in the hippocampus. Aims: To characterize hippocampal place cell activity in mice that exhibit a schizophrenia-like endophenotype. Methods: We recorded CA1 place cell activity in six control mice and six mice that carry a point mutation in the disrupted-in-schizophrenia-1 gene (Disc1-L100P) and have previously been shown to exhibit deficits in spatial working memory. Results: The spatial specificity and stability of Disc1-L100P place cells were similar to wild-type place cells. Importantly, however, Disc1-L100P place cells exhibited a higher propensity to increase their firing rate in a single, large location of the environment, rather than multiple smaller locations, indicating a generalization in their spatial selectivity. Alterations in the signaling and numbers of CA1 putative inhibitory interneurons and decreased hippocampal theta (5–12 Hz) power were also identified in the Disc1-L100P mice. Conclusions: The generalized spatial selectivity of Disc1-L100P place cells suggests a simplification of the ensemble place codes that encode individual locations and subserve spatial working memory. Moreover, these results suggest that deficient working memory in schizophrenia results from an impaired ability to uniquely code the individual components of a memory sequence. PMID:27280123

Genetic variant for behavioral regulation factor of executive function and its possible brain mechanism in attention deficit hyperactivity disorder.

PubMed

Sun, Xiao; Wu, Zhaomin; Cao, Qingjiu; Qian, Ying; Liu, Yong; Yang, Binrang; Chang, Suhua; Yang, Li; Wang, Yufeng

2018-05-16

As a childhood-onset psychiatric disorder, attention deficit hyperactivity disorder (ADHD) is complicated by phenotypic and genetic heterogeneity. Lifelong executive function deficits in ADHD are described in many literatures and have been proposed as endophenotypes of ADHD. However, its genetic basis is still elusive. In this study, we performed a genome-wide association study of executive function, rated with Behavioral Rating Inventory of Executive Function (BRIEF), in ADHD children. We identified one significant variant (rs852004, P = 2.51e-08) for the overall score of BRIEF. The association analyses for each component of executive function found this locus was more associated with inhibit and monitor components. Further principle component analysis and confirmatory factor analysis provided an ADHD-specific executive function pattern including inhibit and monitor factors. SNP rs852004 was mainly associated with the Behavioral Regulation factor. Meanwhile, we found the significant locus was associated with ADHD symptom. The Behavioral Regulation factor mediated its effect on ADHD symptom. Functional magnetic resonance imaging (fMRI) analyses further showed evidence that this variant affected the activity of inhibition control related brain regions. It provided new insights for the genetic basis of executive function in ADHD.

Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings.

PubMed

Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

2015-11-26

Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed - right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed - bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia.

Resting-state cerebellar-cerebral networks are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings

PubMed Central

Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Xiao, Changqing; Zhao, Jingping

2015-01-01

Dysconnectivity hypothesis posits that schizophrenia is a disorder with dysconnectivity of the cortico-cerebellar-thalamic-cortical circuit (CCTCC). However, it remains unclear to the changes of the cerebral connectivity with the cerebellum in schizophrenia patients and unaffected siblings. Forty-nine patients with first-episode, drug-naive schizophrenia patients, 46 unaffected siblings of schizophrenia patients and 46 healthy controls participated in the study. Seed-based resting-state functional connectivity approach was employed to analyze the data. Compared with the controls, the patients and the siblings share increased default-mode network (DMN) seed – right Crus II connectivity. The patients have decreased right dorsal attention network (DAN) seed – bilateral cerebellum 4,5 connectivity relative to the controls. By contrast, the siblings exhibit increased FC between the right DAN seed and the right cerebellum 6 and right cerebellum 4,5 compared to the controls. No other abnormal connectivities (executive control network and salience network) are observed in the patients/siblings relative to the controls. There are no correlations between abnormal cerebellar-cerebral connectivities and clinical variables. Cerebellar-cerebral connectivity of brain networks within the cerebellum are differently affected in first-episode, drug-naive schizophrenia patients and unaffected siblings. Increased DMN connectivity with the cerebellum may serve as potential endophenotype for schizophrenia. PMID:26608842

Bipolar disorder and antithyroid antibodies: review and case series.

PubMed

Bocchetta, Alberto; Traccis, Francesco; Mosca, Enrica; Serra, Alessandra; Tamburini, Giorgio; Loviselli, Andrea

2016-12-01

Mood disorders and circulating thyroid antibodies are very prevalent in the population and their concomitant occurrence may be due to chance. However, thyroid antibodies have been repeatedly hypothesized to play a role in specific forms of mood disorders. Potentially related forms include treatment-refractory cases, severe or atypical depression, and depression at specific phases of a woman's life (early gestation, postpartum depression, perimenopausal). With regard to bipolar disorder, studies of specific subgroups (rapid cycling, mixed, or depressive bipolar) have reported associations with thyroid antibodies. Offspring of bipolar subjects were found more vulnerable to develop thyroid antibodies independently from the vulnerability to develop psychiatric disorders. A twin study suggested thyroid antibodies among possible endophenotypes for bipolar disorder. Severe encephalopathies have been reported in association with Hashimoto's thyroiditis. Cases with pure psychiatric presentation are being reported, the antithyroid antibodies being probably markers of some other autoimmune disorders affecting the brain. Vasculitis resulting in abnormalities in cortical perfusion is one of the possible mechanisms.

Genetics of addictive behavior: the example of nicotine dependence.

PubMed

Gorwood, Philip; Le Strat, Yann; Ramoz, Nicolas

2017-09-01

The majority of addictive disorders have a significant heritability-roughly around 50%. Surprisingly, the most convincing association (a nicotinic acetylcholine receptor CHRNA5-A3-B4 gene cluster in nicotine dependence), with a unique attributable risk of 14%, was detected through a genome-wide association study (GWAS) on lung cancer, although lung cancer has a low heritability. We propose some explanations of this finding, potentially helping to understand how a GWAS strategy can be successful. Many endophenotypes were also assessed as potentially modulating the effect of nicotine, indirectly facilitating the development of nicotine dependence. Challenging the involved phenotype led to the demonstration that other potentially overlapping disorders, such as schizophrenia and Parkinson disease, could also be involved, and further modulated by parent monitoring or the existence of a smoking partner. Such a complex mechanism of action is compatible with a gene-environment interaction, most clearly explained by epigenetic factors, especially as such factors were shown to be, at least partly, genetically driven.

Phenomenology of tics and natural history of tic disorders.

PubMed

Leckman, James F

2003-12-01

Tic symptoms, the hallmark of Tourette's syndrome (TS), may simply be fragments of innate behavior. As such, the sensory urges that precede tics may illuminate some of the normal internal cues that are intimately involved in the assembly of behavioral sequences. The occurrence of tics in time appears to have fractal characteristics that may help to explain the waxing and waning course of tic disorders. Longitudinal studies are currently underway that should permit a close examination of the natural fluctuations in tic severity using valid and reliable clinician-rated scales of tic severity. The natural history of tics typically shows a marked decline during the course of adolescence. However, TS can also be associated with social, emotional, and academic difficulties in early adulthood. Comorbid attention deficit/hyperactivity disorder and obsessive-compulsive disorder are likely to influence the long-term adaptive outcomes of individuals with TS. Future progress may also be expected as endophenotypes, and possibly genetic markers, are identified that are associated with specific comorbid conditions and etiologically distinct forms of TS.

Longitudinal Study of Neurological Soft Signs in First-Episode Early-Onset Psychosis

ERIC Educational Resources Information Center

Mayoral, M.; Bombin, I.; Castro-Fornieles, J.; Gonzalez-Pinto, A.; Otero, S.; Parellada, M.; Moreno, D.; Baeza, I.; Graell, M.; Rapado, M.; Arango, C.

2012-01-01

Background: In recent decades, the assessment of neurological soft signs (NSS) in patients with psychosis has become a subject of special interest. The study of the progression of NSS during adolescence will provide valuable information about the role of NSS as endophenotypes or biomarkers and about brain development at a stage in which brain…

Cognitive Dysfunction Is Worse among Pediatric Patients with Bipolar Disorder Type I than Type II

ERIC Educational Resources Information Center

Schenkel, Lindsay S.; West, Amy E.; Jacobs, Rachel; Sweeney, John A.; Pavuluri, Mani N.

2012-01-01

Background: Impaired profiles of neurocognitive function have been consistently demonstrated among pediatric patients with bipolar disorder (BD), and may aid in the identification of endophenotypes across subtypes of the disorder. This study aims to determine phenotypic cognitive profiles of patients with BD Type I and II. Methods: Subjects (N =…

Performance Variability, Impulsivity Errors and the Impact of Incentives as Gender-Independent Endophenotypes for ADHD

ERIC Educational Resources Information Center

Uebel, Henrik; Albrecht, Bjorn; Asherson, Philip; Borger, Norbert A.; Butler, Louise; Chen, Wai; Christiansen, Hanna; Heise, Alexander; Kuntsi, Jonna; Schafer, Ulrike; Andreou, Penny; Manor, Iris; Marco, Rafaela; Miranda, Ana; Mulligan, Aisling; Oades, Robert D.; van der Meere, Jaap; Faraone, Stephen V.; Rothenberger, Aribert; Banaschewski, Tobias

2010-01-01

Background: Attention-deficit hyperactivity disorder (ADHD) is one of the most common and highly heritable child psychiatric disorders. There is strong evidence that children with ADHD show slower and more variable responses in tasks such as Go/Nogo tapping aspects of executive functions like sustained attention and response control which may be…

Predicting Dyslexia at Age 11 from a Risk Index Questionnaire at Age 5

ERIC Educational Resources Information Center

Helland, Turid; Plante, Elena; Hugdahl, Kenneth

2011-01-01

This study focused on predicting dyslexia in children ahead of formal literacy training. Because dyslexia is a constitutional impairment, risk factors should be seen in preschool. It was hypothesized that data gathered at age 5 using questions targeting the dyslexia endophenotype should be reliable and valid predictors of dyslexia at age 11. A…

Atypical Activation during the Embedded Figures Task as a Functional Magnetic Resonance Imaging Endophenotype of Autism

ERIC Educational Resources Information Center

Spencer, Michael D.; Holt, Rosemary J.; Chura, Lindsay R.; Calder, Andrew J.; Suckling, John; Bullmore, Edward T.; Baron-Cohen, Simon

2012-01-01

Atypical activation during the Embedded Figures Task has been demonstrated in autism, but has not been investigated in siblings or related to measures of clinical severity. We identified atypical activation during the Embedded Figures Task in participants with autism and unaffected siblings compared with control subjects in a number of temporal…

Candidate Electrophysiological Endophenotypes of Hyper-Reactivity to Change in Autism

ERIC Educational Resources Information Center

Gomot, Marie; Blanc, Romuald; Clery, Helen; Roux, Sylvie; Barthelemy, Catherine; Bruneau, Nicole

2011-01-01

Although resistance to change is a main feature of autism, the brain processes underlying this aspect of the disorder remain poorly understood. The aims of this study were to examine neural basis of auditory change-detection in children with autism spectrum disorders (ASD; N = 27) through electrophysiological patterns (MMN, P3a) and to test…

Nonverbal and Verbal Cognitive Discrepancy Profiles in Autism Spectrum Disorders: Influence of Age and Gender

ERIC Educational Resources Information Center

Ankenman, Katy; Elgin, Jenna; Sullivan, Katherine; Vincent, Logan; Bernier, Raphael

2014-01-01

Research suggests that discrepant cognitive abilities are more common in children with autism spectrum disorder (ASD) and may indicate an important ASD endophenotype. The current study examined the frequency of IQ discrepancy profiles (nonverbal IQ greater than verbal IQ [NVIQ greater than VIQ], verbal IQ greater than nonverbal IQ [VIQ greater…

The Autism-Spectrum Quotient and Visual Search: Shallow and Deep Autistic Endophenotypes

ERIC Educational Resources Information Center

Gregory, B. L.; Plaisted-Grant, K. C.

2016-01-01

A high Autism-Spectrum Quotient (AQ) score (Baron-Cohen et al. in "J Autism Dev Disord" 31(1):5-17, 2001) is increasingly used as a proxy in empirical studies of perceptual mechanisms in autism. Several investigations have assessed perception in non-autistic people measured for AQ, claiming the same relationship exists between…

High novelty seeking as a predictor of antisocial behaviour in early adulthood.

PubMed

Foulds, James; Boden, Joseph; Horwood, John; Mulder, Roger

2017-11-01

This study aimed to examine the association between novelty seeking (NS) and antisocial behaviours (age 18-35). A New Zealand general population birth cohort was studied from 1977 to 2012. Sample sizes ranged from n = 962 (age 35) to n = 1025 (age 18). NS was measured at age 16 using the Tridimensional Personality Questionnaire. Perpetration of antisocial behaviours was ascertained by self-report at ages 18, 21, 25, 30 and 35. Generalized estimating equation models investigated the association between NS and antisocial behaviours net of individual factors and correlates of NS before age 16 and alcohol and substance use disorders at age 18-35. Higher NS scores were associated with a higher unadjusted incidence of all forms of antisocial behaviour. Assault, theft, property damage and dishonesty offending remained associated with NS after adjustment for individual factors and correlates of NS before age 16. After further adjustment for alcohol and substance use disorders, NS was not associated with any antisocial behaviour outcomes, suggesting those disorders mediate the association between NS and antisocial behaviours. Alcohol and substance use disorders mediate the association between NS and antisocial behaviours in early adulthood. NS may be a useful endophenotype for investigating the causation of externalizing behaviours. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

PubMed Central

Windemuth, Andreas; Calhoun, Vince D.; Pearlson, Godfrey D.; Kocherla, Mohan; Jagannathan, Kanchana; Ruaño, Gualberto

2009-01-01

The search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes. PMID:18330705

Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting.

PubMed

Walsh, Ryan R; Krismer, Florian; Galpern, Wendy R; Wenning, Gregor K; Low, Phillip A; Halliday, Glenda; Koroshetz, Walter J; Holton, Janice; Quinn, Niall P; Rascol, Olivier; Shaw, Leslie M; Eidelberg, David; Bower, Pam; Cummings, Jeffrey L; Abler, Victor; Biedenharn, Judy; Bitan, Gal; Brooks, David J; Brundin, Patrik; Fernandez, Hubert; Fortier, Philip; Freeman, Roy; Gasser, Thomas; Hewitt, Art; Höglinger, Günter U; Huentelman, Matt J; Jensen, Poul H; Jeromin, Andreas; Kang, Un Jung; Kaufmann, Horacio; Kellerman, Lawrence; Khurana, Vikram; Klockgether, Thomas; Kim, Woojin Scott; Langer, Carol; LeWitt, Peter; Masliah, Eliezer; Meissner, Wassilios; Melki, Ronald; Ostrowitzki, Susanne; Piantadosi, Steven; Poewe, Werner; Robertson, David; Roemer, Cyndi; Schenk, Dale; Schlossmacher, Michael; Schmahmann, Jeremy D; Seppi, Klaus; Shih, Lily; Siderowf, Andrew; Stebbins, Glenn T; Stefanova, Nadia; Tsuji, Shoji; Sutton, Sharon; Zhang, Jing

2018-01-09

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided. Copyright © 2017 American Academy of Neurology.

Differences in Neural Correlates of Speech Perception in 3 Month Olds at High and Low Risk for Autism Spectrum Disorder

ERIC Educational Resources Information Center

Edwards, Laura A.; Wagner, Jennifer B.; Tager-Flusberg, Helen; Nelson, Charles A.

2017-01-01

In this study, we investigated neural precursors of language acquisition as potential endophenotypes of autism spectrum disorder (ASD) in 3-month-old infants at high and low familial ASD risk. Infants were imaged using functional near-infrared spectroscopy while they listened to auditory stimuli containing syllable repetitions; their neural…

N400 Deficits from Semantic Matching of Pictures in Probands and First-Degree Relatives from Multiplex Schizophrenia Families

ERIC Educational Resources Information Center

Guerra, Seidel; Ibanez, Agustin; Martin, Migdyrai; Bobes, Maria Antonieta; Reyes, Adnelys; Mendoza, Raul; Bravo, Tania; Dominguez, Mayelin; Sosa, Mitchell Valdes

2009-01-01

Endophenotypes is one emerging strategy in schizophrenia research that is being used to identify the functional importance of genetically transmitted, brain-based deficits present in this disease. Currently, event-related potentials (ERPs) are timely used in this search. Several ERPs, including N400, present deficits in relation to schizophrenia.…

Annual Research Review: Progress in Using Brain Morphometry as a Clinical Tool for Diagnosing Psychiatric Disorders

ERIC Educational Resources Information Center

Haubold, Alexander; Peterson, Bradley S.; Bansal, Ravi

2012-01-01

Brain morphometry in recent decades has increased our understanding of the neural bases of psychiatric disorders by localizing anatomical disturbances to specific nuclei and subnuclei of the brain. At least some of these disturbances precede the overt expression of clinical symptoms and possibly are endophenotypes that could be used to diagnose an…

Genetics of Preparation and Response Control in ADHD: The Role of DRD4 and DAT1

ERIC Educational Resources Information Center

Albrecht, Björn; Brandeis, Daniel; Uebel-von Sandersleben, Henrik; Valko, Lilian; Heinrich, Hartmut; Xu, Xiaohui; Drechsler, Renate; Heise, Alexander; Kuntsi, Jonna; Müller, Ueli C.; Asherson, Philip; Steinhausen, Hans-Christoph; Rothenberger, Aribert; Banaschewski, Tobias

2014-01-01

Background: Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine…

Integrating Behavioral Economics and Behavioral Genetics: Delayed Reward Discounting as an Endophenotype for Addictive Disorders

ERIC Educational Resources Information Center

MacKillop, James

2013-01-01

Delayed reward discounting is a behavioral economic index of impulsivity, referring to how much an individual devalues a reward based on its delay in time. As a behavioral process that varies considerably across individuals, delay discounting has been studied extensively as a model for self-control, both in the general population and in clinical…

Do Different ADHD-Related Etiological Risks Involve Specific Neuropsychological Pathways? An Analysis of Mediation Processes by Inhibitory Control and Delay Aversion

ERIC Educational Resources Information Center

Pauli-Pott, Ursula; Dalir, Silke; Mingebach, Tanja; Roller, Alisa; Becker, Katja

2013-01-01

Background: Inhibitory control (IC) has been regarded as a neuropsychological basic deficit and as an endophenotype of attention deficit/hyperactivity disorder (ADHD). Implicated here are mediation processes between etiological factors and ADHD symptoms. We thus analyze whether and to what extent executive IC and delay aversion (DA; i.e.,…

Animal Models of Maladaptive Traits: Disorders in Sensorimotor Gating and Attentional Quantifiable Responses as Possible Endophenotypes

PubMed Central

Vargas, Juan P.; Díaz, Estrella; Portavella, Manuel; López, Juan C.

2016-01-01

Traditional diagnostic scales are based on a number of symptoms to evaluate and classify mental diseases. In many cases, this process becomes subjective, since the patient must calibrate the magnitude of his/her symptoms and therefore the severity of his/her disorder. A completely different approach is based on the study of the more vulnerable traits of cognitive disorders. In this regard, animal models of mental illness could be a useful tool to characterize indicators of possible cognitive dysfunctions in humans. Specifically, several cognitive disorders such as schizophrenia involve a dysfunction in the mesocorticolimbic dopaminergic system during development. These variations in dopamine levels or dopamine receptor sensibility correlate with many behavioral disturbances. These behaviors may be included in a specific phenotype and may be analyzed under controlled conditions in the laboratory. The present study provides an introductory overview of different quantitative traits that could be used as a possible risk indicator for different mental disorders, helping to define a specific endophenotype. Specifically, we examine different experimental procedures to measure impaired response in attention linked to sensorimotor gating as a possible personality trait involved in maladaptive behaviors. PMID:26925020

Block design reconstruction skills: not a good candidate for an endophenotypic marker in autism research.

PubMed

de Jonge, Maretha; Kemner, Chantal; Naber, Fabienne; van Engeland, Herman

2009-04-01

Superior performance on block design tasks is reported in autistic individuals, although it is not consistently found in high-functioning individuals or individuals with Asperger Syndrome. It is assumed to reflect weak central coherence: an underlying cognitive deficit, which might also be part of the genetic makeup of the disorder. We assessed block design reconstruction skills in high-functioning individuals with autism spectrum disorders (ASD) from multi-incidence families and in their parents. Performance was compared to relevant matched control groups. We used a task that was assumed to be highly sensitive to subtle performance differences. We did not find individuals with ASD to be significantly faster on this task than the matched control group, not even when the difference between reconstruction time of segmented and pre-segmented designs was compared. However, we found individuals with ASD to make fewer errors during the process of reconstruction which might indicate some dexterity in mental segmentation. However, parents of individuals with ASD did not perform better on the task than control parents. Therefore, based on our data, we conclude that mental segmentation ability as measured with a block design reconstruction task is not a neurocognitive marker or endophenotype useful in genetic studies.

Time reproduction in children with ADHD and their nonaffected siblings.

PubMed

Rommelse, Nanda N J; Oosterlaan, Jaap; Buitelaar, Jan; Faraone, Stephen V; Sergeant, Joseph A

2007-05-01

Time reproduction is deficient in children with attention-deficit/hyperactivity disorder (ADHD). Whether this deficit is familial and could therefore serve as a candidate endophenotype has not been previously investigated. It is unknown whether timing deficits are also measurable in adolescent children with ADHD and nonaffected siblings. These issues were investigated in 226 children with ADHD, 188 nonaffected siblings, and 162 normal controls ages 5 to 19. Children participated in a visual and auditory time reproduction task. They reproduced interval lengths of 4, 8, 12, 16, and 20 seconds. Children with ADHD and their nonaffected siblings were less precise than controls, particularly when task difficulty was systematically increased. Time reproduction skills were familial. Time reproduction deficits were more pronounced in younger children with ADHD than in older children. Children with ADHD could be clearly dissociated from control children until the age of 9. After this age, group differences were somewhat attenuated, but were still present. Differences between nonaffected siblings and controls were constant across the age range studied. Deficits were unaffected by modality. Time reproduction may serve as a candidate endophenotype for ADHD, predominantly in younger children with (a genetic risk for) ADHD.

Establishment of an Italian chronic migraine database: a multicenter pilot study.

PubMed

Barbanti, Piero; Fofi, L; Cevoli, S; Torelli, P; Aurilia, C; Egeo, G; Grazzi, L; D'Amico, D; Manzoni, G C; Cortelli, P; Infarinato, F; Vanacore, N

2018-05-01

To optimize chronic migraine (CM) ascertainment and phenotype definition, provide adequate clinical management and health care procedures, and rationalize economic resources allocation, we performed an exploratory multicenter pilot study aimed at establishing a CM database, the first step for developing a future Italian CM registry. We enrolled 63 consecutive CM patients in four tertiary headache centers screened with face-to-face interviews using an ad hoc dedicated semi-structured questionnaire gathering detailed information on life-style, behavioral and socio-demographic factors, comorbidities, and migraine features before and after chronicization and healthcare resource use. Our pilot study provided useful insights revealing that CM patients (1) presented in most cases symptoms of peripheral trigeminal sensitization, a relatively unexpected feature which could be useful to unravel different CM endophenotypes and to predict trigeminal-targeted treatments' responsiveness; (2) had been frequently admitted to emergency departments; (3) had undergone, sometime repeatedly, unnecessary or inappropriate investigations; (4) got rarely illness benefit exemption or disability allowance only. We deem that the expansion of the database-shortly including many other Italian headache centers-will contribute to more precisely outline CM endophenotypes, hence improving management, treatment, and economic resource allocation, ultimately reducing CM burden on both patients and health system.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

PubMed Central

Wang, Peng; Li, Hui; Barde, Swapnali; Zhang, Ming-Dong; Sun, Jing; Wang, Tong; Zhang, Pan; Luo, Hanjiang; Wang, Yongjun; Yang, Yutao; Wang, Chuanyue; Svenningsson, Per; Theodorsson, Elvar; Hökfelt, Tomas G. M.; Xu, Zhi-Qing David

2016-01-01

The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects. PMID:27457954

Perinatal stress, brain inflammation and risk of autism-Review and proposal

PubMed Central

2012-01-01

Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients. PMID:22747567

The effect of stimulus strength on binocular rivalry rate in healthy individuals: Implications for genetic, clinical and individual differences studies.

PubMed

Law, Phillip C F; Miller, Steven M; Ngo, Trung T

2017-11-01

Binocular rivalry (BR) occurs when conflicting images concurrently presented to corresponding retinal locations of each eye stochastically alternate in perception. Anomalies of BR rate have been examined in a range of clinical psychiatric conditions. In particular, slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) to improve power in large-scale genome-wide association studies. Examining the validity of BR rate as a BD endophenotype however requires large-scale datasets (n=1000s to 10,000s), a standardized testing protocol, and optimization of stimulus parameters to maximize separation between BD and healthy groups. Such requirements are indeed relevant to all clinical psychiatric BR studies. Here we address the issue of stimulus optimization by examining the effect of stimulus parameter variation on BR rate and mixed-percept duration (MPD) in healthy individuals. We aimed to identify the stimulus parameters that induced the fastest BR rates with the least MPD. Employing a repeated-measures within-subjects design, 40 healthy adults completed four BR tasks using orthogonally drifting grating stimuli that varied in drift speed and aperture size. Pairwise comparisons were performed to determine modulation of BR rate and MPD by these stimulus parameters, and individual variation of such modulation was also assessed. From amongst the stimulus parameters examined, we found that 8cycles/s drift speed in a 1.5° aperture induced the fastest BR rate without increasing MPD, but that BR rate with this stimulus configuration was not substantially different to BR rate with stimulus parameters we have used in previous studies (i.e., 4cycles/s drift speed in a 1.5° aperture). In addition to contributing to stimulus optimization issues, the findings have implications for Levelt's Proposition IV of binocular rivalry dynamics and individual differences in such dynamics. Copyright © 2017 Elsevier Inc. All rights reserved.

Rhythmicity in Mice Selected for Extremes in Stress Reactivity: Behavioural, Endocrine and Sleep Changes Resembling Endophenotypes of Major Depression

PubMed Central

Ruschel, Jörg; Palme, Rupert; Holsboer, Florian; Kimura, Mayumi; Landgraf, Rainer

2009-01-01

Background Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors. Methodology/Principle Findings In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice. Conclusion/Significance Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD. PMID:19177162

Differing Developmental Trajectories in Heart Rate Responses to Speech Stimuli in Infants at High and Low Risk for Autism Spectrum Disorder

ERIC Educational Resources Information Center

Perdue, Katherine L.; Edwards, Laura A.; Tager-Flusberg, Helen; Nelson, Charles A.

2017-01-01

We investigated heart rate (HR) in infants at 3, 6, 9, and 12 months of age, at high (HRA) and low (LRC) familial risk for ASD, to identify potential endophenotypes of ASD risk related to attentional responses. HR was extracted from functional near-infrared spectroscopy recordings while infants listened to speech stimuli. Longitudinal analysis…

Abnormal Vestibulo-Ocular Reflexes in Autism: A Potential Endophenotype

DTIC Science & Technology

2013-06-01

Annual Report for 15 May 2012 – 14 May 2013 8 Table 5. Summary of Gaze Evoked Nystagmus Tests (no differences between groups) Target...abnormalities of vestibulo-ocular reflexes (VOR) in Autism Spectrum Disorder (ASD). Specific Aim 1: Characterize horizontal VOR post-rotary nystagmus ...without optokinetic feedback using a velocity step test. We hypothesize that in ASD vertical eye movement intrusions during horizontal nystagmus will

Mild neurological impairment may indicate a psychomotor endophenotype in patients with borderline personality disorder.

PubMed

Arbabi, Mohammad; Paast, Negin; Karim, Hamid Reza; Faghfori, Sara; Memari, Amir Hossein

2016-11-30

The aim of the present study was to determine whether patients with borderline personality disorder (BPD) show any neurological soft signs compared to healthy controls. Furthermore we sought to examine the role of common symptoms related to BPD, such as depression, anxiety or impulsivity, in association with neurological soft signs. Thirty patients with borderline personality disorder and thirty hospital-based controls were examined for neurological soft signs. The total score of neurological soft signs in BPD was significantly higher than controls. In terms of subscales, patients had higher scores in Sensory Integration and Motor Coordination and other neurological soft signs compared to control group. Multiple regression analysis showed that the impulsivity score was the best significant predictor of neurological soft signs in BPD. The increase of neurological soft signs in patients with BPD may address a non-focal neurological dysfunction in borderline personality disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: A genome-wide association study

PubMed Central

VAIDYANATHAN, UMA; MALONE, STEPHEN M.; MILLER, MICHAEL B.; McGUE, MATT; IACONO, WILLIAM G.

2014-01-01

Acoustic startle responses have been studied extensively in relation to individual differences and psychopathology. We examined three indices of the blink response in a picture-viewing paradigm—overall startle magnitude across all picture types, and aversive and pleasant modulation scores—in 3,323 twins and parents. Biometric models and molecular genetic analyses showed that half the variance in overall startle was due to additive genetic effects. No single nucleotide polymorphism was genome-wide significant, but GRIK3 did produce a significant effect when examined as part of a candidate gene set. In contrast, emotion modulation scores showed little evidence of heritability in either biometric or molecular genetic analyses. However, in a genome-wide scan, PARP14 did produce a significant effect for aversive modulation. We conclude that, although overall startle retains potential as an endophenotype, emotion-modulated startle does not. PMID:25387708

Self responses along cingulate cortex reveal quantitative neural phenotype for high functioning autism

PubMed Central

Chiu, Pearl H.; Kayali, M. Amin; Kishida, Kenneth T.; Tomlin, Damon; Klinger, Laura G.; Klinger, Mark R.; Montague, P. Read

2014-01-01

Summary Attributing behavioral outcomes correctly to oneself or to other agents is essential for all productive social exchange. We approach this issue in high-functioning males with autism spectrum disorder (ASD) using two separate fMRI paradigms. First, using a visual imagery task, we extract a basis set for responses along the cingulate cortex of control subjects that reveals an agent-specific eigenvector (self eigenmode) associated with imagining oneself executing a specific motor act. Second, we show that the same self eigenmode arises during one's own decision (the self phase) in an interpersonal exchange game (iterated trust game). Third, using this exchange game, we show that ASD males exhibit a severely diminished self eigenmode when playing the game with a human partner. This diminished response covaries parametrically with their behaviorally assessed symptom severity suggesting its value as an objective endophenotype. These findings may provide a quantitative assessment tool for high functioning ASD. PMID:18255038

Neurological Soft Signs in Schizophrenia: A Meta-analysis

PubMed Central

Chan, Raymond C. K.; Xu, Ting; Heinrichs, R. Walter; Yu, Yue; Wang, Ya

2010-01-01

Background: Neurological soft signs (NSS) are hypothesized as candidate endophenotypes for schizophrenia, but their prevalence and relations with clinical and demographic data are unknown. The authors undertook a quantification (meta-analysis) of the published literature on NSS in patients with schizophrenia and healthy controls. A systematic search was conducted for published articles reporting NSS and related data using standard measures in schizophrenia and healthy comparison groups. Method: A systematic search was conducted for published articles reporting data on the prevalence of NSS in schizophrenia using standard clinical rating scales and healthy comparison groups. Meta-analyses were performed using the Comprehensive Meta-analysis software package. Effect sizes (Cohen d) indexing the difference between schizophrenic patients and the healthy controls were calculated on the basis of reported statistics. Potential moderator variables evaluated included age of patient samples, level of education, sample sex proportions, medication doses, and negative and positive symptoms. Results: A total of 33 articles met inclusion criteria for the meta-analysis. A large and reliable group difference (Cohen d) indicated that, on average, a majority of patients (73%) perform outside the range of healthy subjects on aggregate NSS measures. Cognitive performance and positive and negative symptoms share 2%–10% of their variance with NSS. Conclusions: NSS occur in a majority of the schizophrenia patient population and are largely distinct from symptomatic and cognitive features of the illness. PMID:19377058

Solitary mammals provide an animal model for autism spectrum disorders.

PubMed

Reser, Jared Edward

2014-02-01

Species of solitary mammals are known to exhibit specialized, neurological adaptations that prepare them to focus working memory on food procurement and survival rather than on social interaction. Solitary and nonmonogamous mammals, which do not form strong social bonds, have been documented to exhibit behaviors and biomarkers that are similar to endophenotypes in autism. Both individuals on the autism spectrum and certain solitary mammals have been reported to be low on measures of affiliative need, bodily expressiveness, bonding and attachment, direct and shared gazing, emotional engagement, conspecific recognition, partner preference, separation distress, and social approach behavior. Solitary mammals also exhibit certain biomarkers that are characteristic of autism, including diminished oxytocin and vasopressin signaling, dysregulation of the endogenous opioid system, increased Hypothalamic-pituitary-adrenal axis (HPA) activity to social encounters, and reduced HPA activity to separation and isolation. The extent of these similarities suggests that solitary mammals may offer a useful model of autism spectrum disorders and an opportunity for investigating genetic and epigenetic etiological factors. If the brain in autism can be shown to exhibit distinct homologous or homoplastic similarities to the brains of solitary animals, it will reveal that they may be central to the phenotype and should be targeted for further investigation. Research of the neurological, cellular, and molecular basis of these specializations in other mammals may provide insight for behavioral analysis, communication intervention, and psychopharmacology for autism.

Prospective memory performance in non-psychotic first-degree relatives of patients with schizophrenia: a controlled study.

PubMed

Zhou, Fu-Chun; Hou, Wei-Min; Wang, Chuan-Yue; Ungvari, Gabor S; Chiu, Helen F K; Correll, Christoph U; Shum, David H K; Man, David; Liu, Deng-Tang; Xiang, Yu-Tao

2014-01-01

We aimed at investigating prospective memory and its socio-demographic and neurocognitive correlates in non-psychotic, first-degree relatives (FDRs) of patients with schizophrenia compared to patients with first episode schizophrenia (FES), and healthy controls (HCs). Forty-seven FES patients, 50 non-psychotic FDRs (23 offspring and 27 siblings) of patients with chronic schizophrenia (unrelated to the FES group) and 51 HCs were studied. The Chinese version of the Cambridge Prospective Memory Test (C-CAMPROMPT) was used to measure time-based prospective memory (TBPM) and event-based prospective memory (EBPM) performance. Other cognitive functions (involving respective memory and executive functions) were evaluated with standardized tests. After controlling for basic demographic characteristics including age, gender and educational level, there was a significant difference between FDRs, FES and HCs with respect to both TBPM (F(2,142) = 10.4, p<0.001) and EBPM (F(2,142) = 10.8, p<0.001). Multiple linear regression analyses revealed that lower scores of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the STROOP Word-Color Test (SWCT) contributed to TBPM impairment, while lower educational level and higher scores of the Color Trails Test-2 (CTT-2) contributed to EBPM deficit in FDRs. FDRs share similar but attenuated prospective memory impairments with schizophrenia patients, suggesting that prospective memory deficits may represent an endophenotype of schizophrenia.

Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder.

PubMed

Lopez, A Y; Wang, X; Xu, M; Maheshwari, A; Curry, D; Lam, S; Adesina, A M; Noebels, J L; Sun, Q-Q; Cooper, E C

2017-10-01

ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3's important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.

Event-Related Oscillations in Alcoholism Research: A Review

PubMed Central

Pandey, Ashwini K; Kamarajan, Chella; Rangaswamy, Madhavi; Porjesz, Bernice

2013-01-01

Alcohol dependence is characterized as a multi-factorial disorder caused by a complex interaction between genetic and environmental liabilities across development. A variety of neurocognitive deficits/dysfunctions involving impairments in different brain regions and/or neural circuitries have been associated with chronic alcoholism, as well as with a predisposition to develop alcoholism. Several neurobiological and neurobehavioral approaches and methods of analyses have been used to understand the nature of these neurocognitive impairments/deficits in alcoholism. In the present review, we have examined relatively novel methods of analyses of the brain signals that are collectively referred to as event-related oscillations (EROs) and show promise to further our understanding of human brain dynamics while performing various tasks. These new measures of dynamic brain processes have exquisite temporal resolution and allow the study of neural networks underlying responses to sensory and cognitive events, thus providing a closer link to the physiology underlying them. Here, we have reviewed EROs in the study of alcoholism, their usefulness in understanding dynamical brain functions/dysfunctions associated with alcoholism as well as their utility as effective endophenotypes to identify and understand genes associated with both brain oscillations and alcoholism. PMID:24273686

Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder

PubMed Central

Lopez, Angel Y.; Wang, Xinjun; Xu, Mingxuan; Maheshwari, Atul; Curry, Daniel; Lam, Sandi; Adesina, Adekunle M.; Noebels, Jeffrey L.; Sun, Qian-Quan; Cooper, Edward C.

2016-01-01

ANK3, encoding the adaptor protein Ankyrin-G, has been implicated in bipolar disorder by genome wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin interneurons and principal cells differentially express ANK3 first exon subtypes. Parvalbumin interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone, or both 1e and 1b. In transgenic mice deficient for exon 1b, parvalbumin interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy, and sudden death. Thus, ANK3’s important association with human bipolar susceptibility may arise from imbalance between ankyrin-G function in interneurons and principal cells and resultant excessive circuit sensitivity and output. Ankyrin-G isoform imbalance is a novel molecular endophenotype and potential therapeutic target. PMID:27956739

Beliefs about genetic influences on eating behaviors: Characteristics and associations with weight management confidence.

PubMed

Persky, Susan; Bouhlal, Sofia; Goldring, Megan R; McBride, Colleen M

2017-08-01

The development of precision approaches for customized health interventions is a promising application of genomic discovery. To optimize such weight management interventions, target audiences will need to be engaged in research and implementation efforts. Investigation into approaches that engage these audiences will be required to ensure that genomic information, particularly with respect to genomic influences on endophenotypes like eating behavior, is understood and accepted, and not associated with unintended adverse outcomes. We took steps to characterize healthy individuals' beliefs about genetic influences on eating behavior. Data were collected via online survey from 261 participants selected at random from a database. Respondents infrequently spontaneously identified eating behavior-related factors as running in families. However, those who perceived themselves as overweight and perceived a family history of overweight were more likely to attribute eating behavior to genetics on closed-ended assessments, β=0.252, p=0.039. Genetic attributions for eating behaviors were associated with lower confidence in ability to control eating and weight, β=-0.119, p=0.035. These exploratory findings shed light on beliefs about genetic influences on eating, a behavioral trait (rather than a disease). This investigation can inform future health intervention efforts. Published by Elsevier Ltd.

Facial emotion recognition deficits in relatives of children with autism are not associated with 5HTTLPR.

PubMed

Neves, Maila de Castro Lourenço das; Tremeau, Fabien; Nicolato, Rodrigo; Lauar, Hélio; Romano-Silva, Marco Aurélio; Correa, Humberto

2011-09-01

A large body of evidence suggests that several aspects of face processing are impaired in autism and that this impairment might be hereditary. This study was aimed at assessing facial emotion recognition in parents of children with autism and its associations with a functional polymorphism of the serotonin transporter (5HTTLPR). We evaluated 40 parents of children with autism and 41 healthy controls. All participants were administered the Penn Emotion Recognition Test (ER40) and were genotyped for 5HTTLPR. Our study showed that parents of children with autism performed worse in the facial emotion recognition test than controls. Analyses of error patterns showed that parents of children with autism over-attributed neutral to emotional faces. We found evidence that 5HTTLPR polymorphism did not influence the performance in the Penn Emotion Recognition Test, but that it may determine different error patterns. Facial emotion recognition deficits are more common in first-degree relatives of autistic patients than in the general population, suggesting that facial emotion recognition is a candidate endophenotype for autism.

Maoa and Maob polymorphisms and personality traits in suicide attempters and healthy controls: a preliminary study.

PubMed

Balestri, Martina; Calati, Raffaella; Serretti, Alessandro; Hartmann, Annette M; Konte, Bettina; Friedl, Marion; Giegling, Ina; Rujescu, Dan

2017-03-01

Serotonergic neurotransmission dysfunctions have been well documented in patients with suicidal behaviour. We investigated monoamine oxidase A (MAOA: rs2064070, rs6323, rs909525) and B (MAOB: rs1799836, rs2311013, rs2205655) genetic modulation of personality traits (Temperament and Character Inventory, TCI) as endophenotype for suicidal behaviour. 108 suicide attempters and 286 healthy controls of German origin were screened. Among females, allelic analyses revealed associations between MAOA rs6323 A allele and higher Harm Avoidance in suicide attempters and MAOB rs2205655 A allele and higher Cooperativeness scores in healthy controls. Among males, MAOA rs909525 A allele was associated with higher Reward Dependence in suicide attempters. Multivariate analyses controlling for age and educational level mainly confirmed results. Case-control analyses in this subsample do not differ from our previously reported one. Despite of the small sample size, a possible involvement of these genes in the modulation of personality traits closely related to suicidal behaviour cannot be excluded. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Biomarkers of Risk for Post-Traumatic Stress Disorder (PTSD)

DTIC Science & Technology

2010-05-01

Price, L.H., Carpenter, L.L., Alberto Del Porto, J. Depression and stress: is there an endophenotype? Revista Brasileira de Psiquiatria, 29 (Supl...insufficient power, and the lack of inclusion of subsequent diagnoses as well as lifetime diagnoses in these analyses. Further analyses will include...partial or nonresponse to antidepressants. Journal of Clinical Psychiatry, 66, 1234- 8, 2005. 16. Carpenter, L.L, Schecter, J.M., Tyrka, A.R., Feijo de

Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype?

ERIC Educational Resources Information Center

Angkustsiri, Kathleen; Goodlin-Jones, Beth; Deprey, Lesley; Brahmbhatt, Khyati; Harris, Susan; Simon, Tony J.

2014-01-01

High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation…

Animal models of human anxiety disorders: reappraisal from a developmental psychopathology vantage point.

PubMed

Lampis, Valentina; Maziade, Michel; Battaglia, Marco

2011-05-01

We are witnessing a tremendous expansion of strategies and techniques that derive from basic and preclinical science to study the fine genetic, epigenetic, and proteomic regulation of behavior in the laboratory animal. In this endeavor, animal models of psychiatric illness are becoming the almost exclusive domain of basic researchers, with lesser involvement of clinician researchers in their conceptual design, and transfer into practice of new paradigms. From the side of human behavioral research, the growing interest in gene-environment interplay and the fostering of valid endophenotypes are among the few substantial innovations in the effort of linking common mental disorders to cutting-edge clinical research questions. We argue that it is time for cross-fertilization between these camps. In this article, we a) observe that the "translational divide" can-and should-be crossed by having investigators from both the basic and the clinical sides cowork on simpler, valid "endophenotypes" of neurodevelopmental relevance; b) emphasize the importance of unambiguous physiological readouts, more than behavioral equivalents of human symptoms/syndromes, for animal research; c) indicate and discuss how this could be fostered and implemented in a developmental framework of reference for some common anxiety disorders and ultimately lead to better animal models of human mental disorders.

STRESS RISK FACTORS AND STRESS-RELATED PATHOLOGY: NEUROPLASTICITY, EPIGENETICS AND ENDOPHENOTYPES

PubMed Central

Radley, Jason J.; Kabbaj, Mohamed; Jacobson, Lauren; Heydendael, Willem; Yehuda, Rachel; Herman, James P.

2013-01-01

This review highlights a symposium on stress risk factors and stress susceptibility, presented at the Neurobiology of Stress workshop in Boulder, Colorado, June 2010. This symposium addressed factors linking stress plasticity and reactivity to stress pathology in animal models and in humans. Dr. Jason Radley discussed studies demonstrating prefrontal cortical neuroplasticity and prefrontal control of hypothalamo-pituitary-adrenocortical axis function in rat, highlighting emerging evidence for a critical role of this region in normal and pathological stress integration. Dr. Mohamed Kabbaj summarized his studies of possible epigenetic mechanisms underlying behavioral differences in rat populations bred for differential stress reactivity. Dr. Lauren Jacobson described studies using a mouse model to explore the diverse actions of antidepressant action in brain, suggesting mechanisms whereby antidepressants may be differentially effective in treating specific depression endophenotypes. Dr. Rachel Yehuda discussed the role of glucocorticoids in post-traumatic stress disorder (PTSD), indicating that low cortisol may be a trait that predisposes the individual to development of the disorder. Furthermore, she presented evidence indicating that traumatic events can have transgenerational impact on cortisol reactivity and development of PTSD symptoms. Together, the symposium highlighted emerging themes regarding the role of brain reorganization, individual differences and epigenetics in determining stress plasticity and pathology. PMID:21848436

Atypical lateralization of ERP response to native and non-native speech in infants at risk for autism spectrum disorder.

PubMed

Seery, Anne M; Vogel-Farley, Vanessa; Tager-Flusberg, Helen; Nelson, Charles A

2013-07-01

Language impairment is common in autism spectrum disorders (ASD) and is often accompanied by atypical neural lateralization. However, it is unclear when in development language impairment or atypical lateralization first emerges. To address these questions, we recorded event-related-potentials (ERPs) to native and non-native speech contrasts longitudinally in infants at risk for ASD (HRA) over the first year of life to determine whether atypical lateralization is present as an endophenotype early in development and whether these infants show delay in a very basic precursor of language acquisition: phonemic perceptual narrowing. ERP response for the HRA group to a non-native speech contrast revealed a trajectory of perceptual narrowing similar to a group of low-risk controls (LRC), suggesting that phonemic perceptual narrowing does not appear to be delayed in these high-risk infants. In contrast there were significant group differences in the development of lateralized ERP response to speech: between 6 and 12 months the LRC group displayed a lateralized response to the speech sounds, while the HRA group failed to display this pattern. We suggest the possibility that atypical lateralization to speech may be an ASD endophenotype over the first year of life. Copyright © 2012 Elsevier Ltd. All rights reserved.

Higher-order language dysfunctions as a possible neurolinguistic endophenotype for schizophrenia: Evidence from patients and their unaffected first degree relatives.

PubMed

Pawełczyk, Agnieszka; Łojek, Emila; Żurner, Natalia; Gawłowska-Sawosz, Marta; Pawełczyk, Tomasz

2018-05-31

The purpose of the study was to examine the presence of pragmatic dysfunctions in first episode (FE) subjects and their healthy first degree relatives as a potential endophenotype for schizophrenia. Thirty-four FE patients, 34 parents of the patients (REL) and 32 healthy controls (HC) took part in the study. Pragmatic language functions were evaluated with the Right Hemisphere Language Battery, attention and executive functions were controlled, as well as age and education level. The parents differed from HC but not from their FE offspring with regard to overall level of language and communication and the general knowledge component of language processing. The FE participants differed from HC in comprehension of inferred meaning, emotional prosody, discourse dimensions, overall level of language and communication, language processing with regard to general knowledge and communication competences. The FE participants differed from REL regarding discourse dimensions. Our findings suggest that pragmatic dysfunctions may act as vulnerability markers of schizophrenia; their assessment may help in the diagnosis of early stages of the illness and in understanding its pathophysiology. In future research the adoptive and biological parents of schizophrenia patients should be compared to elucidate which language failures reflect genetic vulnerability and which ones environmental factors. Copyright © 2018. Published by Elsevier B.V.

Associations between regional brain physiology and trait impulsivity, motor inhibition, and impaired control over drinking

PubMed Central

Weafer, Jessica; Dzemidzic, Mario; Eiler, William; Oberlin, Brandon G.; Wang, Yang; Kareken, David A.

2015-01-01

Trait impulsivity and poor inhibitory control are well-established risk factors for alcohol misuse, yet little is known about the associated neurobiological endophenotypes. Here we examined correlations among brain physiology and self-reported trait impulsive behavior, impaired control over drinking, and a behavioral measure of response inhibition. A sample of healthy drinkers (n=117) completed a pulsed arterial spin labeling (PASL) scan to quantify resting regional cerebral blood flow (rCBF), and measures of self-reported impulsivity (Eysenck I7 Impulsivity scale) and impaired control over drinking. A subset of subjects (n=40) performed a stop signal task during blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess brain regions involved in response inhibition. Eysenck I7 scores were inversely related to blood flow in the right precentral gyrus. Significant BOLD activation during response inhibition occurred in an overlapping right frontal motor/premotor region. Moreover, impaired control over drinking was associated with reduced BOLD response in the same region. These findings suggest that impulsive personality and impaired control over drinking are associated with brain physiology in areas implicated in response inhibition. This is consistent with the idea that difficulty controlling behavior is due in part to impairment in motor restraint systems. PMID:26065376

Decreased C-reactive protein levels in Alzheimer disease.

PubMed

O'Bryant, Sid E; Waring, Stephen C; Hobson, Valerie; Hall, James R; Moore, Carol B; Bottiglieri, Teodoro; Massman, Paul; Diaz-Arrastia, Ramon

2010-03-01

C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histopathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 +/- 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 +/- 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 microg/mL) versus controls (4.9 microg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD.

Decreased C-Reactive Protein Levels in Alzheimer Disease

PubMed Central

O’Bryant, Sid E.; Waring, Stephen C.; Hobson, Valerie; Hall, James R.; Moore, Carol B.; Bottiglieri, Teodoro; Massman, Paul; Diaz-Arrastia, Ramon

2011-01-01

C-reactive protein (CRP) is an acute-phase reactant that has been found to be associated with Alzheimer disease (AD) in histo-pathological and longitudinal studies; however, little data exist regarding serum CRP levels in patients with established AD. The current study evaluated CRP levels in 192 patients diagnosed with probable AD (mean age = 75.8 ± 8.2 years; 50% female) as compared to 174 nondemented controls (mean age = 70.6 ± 8.2 years; 63% female). Mean CRP levels were found to be significantly decreased in AD (2.9 µg/mL) versus controls (4.9 µg/mL; P = .003). In adjusted models, elevated CRP significantly predicted poorer (elevated) Clinical Dementia Rating Scale sum of boxes (CDR SB) scores in patients with AD. In controls, CRP was negatively associated with Mini-Mental State Examination (MMSE) scores and positively associated with CDR SB scores. These findings, together with previously published results, are consistent with the hypothesis that midlife elevations in CRP are associated with increased risk of AD development though elevated CRP levels are not useful for prediction in the immediate prodrome years before AD becomes clinically manifest. However, for a subgroup of patients with AD, elevated CRP continues to predict increased dementia severity suggestive of a possible proinflammatory endophenotype in AD. PMID:19933496

Task-switching deficits and repetitive behaviour in genetic neurodevelopmental disorders: data from children with Prader-Willi syndrome chromosome 15 q11-q13 deletion and boys with Fragile X syndrome.

PubMed

Woodcock, Kate A; Oliver, Chris; Humphreys, Glyn W

2009-03-01

Prader-Willi syndrome (PWS) and Fragile X syndrome (FraX) are associated with distinctive cognitive and behavioural profiles. We examined whether repetitive behaviours in the two syndromes were associated with deficits in specific executive functions. PWS, FraX, and typically developing (TD) children were assessed for executive functioning using the Test of Everyday Attention for Children and an adapted Simon spatial interference task. Relative to the TD children, children with PWS and FraX showed greater costs of attention switching on the Simon task, but after controlling for intellectual ability, these switching deficits were only significant in the PWS group. Children with PWS and FraX also showed significantly increased preference for routine and differing profiles of other specific types of repetitive behaviours. A measure of switch cost from the Simon task was positively correlated to scores on preference for routine questionnaire items and was strongly associated with scores on other items relating to a preference for predictability. It is proposed that a deficit in attention switching is a component of the endophenotypes of both PWS and FraX and is associated with specific behaviours. This proposal is discussed in the context of neurocognitive pathways between genes and behaviour.

Genome-wide association identifies candidate genes that influence the human electroencephalogram

PubMed Central

Hodgkinson, Colin A.; Enoch, Mary-Anne; Srivastava, Vibhuti; Cummins-Oman, Justine S.; Ferrier, Cherisse; Iarikova, Polina; Sankararaman, Sriram; Yamini, Goli; Yuan, Qiaoping; Zhou, Zhifeng; Albaugh, Bernard; White, Kenneth V.; Shen, Pei-Hong; Goldman, David

2010-01-01

Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (α), beta (β), and theta (θ) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of θ or α power. SGIP1 was estimated to account for 8.8% of variance in θ power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with θ power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by θ EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism. PMID:20421487

Abnormal Vestibulo-Ocular Reflexes in Autism: A Potential Endophenotype

DTIC Science & Technology

2014-08-01

among. Saccades and smooth pursuit are complex sensorimotor behaviors that involve several spatially distant brain regions and long- fiber tracts between...time, at a rate of 100 Hz. Visual stimuli were presented as a red laser -light, generated by NKI Pursuit Tracker® laser . The Pursuit Tracker® laser ...the testing equipment by projecting a laser stimulus onto the cylindrical screen and providing a fixed target at + 10º in both the horizontal and

Self-Injurious Behavior: An Animal Model of an Autism Endophenotype

DTIC Science & Technology

2012-01-01

time there was a visible release of the pasta (not a drop) or a reformation of the digits holding the pasta via motor patterns of flexion/extension...review of 18 pasta -trials, nine trials randomly selected from each experimental group. Behaviors included on the code sheet were number of drops...failure to contact reaches, angling with head tilt, abnormal posture, use of a unilateral paw technique, and twirling of the pasta . Specific descriptions

GABA(A) Receptor Alpha5 Subunit as a Candidate Gene for Autism and Bipolar Disorder: A Proposed Endophenotype with Parent-of-Origin and Gain-of-Function Features, with or without Oculocutaneous Albinism

ERIC Educational Resources Information Center

Delong, Robert

2007-01-01

Our earlier family history studies of individuals with autism found a high incidence of major affective disorder, especially bipolar disorder, and unusual talents or intellectual abilities among family members. We now describe a subgroup of such families, selected from a large clinical experience, illustrating specific features of major affective…

Clarifying the role of neuroticism in suicidal ideation and suicide attempt among women with major depressive disorder.

PubMed

Rappaport, L M; Flint, J; Kendler, K S

2017-10-01

Prior research consistently demonstrates that neuroticism increases risk for suicidal ideation, but the association between neuroticism and suicidal behavior has been inconsistent. Whereas neuroticism is recommended as an endophenotype for suicidality, the association of neuroticism with attempted suicide warrants clarification. In particular, prior research has not distinguished between correlates of attempted suicide, correlates of suicidal ideation, and correlates of comorbid psychopathology. The present study used the CONVERGE study, a sample of 5864 women with major depressive disorder (MD) and 5783 women without MD throughout China. Diagnoses, suicidal ideation, and attempted suicide were assessed with the Composite International Diagnostic Interview (CIDI). Neuroticism was assessed with the neuroticism portion of the Eysenck Personality Questionnaire. Results replicate prior findings on the correlates of suicidal ideation, particularly elevated neuroticism among individuals who report prior suicidal ideation. Moreover, as compared with individuals who reported having experienced only suicidal ideation, neuroticism was associated with decreased likelihood of having attempted suicide. The association of neuroticism with suicidality is more complicated than has been previously described. Whereas neuroticism increases risk for suicidal ideation, neuroticism may decrease risk for a suicide attempt among individuals with suicidal ideation. These results have implications for the assessment of risk for a suicide attempt among individuals who report suicidal ideation and addresses prior discordant findings by clarifying the association between neuroticism and attempted suicide.

Clarifying the Role of Neuroticism in Suicidal Ideation and Suicide Attempt among Women with Major Depressive Disorder

PubMed Central

Rappaport, Lance M; Flint, Jonathan; Kendler, Kenneth S

2017-01-01

Background Prior research consistently demonstrates that neuroticism increases risk for suicidal ideation, but the association between neuroticism and suicidal behavior has been inconsistent. Whereas neuroticism is recommended as an endophenotype for suicidality, the association of neuroticism with attempted suicide warrants clarification. In particular, prior research has not distinguished between correlates of attempted suicide, correlates of suicidal ideation, and correlates of comorbid psychopathology. Methods The present study used the CONVERGE study, a sample of 5,864 women with major depressive disorder and 5,783 women without major depressive disorder throughout China. Diagnoses, suicidal ideation, and attempted suicide were assessed with the Composite International Diagnostic Interview (CIDI). Neuroticism was assessed with the neuroticism portion of the Eysenck Personality Questionnaire. Results Results replicate prior findings on the correlates of suicidal ideation, particularly elevated neuroticism among individuals who report prior suicidal ideation. Moreover, as compared to individuals who reported having experienced only suicidal ideation, neuroticism was associated with decreased likelihood of having attempted suicide. Conclusions The association of neuroticism with suicidality is more complicated than has been previously described. Whereas neuroticism increases risk for suicidal ideation, neuroticism may decrease risk for a suicide attempt among individuals with suicidal ideation. These results have implications for the assessment of risk for a suicide attempt among individuals who report suicidal ideation and addresses prior discordant findings by clarifying the association between neuroticism and attempted suicide. PMID:28397619

A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53

PubMed Central

Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L; Le, Nhung XH; Bertelsen, Sarah; Budde, John P; Harari, Oscar; Koller, Daniel L; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor; Johnson, Eric O; Kang, Sun; Kapoor, Manav; Kramer, John; Kuperman, Samuel; Madden, Pamela AF; Manz, Niklas; Martin, Nicholas G; McClintick, Jeanette N; Montgomery, Grant W; Nurnberger, John I; Rangaswamy, Madhavi; Rice, John; Schuckit, Marc; Tischfield, Jay A; Whitfield, John B; Xuei, Xiaoling; Porjesz, Bernice; Heath, Andrew C; Edenberg, Howard J; Bierut, Laura J; Goate, Alison M

2013-01-01

Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with symptom count were also associated with the dichotomous phenotype, DSM-IV alcohol dependence. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol (p=4.5×10−8, inflation corrected p=9.4×10−7). Results with DSM-IV alcohol dependence in the regions of interest support our findings with symptom count, though the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: non-overlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian twin-family study of alcohol use disorders (OZALC). Nominal association of C15orf53 with symptom count was observed in SAGE. The variant that showed strongest association with symptom count, rs12912251 and its highly correlated variants (D′=1, r2≥ 0.95), has previously been associated with risk for bipolar disorder. PMID:23089632

[Emotional endophenotypes and bipolar disorder].

PubMed

Dubois, M; Azorin, J-M; Fakra, E; Adida, M; Belzeaux, R

2012-12-01

Emotion can be described as a multidimensional affective state, accompanied with physiological, cognitive and subjective manifestations. Most bipolar patients spontaneously claim they have a higher sensitivity than average, which may lead to extreme emotional reactions, even during intercrisis periods. Few studies have focused on this particular affective dimension. Moreover, the emotional reactivity is a way to raise the question of bipolar patients' vulnerability to stress during euthymic periods. The aim of this study is to examine the emotional reactivity of euthymic bipolar patients in comparison with a control group, using a test of emotional induction with short films, in order to determine whether this particular affective dimension can be a potential endophenotype. Our hypothesis is that euthymic bipolar patients have a higher emotional reactivity than controls. 20 euthymic bipolar patients and 15 healthy control subjects were recruited. The emotional reactivity was assessed using a method of emotional induction, based on viewing a set of positive, negative and neutral short films. The subjects have to appreciate the valence (pleasant, unpleasant or neutral) and the arousal (degree of emotion triggered by each film), while physiological parameters (heart rate and galvanic skin response) were measured. On average, euthymic bipolar patients report the same valence for each set of films and the same arousal to positive and negative movies as control subjects. Neutral pictures, however, were considered more moving by euthymic bipolar patients than by control subjects. Bipolar patient showed a higher heart rate than the control group, and no statistically difference was shown considering the galvanic skin response. Euthymic bipolar patients seem to present an emotional hypereactivity which occurs especially during neutral situations.These results partly corroborate other authors outcomes, using a new and more ecologic methodology through an emotional induction by short films. While results of subjective evaluation are significant, results of physiological evaluation are controversial and need further exploration. This emotional hypereactivity during intercrisis periods allow us to understand the basal emotional functioning of bipolar patients, and could be linked with an emotional dysregulation, potential endophenotype of the bipolar disorder. It could have several clinical and research applications, particularly in the study of the emotional functioning of bipolar patients' first degree relatives. Copyright © 2012 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

Consumer and relationship factors associated with shared decision making in mental health consultations.

PubMed

Matthias, Marianne S; Fukui, Sadaaki; Kukla, Marina; Eliacin, Johanne; Bonfils, Kelsey A; Firmin, Ruth L; Oles, Sylwia K; Adams, Erin L; Collins, Linda A; Salyers, Michelle P

2014-12-01

This study explored the association between shared decision making and consumers' illness management skills and consumer-provider relationships. Medication management appointments for 79 consumers were audio recorded. Independent coders rated overall shared decision making, minimum level of shared decision making, and consumer-provider agreement for 63 clients whose visit included a treatment decision. Mental health diagnoses, medication adherence, patient activation, illness management, working alliance, and length of consumer-provider relationships were also assessed. Correlation analyses were used to determine relationships among measures. Overall shared decision making was not associated with any variables. Minimum levels of shared decision making were associated with higher scores on the bond subscale of the Working Alliance Inventory, indicating a higher degree of liking and trust, and with better medication adherence. Agreement was associated with shorter consumer-provider relationships. Consumer-provider relationships and shared decision making might have a more nuanced association than originally thought.

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories.

PubMed

Zerbi, Valerio; Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

2018-07-01

Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa.

PubMed

Acevedo, Summer F; Valencia, Celeste; Lutter, Michael; McAdams, Carrie J

2015-08-30

Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN-C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.

PubMed

Spanagel, Rainer

2013-01-01

Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.

Abnormal brain structure implicated in stimulant drug addiction.

PubMed

Ersche, Karen D; Jones, P Simon; Williams, Guy B; Turton, Abigail J; Robbins, Trevor W; Bullmore, Edward T

2012-02-03

Addiction to drugs is a major contemporary public health issue, characterized by maladaptive behavior to obtain and consume an increasing amount of drugs at the expense of the individual's health and social and personal life. We discovered abnormalities in fronto-striatal brain systems implicated in self-control in both stimulant-dependent individuals and their biological siblings who have no history of chronic drug abuse; these findings support the idea of an underlying neurocognitive endophenotype for stimulant drug addiction.

Abnormal Vestibulo-Ocular Reflexes in Autism: A Potential Endophenotype

DTIC Science & Technology

2011-06-01

differentiates autistic from children with asperger syndrome , Journal of Autism and Developmental Disorders, 32 (2002), 231-238. Proposal AR093169...three male children with diagnoses of ASD as follows: Autism (8 years 6 months), PDD-NOS (7 years 3 months), and Asperger’s Syndrome (10 years 6...Asperger’s syndrome *15+. Such behavioral evidence further suggests that Proposal AR093169 Award W81XWH-10-1-0382 Annual Report for 15 May 2010 – 14 May

Beyond Reliability

PubMed Central

2008-01-01

The validity of psychiatric diagnosis rests in part on a demonstration that identifiable biomarkers exist for major psychiatric illnesses. Recent evidence supports the existence of several biomarkers or endophenotypes for both schizophrenia and bipolar disorder. As we learn more about how these biomarkers relate to the symptoms, course, and treatment response of major psychiatric disorders, the “objectivity” of psychiatric diagnosis will increase. However, psychiatry is and will remain a clinically based discipline, aimed at comprehensively understanding and relieving human suffering. PMID:19727304

Mapping complex traits as a dynamic system

PubMed Central

Sun, Lidan; Wu, Rongling

2017-01-01

Despite increasing emphasis on the genetic study of quantitative traits, we are still far from being able to chart a clear picture of their genetic architecture, given an inherent complexity involved in trait formation. A competing theory for studying such complex traits has emerged by viewing their phenotypic formation as a “system” in which a high-dimensional group of interconnected components act and interact across different levels of biological organization from molecules through cells to whole organisms. This system is initiated by a machinery of DNA sequences that regulate a cascade of biochemical pathways to synthesize endophenotypes and further assemble these endophenotypes toward the end-point phenotype in virtue of various developmental changes. This review focuses on a conceptual framework for genetic mapping of complex traits by which to delineate the underlying components, interactions and mechanisms that govern the system according to biological principles and understand how these components function synergistically under the control of quantitative trait loci (QTLs) to comprise a unified whole. This framework is built by a system of differential equations that quantifies how alterations of different components lead to the global change of trait development and function, and provides a quantitative and testable platform for assessing the multiscale interplay between QTLs and development. The method will enable geneticists to shed light on the genetic complexity of any biological system and predict, alter or engineer its physiological and pathological states. PMID:25772476

Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance

PubMed Central

Ghezzi, Alfredo; Krishnan, Harish R.; Lew, Linda; Prado, Francisco J.; Ong, Darryl S.; Atkinson, Nigel S.

2013-01-01

Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol. PMID:24348266

Appetitive traits from infancy to adolescence: Using behavioral and neural measures to investigate obesity risk

PubMed Central

Carnell, Susan; Benson, Leora; Pryor, Katherine; Driggin, Elissa

2013-01-01

We come into the world with enduring predispositions towards food, which interact with environmental factors to influence our eating behaviors and weight trajectories. But our fates are not sealed – by learning more about this process we can identify ways to intervene. To advance this goal this we need to be able to assess appetitive traits such as food cue responsiveness and satiety sensitivity at different developmental stages. Assessment methods might include behavioral measures (e.g. eating behavior tests, psychometric questionnaires), but also biomarkers such as brain responses to food cues measured using fMRI. Evidence from infants, children and adolescents suggests that these indices of appetite differ not only with body weight, but also with familial obesity risk as assessed by parent weight, which reflects both genetic and environmental influences, and may provide a useful predictor of obesity development. Behavioral and neural approaches have great potential to inform each other: examining eating behavior can help us identify meaningful appetitive endophenotypes whose neural bases can be probed, while increasing knowledge of the shared neurobiology underlying appetite, obesity, and related behaviors and disorders may ultimately lead to innovative generalized interventions. Another challenge will be to combine comprehensive behavioral and neural assessments of appetitive traits with measures of relevant genetic and environmental factors within long-term prospective studies. This approach may help to identify the biobehavioral precursors of obesity, and lay the foundations for targeted neurobehavioral interventions that can interrupt the pathway to excess weight. PMID:23458627

Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues.

PubMed

Dykens, Elisabeth M; Sutcliffe, James S; Levitt, Pat

2004-01-01

New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare specific clusters of autistic symptomatology to features of chromosome 15q11-q13 disorders. Paternally or maternally derived deficiencies of 15q11-q13 result in Prader-Willi or Angelman syndromes, and we first use a global approach to review potential autism susceptibility genes in the 15q11-q13 region. We then use a more trait-based approach to suggest possible ties between specific phenotypic characteristics of autism and Prader-Willi syndrome, namely savant-like skills. We conclude with insights from pathophysiological studies that implicate altered development of specific neuron types and circuits in the cerebral cortex as part of the pathophysiological processes associated with autism and mental retardation. Copyright 2004 Wiley-Liss, Inc.

The genetics of addiction—a translational perspective

PubMed Central

Agrawal, A; Verweij, K J H; Gillespie, N A; Heath, A C; Lessov-Schlaggar, C N; Martin, N G; Nelson, E C; Slutske, W S; Whitfield, J B; Lynskey, M T

2012-01-01

Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene–environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions. PMID:22806211

Disentangling the heterogeneity of autism spectrum disorder through genetic findings

PubMed Central

Jeste, Shafali S.; Geschwind, Daniel H.

2014-01-01

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On.

PubMed

Everitt, Barry J; Robbins, Trevor W

2016-01-01

A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use.

Neuroeconomics: A bridge for translational research

PubMed Central

Sharp, Carla; Monterosso, John; Montague, Read

2014-01-01

Neuroeconomic methods combine behavioral economic experiments to parameterize aspects of reward-related decision-making with neuroimaging techniques to record corresponding brain activity. In this introductory paper to the current special issue, we propose that neuroeconomics is a potential bridge for translational research in psychiatry for several reasons. First, neuroeconomics-derived theoretical predictions about optimal adaptation in a changing environment provide an objective metric to examine psychopathology. Second, neuroeconomics provides a ‘multi-level’ research approach that combines performance (behavioral) measures with intermediate measures between behavior and neurobiology (e.g, neuroimaging) and uses a common metaphor to describe decision-making across multiple levels of explanation. As such, ecologically valid behavioral paradigms closely mirror the physical mechanisms of reward processing. Third, neuroeconomics provides a platform for investigators from neuroscience, economics, psychiatry and social and clinical psychology to develop a common language for studying reward-related decision making in psychiatric disorders. Therefore, neuroeconomics can provide promising candidate endophenotypes that may help clarify the basis of high heritability associated with psychiatric disorders and that may, in turn, inform treatment. PMID:22727459

Functional Biomarkers of Depression: Diagnosis, Treatment, and Pathophysiology

PubMed Central

Schmidt, Heath D; Shelton, Richard C; Duman, Ronald S

2011-01-01

Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response. PMID:21814182

Genetics of generalized anxiety disorder and related traits.

PubMed

Gottschalk, Michael G; Domschke, Katharina

2017-06-01

This review serves as a systematic guide to the genetics of generalized anxiety disorder (GAD) and further focuses on anxiety-relevant endophenotypes, such as pathological worry fear of uncertainty, and neuroticism. We inspect clinical genetic evidence for the familialityl heritability of GAD and cross-disorder phenotypes based on family and twin studies. Recent advances of linkage studies, genome-wide association studies, and candidate gene studies (eg, 5-HTT, 5-HT1A, MAOA, BDNF ) are outlined. Functional and structural neuroimaging and neurophysiological readouts relating to peripheral stress markers and psychophysiology are further integrated, building a multilevel disease framework. We explore etiologic factors in gene-environment interaction approaches investigating childhood trauma, environmental adversity, and stressful life events in relation to selected candidate genes ( 5-HTT, NPSR1, COMT, MAOA, CRHR1, RGS2 ), Additionally, the pharmacogenetics of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor treatment are summarized ( 5-HTT, 5-HT2A, COMT, CRHR1 ). Finally, GAD and trait anxiety research challenges and perspectives in the field of genetics, including epigenetics, are discussed.

Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

PubMed Central

Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V.; Balsevich, Georgia; Schmidt, Mathias V.; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E.; Conley, Emily Drabant; Ripke, Stephan; Wray, Naomi R.; Lewis, Cathryn M.; Hamilton, Steven P.; Weissman, Myrna M.; Breen, Gerome; Byrne, Enda M.; Blackwood, Douglas H.R.; Boomsma, Dorret I.; Cichon, Sven; Heath, Andrew C.; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A.F.; Martin, Nicholas G.; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M.; Penninx, Brenda P.; Pergadia, Michele L.; Potash, James B.; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J.; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H.; Preisig, Martin; Smoller, Jordan W.; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E.; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R.; Bettecken, Thomas; Binder, Elisabeth B.; Breuer, René; Castro, Victor M.; Churchill, Susanne E.; Coryell, William H.; Craddock, Nick; Craig, Ian W.; Czamara, Darina; De Geus, Eco J.; Degenhardt, Franziska; Farmer, Anne E.; Fava, Maurizio; Frank, Josef; Gainer, Vivian S.; Gallagher, Patience J.; Gordon, Scott D.; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V.; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A.; Kohane, Isaac S.; Kohli, Martin A.; Korszun, Ania; Landen, Mikael; Lawson, William B.; Lewis, Glyn; MacIntyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Middleton, Lefkos; Montgomery, Grant M.; Murphy, Shawn N.; Nauck, Matthias; Nolen, Willem A.; Nyholt, Dale R.; O’Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A.; Schulz, Andrea; Schulze, Thomas G.; Shyn, Stanley I.; Sigurdsson, Engilbert; Slager, Susan L.; Smit, Johannes H.; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J.C.G.; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B.; Willemsen, Gonneke; Zitman, Frans G.; Neale, Benjamin; Daly, Mark; Levinson, Douglas F.; Sullivan, Patrick F.; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R.; Binder, Elisabeth B.

2015-01-01

Summary Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. Video Abstract PMID:26050039

Genetic Determinants Influencing Human Serum Metabolome among African Americans

PubMed Central

Yu, Bing; Zheng, Yan; Alexander, Danny; Morrison, Alanna C.; Coresh, Josef; Boerwinkle, Eric

2014-01-01

Phenotypes proximal to gene action generally reflect larger genetic effect sizes than those that are distant. The human metabolome, a result of multiple cellular and biological processes, are functional intermediate phenotypes proximal to gene action. Here, we present a genome-wide association study of 308 untargeted metabolite levels among African Americans from the Atherosclerosis Risk in Communities (ARIC) Study. Nineteen significant common variant-metabolite associations were identified, including 13 novel loci (p<1.6×10−10). These loci were associated with 7–50% of the difference in metabolite levels per allele, and the variance explained ranged from 4% to 20%. Fourteen genes were identified within the nineteen loci, and four of them contained non-synonymous substitutions in four enzyme-encoding genes (KLKB1, SIAE, CPS1, and NAT8); the other significant loci consist of eight other enzyme-encoding genes (ACE, GATM, ACY3, ACSM2B, THEM4, ADH4, UGT1A, TREH), a transporter gene (SLC6A13) and a polycystin protein gene (PKD2L1). In addition, four potential disease-associated paths were identified, including two direct longitudinal predictive relationships: NAT8 with N-acetylornithine, N-acetyl-1-methylhistidine and incident chronic kidney disease, and TREH with trehalose and incident diabetes. These results highlight the value of using endophenotypes proximal to gene function to discover new insights into biology and disease pathology. PMID:24625756

Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study.

PubMed

Bertelsen, Birgitte; Oranje, Bob; Melchior, Linea; Fagerlund, Birgitte; Werge, Thomas M; Mikkelsen, Jens D; Tümer, Zeynep; Glenthøj, Birte Y

2015-12-01

Schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human α7 nicotinic acetylcholine receptor (α7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the α7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the α7nAChR could be involved in sensory registration processes.

AGT M235T genotype/anxiety interaction and gender in the HyperGEN study.

PubMed

Knox, Sarah S; Guo, Xinxin; Zhang, Yuqing; Weidner, G; Williams, Scott; Ellison, R Curtis

2010-10-13

Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style). Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype. The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.

Electrophysiological correlates of reading in children with attention deficit hyperactivity disorder.

PubMed

Gonzalez-Perez, P A; Hernandez-Exposito, S; Perez, J; Ramirez, G; Dominguez, A

2018-03-16

To investigate whether or not the deficits in executive functions in the attention deficit hyperactivity disorder (ADHD) affect reading comprehension and identify a potential biological marker of this neuropsychological endophenotype through event-related potentials (ERP). The phenotypic association between reading comprehension and the specific functions of inhibition and working memory is studied. The sample consisted of 52 children with ADHD (8-13 years) divided in two groups according to the presence (TDAH-; n = 27; percentile < 30) or the absence (TDAH+; n = 25; percentile > 50) of reading comprehension deficits and a control group (n = 27). The executive functions were evaluated. The ERPs were assessed during a task in which anaphoric sentences of different lengths were presented, recording the ERP in the last adjective of the sentence that required a gender agreement. Working memory and inhibition were associated to reading comprehension performance. The ADHD+ group and the control group seem to detect the disagreement at 100 ms, while the ADHD- group does not activate its working memory until 250 ms. The delay in the implementation of the working memory mechanisms helps us to understand the deficits in reading comprehension of the ADHD- group.

Cohort Profile Update: the TRacking Adolescents' Individual Lives Survey (TRAILS).

PubMed

Oldehinkel, Albertine J; Rosmalen, Judith Gm; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma Am; Hartman, Catharina A

2015-02-01

TRAILS consists of a population cohort (N=2230) and a clinical cohort (N=543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). © The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Animal Models of Post-Traumatic Stress Disorder and Recent Neurobiological Insights

PubMed Central

Whitaker, Annie M.; Gilpin, Nicholas W.; Edwards, Scott

2014-01-01

Post-traumatic stress disorder (PTSD) is a complex psychiatric disorder characterized by the intrusive re-experiencing of past trauma, avoidant behavior, enhanced fear, and hyperarousal following a traumatic event in vulnerable populations. Preclinical animal models do not replicate the human condition in its entirety, but seek to mimic symptoms or endophenotypes associated with PTSD. Although many models of traumatic stress exist, few adequately capture the complex nature of the disorder and the observed individual variability in susceptibility of humans to develop PTSD. In addition, various types of stressors may produce different molecular neuroadaptations that likely contribute to the various behavioral disruptions produced by each model, although certain consistent neurobiological themes related to PTSD have emerged. For example, animal models report traumatic stress- and trauma reminder-induced alterations in neuronal activity in the amygdala and prefrontal cortex, in agreement with the human PTSD literature. Models have also provided a conceptual framework for the often observed combination of PTSD and co-morbid conditions such as alcohol use disorder (AUD). Future studies will continue to refine preclinical PTSD models in hopes of capitalizing on their potential to deliver new and more efficacious treatments for PTSD and associated psychiatric disorders. PMID:25083568

Plasma homovanillic acid levels in schizophrenic patients: correlation with negative symptoms.

PubMed

Dávila, Ricardo; Zumárraga, Mercedes; Basterreche, Nieves; Arrúe, Aurora; Anguiano, Juan B

2007-05-30

The relation between changes in the levels of plasma homovanillic acid (pHVA) and clinical evolution during neuroleptic treatment of schizophrenic patients has not been satisfactorily characterized, as a number of conflicting findings have been reported. Significant correlations have generally been found using the assessment of positive symptoms as an index of clinical outcome. Nevertheless, attempts to correlate pHVA concentrations with negative symptoms have yielded contradictory results. With a view to evaluating if different responses in negative symptoms are associated with distinct pHVA profiles, we examined the levels of pHVA in 46 neuroleptic-free schizophrenic patients and in these patients after neuroleptic treatment. Negative and positive symptoms were also addressed before and after treatment. Our results reveal that at least two classes of negative symptoms exist; the clinical evolution of the first class of negative symptoms parallels that of positive symptoms, and clinical improvement correlates with reduced dopaminergic activity. In contrast, in the second class, reduced dopaminergic activity is associated with a further deterioration of negative symptoms. These findings corroborate the heterogeneity of negative symptoms and may contribute to a better definition of endophenotypes in the schizophrenic syndrome.

GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC.

PubMed

Colic, Lejla; Li, Meng; Demenescu, Liliana Ramona; Li, Shija; Müller, Iris; Richter, Anni; Behnisch, Gusalija; Seidenbecher, Constanze I; Speck, Oliver; Schott, Björn H; Stork, Oliver; Walter, Martin

2018-05-30

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene-personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes ( GAD1 , GAD2 , and GLS ) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women. SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women. Copyright © 2018 the authors 0270-6474/18/385068-11$15.00/0.

Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm.

PubMed

Brzózka, M M; Rossner, M J; de Hoz, L

2016-09-01

Schizophrenia (SZ) is a severe mental disorder affecting about 1 % of the human population. Patients show severe deficits in cognitive processing often characterized by an improper filtering of environmental stimuli. Independent genome-wide association studies confirmed a number of risk variants for SZ including several associated with the gene encoding the transcription factor 4 (TCF4). TCF4 is widely expressed in the central nervous system of mice and humans and seems to be important for brain development. Transgenic mice overexpressing murine Tcf4 (Tcf4tg) in the adult brain display cognitive impairments and sensorimotor gating disturbances. To address the question of whether increased Tcf4 gene dosage may affect cognitive flexibility in an auditory associative task, we tested latent inhibition (LI) in female Tcf4tg mice. LI is a widely accepted translational endophenotype of SZ and results from a maladaptive delay in switching a response to a previously unconditioned stimulus when this becomes conditioned. Using an Audiobox, we pre-exposed Tcf4tg mice and their wild-type littermates to either a 3- or a 12-kHz tone before conditioning them to a 12-kHz tone. Tcf4tg animals pre-exposed to a 12-kHz tone showed significantly delayed conditioning when the previously unconditioned tone became associated with an air puff. These results support findings that associate TCF4 dysfunction with cognitive inflexibility and improper filtering of sensory stimuli observed in SZ patients.

Inference of domain-disease associations from domain-protein, protein-disease and disease-disease relationships.

PubMed

Zhang, Wangshu; Coba, Marcelo P; Sun, Fengzhu

2016-01-11

Protein domains can be viewed as portable units of biological function that defines the functional properties of proteins. Therefore, if a protein is associated with a disease, protein domains might also be associated and define disease endophenotypes. However, knowledge about such domain-disease relationships is rarely available. Thus, identification of domains associated with human diseases would greatly improve our understanding of the mechanism of human complex diseases and further improve the prevention, diagnosis and treatment of these diseases. Based on phenotypic similarities among diseases, we first group diseases into overlapping modules. We then develop a framework to infer associations between domains and diseases through known relationships between diseases and modules, domains and proteins, as well as proteins and disease modules. Different methods including Association, Maximum likelihood estimation (MLE), Domain-disease pair exclusion analysis (DPEA), Bayesian, and Parsimonious explanation (PE) approaches are developed to predict domain-disease associations. We demonstrate the effectiveness of all the five approaches via a series of validation experiments, and show the robustness of the MLE, Bayesian and PE approaches to the involved parameters. We also study the effects of disease modularization in inferring novel domain-disease associations. Through validation, the AUC (Area Under the operating characteristic Curve) scores for Bayesian, MLE, DPEA, PE, and Association approaches are 0.86, 0.84, 0.83, 0.83 and 0.79, respectively, indicating the usefulness of these approaches for predicting domain-disease relationships. Finally, we choose the Bayesian approach to infer domains associated with two common diseases, Crohn's disease and type 2 diabetes. The Bayesian approach has the best performance for the inference of domain-disease relationships. The predicted landscape between domains and diseases provides a more detailed view about the disease mechanisms.

Reaction time, inhibition, working memory and ‘delay aversion’ performance: genetic influences and their interpretation

PubMed Central

KUNTSI, JONNA; ROGERS, HANNAH; SWINARD, GREER; BÖRGER, NORBERT; van der MEERE, JAAP; RIJSDIJK, FRUHLING; ASHERSON, PHILIP

2013-01-01

Background For candidate endophenotypes to be useful for psychiatric genetic research, they first of all need to show significant genetic influences. To address the relative lack of previous data, we set to investigate the extent of genetic and environmental influences on performance in a set of theoretically driven cognitive-experimental tasks in a large twin sample. We further aimed to illustrate how test–retest reliability of the measures affects the estimates. Method Four-hundred 7- to 9-year-old twin pairs were assessed individually on tasks measuring reaction time, inhibition, working memory and ‘delay aversion’ performance. Test–retest reliability data on some of the key measures were available from a previous study. Results Several key measures of reaction time, inhibition and working-memory performance indicated a moderate degree of genetic influence. Combining data across theoretically related tasks increased the heritability estimates, as illustrated by the heritability estimates of 60% for mean reaction time and 50% for reaction-time variability. Psychometric properties (reliability or ceiling effects) had a substantial influence on the estimates for some measures. Conclusions The data support the usefulness of several of the variables for endophenotype studies that aim to link genes to cognitive and motivational processes. Importantly, the data also illustrate specific conditions under which the true extent of genetic influences may be underestimated and hence the usefulness for genetic mapping studies compromised, and suggest ways to address this. PMID:16882357

[Theory of mind in schizophrenia spectrum disorders].

PubMed

Bora, Emre

2009-01-01

To review studies that investigated theory of mind (ToM) deficits in schizophrenia spectrum disorders. After a thorough literature search, 71 studies were included in this review. Data regarding the relationship between ToM, and other cognitive skills, symptoms, and the impact of the state of illness were reviewed. ToM instruments used in schizophrenia spectrum disorders have some major psychometric limitations; however, previous research was still able to provide some important findings regarding mentalizing impairments in schizophrenia. While ToM deficits are more pronounced in the acute phase of illness, it seems to persist during periods of remission. There is also evidence of ToM deficits in the healthy relatives of schizophrenics, patients with delusional disorder and bipolar disorder (BD), and individuals with high schizotypy scores. ToM dysfunction might be secondary to other cognitive deficits in patients with schizophrenia that have a good prognosis, asymptomatic schizophrenia, delusional disorder, and BD. Other cognitive deficits do not seem to explain ToM dysfunction in patients with psychosis and severe negative symptoms. These findings support the contribution of impairment in both domain-general and domain-specific mechanisms to ToM deficits in schizophrenia spectrum disorders. ToM deficits may be important for understanding poor social functioning and poor insight in psychotic disorders. While ToM is influenced by state variables, it might be an endophenotype of schizophrenia; however, ToM is likely to be an indicator of other frontal lobe-related endophenotypes. Longitudinal studies conducted with high-risk individuals are particularly important.

Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies.

PubMed

Radant, Allen D; Millard, Steven P; Braff, David L; Calkins, Monica E; Dobie, Dorcas J; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Meichle, Sean P; Nuechterlein, Keith H; Olincy, Ann; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Swerdlow, Neal R; Sugar, Catherine A; Tsuang, Ming T; Turetsky, Bruce I; Tsuang, Debby W

2015-04-01

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors. Published by Elsevier B.V.

Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies

PubMed Central

Radant, Allen D.; Millard, Steven P.; Braff, David; Calkins, Monica E.; Dobie, Dorcas J.; Freedman, Robert; Green, Michael F.; Greenwood, Tiffany A.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura; Light, Gregory A.; Meichle, Sean; Nuechterlein, Keith H.; Olincy, Ann; Seidman, Larry J.; Siever, Larry; Silverman, Jeremy; Stone, William S.; Swerdlow, Neal R.; Sugar, Catherine; Tsuang, Ming T.; Turetsky, Bruce I.; Tsuang, Debby W.

2015-01-01

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen’s d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors. PMID:25553977

Selective anterior cingulate cortex deficit during conflict solution in schizophrenia: an event-related potential study.

PubMed

Neuhaus, Andres H; Koehler, Simone; Opgen-Rhein, Carolin; Urbanek, Carsten; Hahn, Eric; Dettling, Michael

2007-10-01

Schizophrenia research has gained a new focus on identification and further characterization of neurocognitive deficits in the search for behavioural endophenotypes of this disorder. The objective of this study was to explore differential cortical processing during executive control in schizophrenia as assessed with the attention network test (ANT). Sixteen schizophrenic patients and sixteen healthy controls matched for gender, age, education, and nicotine consumption were tested with the ANT while recording 29-channel-electroencephalogram (EEG). Visual event-related potentials (ERP) N200 and P300 were topographically analyzed and cortical mapping using low resolution brain electromagnetic tomography (LORETA) was applied to localize neuroelectric generators of ERP. Behaviourally, significant differences between schizophrenic patients and controls were found only for the conflict condition (p<0.05) and for conflict adjusted by mean reaction time (p<0.01). Examining ERP of control subjects, N200 failed to show robust flanker congruency effects. P300 amplitude was reduced at Pz (p<0.05) and P300 latency was increased at Cz (p<0.005) for the conflict condition. Schizophrenic patients differed significantly in P300 latency at Cz during late conflict processing (p<0.005). Source analysis revealed a deficit in anterior cingulate cortex (p<0.05). Our results are in line with previous reports about dysfunctional ACC activation in schizophrenia and argue in favour of a selective deficit of cortical conflict resolution. It is further proposed that dysfunctional ACC activation during executive processing may be a neurophysiologic endophenotype candidate of schizophrenia.

Central coherence in adolescents with bulimia nervosa spectrum eating disorders.

PubMed

Darcy, Alison M; Fitzpatrick, Kathleen Kara; Manasse, Stephanie M; Datta, Nandini; Klabunde, Megan; Colborn, Danielle; Aspen, Vandana; Stiles-Shields, Colleen; Labuschagne, Zandre; Le Grange, Daniel; Lock, James

2015-07-01

Weak central coherence-a tendency to process details at the expense of the gestalt-has been observed among adults with bulimia nervosa (BN) and is a potential candidate endophenotype for eating disorders (EDs). However, as BN behaviors typically onset during adolescence it is important to assess central coherence in this younger age group to determine whether the findings in adults are likely a result of BN or present earlier in the evolution of the disorder. This study examines whether the detail-oriented and fragmented cognitive inefficiency observed among adults with BN is observable among adolescents with shorter illness duration, relative to healthy controls. The Rey-Osterrieth Complex Figure Test (RCFT) was administered to a total of 47 adolescents with DSM5 BN, 42 with purging disorder (PD), and 25 healthy controls (HC). Performance on this measure was compared across the three groups. Those with BN and PD demonstrated significantly worse accuracy scores compared to controls in the copy and delayed recall condition with a moderate effect size. These findings were exacerbated when symptoms of BN increased. Poorer accuracy scores reflect a fragmented and piecemeal strategy that interferes with visual-spatial integration in BN spectrum disorders. This cognitive inefficiency likely contributes to broad difficulties in executive functioning in this population especially in the context of worsening bulimic symptoms. The findings of this study support the hypothesis that poor global integration may constitute a cognitive endophenotype for BN. © 2014 Wiley Periodicals, Inc.

Motor co-activation in siblings of patients with juvenile myoclonic epilepsy: an imaging endophenotype?

PubMed Central

Wandschneider, Britta; Centeno, Maria; Vollmar, Christian; Symms, Mark; Thompson, Pamela J.; Duncan, John S.

2014-01-01

Juvenile myoclonic epilepsy is a heritable idiopathic generalized epilepsy syndrome, characterized by myoclonic jerks and frequently triggered by cognitive effort. Impairment of frontal lobe cognitive functions has been reported in patients with juvenile myoclonic epilepsy and their unaffected siblings. In a recent functional magnetic resonance imaging study we reported abnormal co-activation of the motor cortex and increased functional connectivity between the motor system and prefrontal cognitive networks during a working memory paradigm, providing an underlying mechanism for cognitively triggered jerks. In this study, we used the same task in 15 unaffected siblings (10 female; age range 18–65 years, median 40) of 11 of those patients with juvenile myoclonic epilepsy (six female; age range 22–54 years, median 35) and compared functional magnetic resonance imaging activations with 20 age- and gender-matched healthy control subjects (12 female; age range 23–46 years, median 30.5). Unaffected siblings showed abnormal primary motor cortex and supplementary motor area co-activation with increasing cognitive load, as well as increased task-related functional connectivity between motor and prefrontal cognitive networks, with a similar pattern to patients (P < 0.001 uncorrected; 20-voxel threshold extent). This finding in unaffected siblings suggests that altered motor system activation and functional connectivity is not medication- or seizure-related, but represents a potential underlying mechanism for impairment of frontal lobe functions in both patients and siblings, and so constitutes an endophenotype of juvenile myoclonic epilepsy. PMID:25001494

Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci

PubMed Central

Gray, Joshua C; MacKillop, James

2014-01-01

Introduction Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards. It has been consistently linked to pathological gambling and other forms of addictive behavior, and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders (i.e., an endophenotype). Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission. The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers. Methods Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva. Results In a priori tests, two loci previously associated with delayed reward discounting (rs1800497 and rs4680) were not replicated, however, the long form of DRD4 VNTR was significantly associated with lower discounting of delayed rewards. Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis, breakdown, reuptake, and receptor function (DRD3, SLC6A3, DDC, DBH, and SLC18A2). An aggregate genetic risk score from the nominally significant loci accounted for 17% of the variance in discounting. Mediational analyses largely supported the presence of indirect effects between the associated loci, delay discounting, and pathological gambling severity. Conclusions These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting. PMID:25365808

ASSOCIATION BETWEEN INFANT NIGHTTIME-SLEEP LOCATION AND ATTACHMENT SECURITY: NO EASY VERDICT.

PubMed

Mileva-Seitz, Viara R; Luijk, Maartje P C M; van Ijzendoorn, Marinus H; Bakermans-Kranenburg, Marian J; Jaddoe, Vincent W V; Hofman, Albert; Verhulst, Frank C; Tiemeier, Henning

2016-01-01

We tested whether mother-infant bed-sharing is associated with increased secure infant-mother attachment, a previously unexplored association. Frequency of bed-sharing and mothers' nighttime comforting measures at 2 months were assessed with questionnaires in 550 Caucasian mothers from a population-based cohort. Attachment security was assessed with the Strange Situation Procedure (M.D.S. Ainsworth, M.C. Blehar, E. Waters, & S. Wall, 1978) at 14 months. When using a dichotomous variable, "never bed-sharing" (solitary sleepers) versus "any bed-sharing," the relative risk of being classified as insecurely attached for solitary-sleeping infants (vs. bed-sharers) was 1.21 (95% confidence interval: 1.05-1.40). In multivariate models, solitary sleeping was associated with greater odds of insecure attachment, adjusted odds ratio (OR): 1.50, 95% CI = 1.02-2.20) and, in particular, with greater odds of resistant attachment, adjusted OR = 1.74, 95% CI = 1.10-2.76); and with a lower attachment security score, β = -0.12, t(495) = -2.61, p = .009. However, we found no evidence of a dose-response association between bed-sharing and secure attachment when using a trichotomous bed-sharing variable based on frequency of bed-sharing. Our findings demonstrate some evidence that solitary sleeping is associated with insecure attachment. However, the lack of a dose-response association suggests that further experimental study is necessary before accepting common notions that sharing a bed leads to children who are better or not better adjusted. © 2015 Michigan Association for Infant Mental Health.

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB

PubMed Central

Need, Anna C.; Attix, Deborah K.; McEvoy, Jill M.; Cirulli, Elizabeth T.; Linney, Kristen L.; Hunt, Priscilla; Ge, Dongliang; Heinzen, Erin L.; Maia, Jessica M.; Shianna, Kevin V.; Weale, Michael E.; Cherkas, Lynn F.; Clement, Gail; Spector, Tim D.; Gibson, Greg; Goldstein, David B.

2009-01-01

Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in ∼750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics. PMID:19734545

A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB.

PubMed

Need, Anna C; Attix, Deborah K; McEvoy, Jill M; Cirulli, Elizabeth T; Linney, Kristen L; Hunt, Priscilla; Ge, Dongliang; Heinzen, Erin L; Maia, Jessica M; Shianna, Kevin V; Weale, Michael E; Cherkas, Lynn F; Clement, Gail; Spector, Tim D; Gibson, Greg; Goldstein, David B

2009-12-01

Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

Fear extinction, persistent disruptive behavior and psychopathic traits: fMRI in late adolescence.

PubMed

Cohn, Moran D; van Lith, Koen; Kindt, Merel; Pape, Louise E; Doreleijers, Theo A H; van den Brink, Wim; Veltman, Dick J; Popma, Arne

2016-07-01

Children diagnosed with a Disruptive Behavior Disorder (DBD, i.e. Oppositional Defiant Disorder or Conduct Disorder), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Reduced fear conditioning has been proposed to underlie persistent antisocial development. However, we have recently shown that both DBD persisters and desisters are characterized by increased fear conditioning compared with healthy controls (HCs). In this study, we investigated whether brain function during fear extinction is associated with DBD subgroup-membership and psychopathic traits. Adolescents from a childhood arrestee cohort (mean age 17.6 years, s.d. 1.4) who met criteria for a DBD diagnosis during previous assessments were re-assessed and categorized as persistent DBD (n = 25) or desistent DBD (n = 25). Functional MRI during the extinction phase of a classical fear-conditioning task was used to compare regional brain function between these subgroups and 25 matched controls. Both DBD persisters and desisters showed hyperreactivity during fear extinction, when compared with HCs. Impulsive-irresponsible psychopathic traits were positively associated with responses in the fear neurocircuitry and mediated the association between neural activation and group membership. These results suggest that fear acquisition and fear extinction deficits may provide an endophenotype for an emotionally hyperreactive subtype of antisocial development. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories

PubMed Central

Ielacqua, Giovanna D; Markicevic, Marija; Haberl, Matthias Georg; Ellisman, Mark H; A-Bhaskaran, Arjun; Frick, Andreas; Rudin, Markus; Wenderoth, Nicole

2018-01-01

Abstract Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1−/y) and contactin-associated (CNTNAP2−/−) knockout mice. Young Fmr1−/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2−/− mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes. PMID:29901787

The role of race and ethnicity in sleep, circadian rhythms and cardiovascular health.

PubMed

Egan, Kieren J; Knutson, Kristen L; Pereira, Alexandre C; von Schantz, Malcolm

2017-06-01

In recent years, strong evidence has emerged suggesting that insufficient duration, quality, and/or timing of sleep are associated with cardiovascular disease (CVD), and various mechanisms for this association have been proposed. Such associations may be related to endophenotypic features of the sleep homeostat and the circadian oscillator, or may be state-like effects of the environment. Here, we review recent literature on sleep, circadian rhythms and CVD with a specific emphasis on differences between racial/ethnic groups. We discuss the reported differences, mainly between individuals of European and African descent, in parameters related to sleep (architecture, duration, quality) and circadian rhythms (period length and phase shifting). We further review racial/ethnic differences in cardiovascular disease and its risk factors, and develop the hypothesis that racial/ethnic health disparities may, to a greater or smaller degree, relate to differences in parameters related to sleep and circadian rhythms. When humans left Africa some 100,000 years ago, some genetic differences between different races/ethnicities were acquired. These genetic differences have been proposed as a possible predictor of CVD disparities, but concomitant differences in culture and lifestyle between different groups may equally explain CVD disparities. We discuss the evidence for genetic and environmental causes of these differences in sleep and circadian rhythms, and their usefulness as health intervention targets. Copyright © 2016 Elsevier Ltd. All rights reserved.

No association of the GABAA receptor genes on chromosome 5 with alcoholism in the collaborative study on the genetics of alcoholism sample.

PubMed

Dick, Danielle M; Edenberg, Howard J; Xuei, Xiaoling; Goate, Alison; Hesselbrock, Victor; Schuckit, Marc; Crowe, Raymond; Foroud, Tatiana

2005-01-05

A substantial body of literature suggests that gamma-aminobutyric acid (GABA) may be involved in the neurochemical pathways contributing to alcohol use and related disorders. Chromosome 5 contains a cluster of GABA(A) receptor genes, GABRA1, GABRA6, GABRB2, and GABRG2, which have been among the most extensively studied in relation to alcohol use. These studies have yielded mixed results. Using data from large, multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA), we sought to provide more conclusive evidence regarding the role of the GABA(A) receptor genes on chromosome 5. Multiple single nucleotide polymorphisms (SNPs) were tested in each of the four chromosome 5q GABA(A) receptor genes, and we conducted both classic trio-based association analyzes and extended pedigree analyzes. We found no consistent evidence of association with alcohol dependence or alcohol dependence comorbid with antisocial personality disorder (ASPD) for any of the regions tested in the chromosome 5 GABA(A) receptor genes. These analyses suggest that the GABA(A) receptor genes on chromosome 5 do not play a strong role in alcohol dependence. Future studies are planned to test whether these genes are more important in influencing behavioral endophenotypes related to the risk of alcohol dependence. Copyright 2004 Wiley-Liss, Inc.

AGT M235T Genotype/Anxiety Interaction and Gender in the HyperGEN Study

PubMed Central

Knox, Sarah S.; Guo, Xinxin; Zhang, Yuqing; Weidner, G.; Williams, Scott; Ellison, R. Curtis

2010-01-01

Background Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. Methodology The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style). Principal Findings Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype. Conclusion/Significance The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors. PMID:20967221

Functional connectivity in the resting brain as biological correlate of the Affective Neuroscience Personality Scales.

PubMed

Deris, Nadja; Montag, Christian; Reuter, Martin; Weber, Bernd; Markett, Sebastian

2017-02-15

According to Jaak Panksepp's Affective Neuroscience Theory and the derived self-report measure, the Affective Neuroscience Personality Scales (ANPS), differences in the responsiveness of primary emotional systems form the basis of human personality. In order to investigate neuronal correlates of personality, the underlying neuronal circuits of the primary emotional systems were analyzed in the present fMRI-study by associating the ANPS to functional connectivity in the resting brain. N=120 healthy participants were invited for the present study. The results were reinvestigated in an independent, smaller sample of N=52 participants. A seed-based whole brain approach was conducted with seed-regions bilaterally in the basolateral and superficial amygdalae. The selection of seed-regions was based on meta-analytic data on affective processing and the Juelich histological atlas. Multiple regression analyses on the functional connectivity maps revealed associations with the SADNESS-scale in both samples. Functional resting-state connectivity between the left basolateral amygdala and a cluster in the postcentral gyrus, and between the right basolateral amygdala and clusters in the superior parietal lobe and subgyral in the parietal lobe was associated with SADNESS. No other ANPS-scale revealed replicable results. The present findings give first insights into the neuronal basis of the SADNESS-scale of the ANPS and support the idea of underlying neuronal circuits. In combination with previous research on genetic associations of the ANPS functional resting-state connectivity is discussed as a possible endophenotype of personality. Copyright © 2016 Elsevier Inc. All rights reserved.

Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world.

PubMed

Vrieze, Scott I; Iacono, William G; McGue, Matt

2012-11-01

This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoffs. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention in the history of psychology and is informed by psychometrics, whereas the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene-environment correlation). Genetically informed designs, which are no longer limited to twin and adoption studies thanks to ever-cheaper genotyping, are required to understand environmental influences. Finally, we outline the vast amount of individual difference in structural genomic variation, most of which remains to be leveraged in genetic association tests. Although the genetic data can be massive and burdensome (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research but with less confusion and more payoff than candidate gene research has to date.

Schizophrenic patients and their unaffected siblings share increased resting-state connectivity in the task-negative network but not its anticorrelated task-positive network.

PubMed

Liu, Haihong; Kaneko, Yoshio; Ouyang, Xuan; Li, Li; Hao, Yihui; Chen, Eric Y H; Jiang, Tianzi; Zhou, Yuan; Liu, Zhening

2012-03-01

Abnormal connectivity of the anticorrelated intrinsic networks, the task-negative network (TNN), and the task-positive network (TPN) is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings enable further understanding of illness susceptibility and pathophysiology. We examined the resting-state connectivity differences in the intrinsic networks between schizophrenic patients, their unaffected siblings, and healthy controls. Resting-state functional magnetic resonance images were obtained from 25 individuals in each subject group. The posterior cingulate cortex/precuneus and right dorsolateral prefrontal cortex were used as seed regions to identify the TNN and TPN through functional connectivity analysis. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to all subject groups. Schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. By contrast, schizophrenic patients alone demonstrated increased connectivity between the posterior cingulate cortex/precuneus and left inferior temporal gyrus and between the ventral medial prefrontal cortex and right lateral parietal cortex in the TNN. Schizophrenic patients exhibited increased connectivity between the left dorsolateral prefrontal cortex and right inferior frontal gyrus in the TPN relative to their unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls. Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.

Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study.

PubMed

Kremen, William S; Prom-Wormley, Elizabeth; Panizzon, Matthew S; Eyler, Lisa T; Fischl, Bruce; Neale, Michael C; Franz, Carol E; Lyons, Michael J; Pacheco, Jennifer; Perry, Michele E; Stevens, Allison; Schmitt, J Eric; Grant, Michael D; Seidman, Larry J; Thermenos, Heidi W; Tsuang, Ming T; Eisen, Seth A; Dale, Anders M; Fennema-Notestine, Christine

2010-01-15

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

HIGHER SERUM TOTAL CHOLESTEROL LEVELS IN LATE MIDDLE AGE ARE ASSOCIATED WITH GLUCOSE HYPOMETABOLISM IN BRAIN REGIONS AFFECTED BY ALZHEIMER’S DISEASE AND NORMAL AGING

PubMed Central

Reiman, Eric M.; Chen, Kewei; Langbaum, Jessica B.S.; Lee, Wendy; Reschke, Cole; Bandy, Daniel; Alexander, Gene E.; Caselli, Richard J.

2010-01-01

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer’s disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late-middle-aged people, we demonstrated an association between apolipoprotein E (APOE) ε4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a presymptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and noncarriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE ε4 carriers than non-carriers in some of the AD-affected brain regions. We postulate the higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD. PMID:19631758

Count Your Calories and Share Them: Health Benefits of Sharing mHealth Information on Social Networking Sites.

PubMed

Oeldorf-Hirsch, Anne; High, Andrew C; Christensen, John L

2018-04-23

This study investigates the relationship between sharing tracked mobile health (mHealth) information online, supportive communication, feedback, and health behavior. Based on the Integrated Theory of mHealth, our model asserts that sharing tracked health information on social networking sites benefits users' perceptions of their health because of the supportive communication they gain from members of their online social networks and that the amount of feedback people receive moderates these associations. Users of mHealth apps (N = 511) completed an online survey, and results revealed that both sharing tracked health information and receiving feedback from an online social network were positively associated with supportive communication. Network support both corresponded with improved health behavior and mediated the association between sharing health information and users' health behavior. As users received greater amounts of feedback from their online social networks, however, the association between sharing tracked health information and health behavior decreased. Theoretical implications for sharing tracked health information and practical implications for using mHealth apps are discussed.

National evidence on the use of shared decision making in prostate-specific antigen screening.

PubMed

Han, Paul K J; Kobrin, Sarah; Breen, Nancy; Joseph, Djenaba A; Li, Jun; Frosch, Dominick L; Klabunde, Carrie N

2013-01-01

Recent clinical practice guidelines on prostate cancer screening using the prostate-specific antigen (PSA) test (PSA screening) have recommended that clinicians practice shared decision making-a process involving clinician-patient discussion of the pros, cons, and uncertainties of screening. We undertook a study to determine the prevalence of shared decision making in both PSA screening and nonscreening, as well as patient characteristics associated with shared decision making. A nationally representative sample of 3,427 men aged 50 to 74 years participating in the 2010 National Health Interview Survey responded to questions on the extent of shared decision making (past physician-patient discussion of advantages, disadvantages, and scientific uncertainty associated with PSA screening), PSA screening intensity (tests in past 5 years), and sociodemographic and health-related characteristics. Nearly two-thirds (64.3%) of men reported no past physician-patient discussion of advantages, disadvantages, or scientific uncertainty (no shared decision making); 27.8% reported discussion of 1 to 2 elements only (partial shared decision making); 8.0% reported discussion of all 3 elements (full shared decision making). Nearly one-half (44.2%) reported no PSA screening, 27.8% reported low-intensity (less-than-annual) screening, and 25.1% reported high-intensity (nearly annual) screening. Absence of shared decision making was more prevalent in men who were not screened; 88% (95% CI, 86.2%-90.1%) of nonscreened men reported no shared decision making compared with 39% (95% CI, 35.0%-43.3%) of men undergoing high-intensity screening. Extent of shared decision making was associated with black race, Hispanic ethnicity, higher education, health insurance, and physician recommendation. Screening intensity was associated with older age, higher education, usual source of medical care, and physician recommendation, as well as with partial vs no or full shared decision making. Most US men report little shared decision making in PSA screening, and the lack of shared decision making is more prevalent in nonscreened than in screened men. Screening intensity is greatest with partial shared decision making, and different elements of shared decision making are associated with distinct patient characteristics. Shared decision making needs to be improved in decisions for and against PSA screening.

The utility of combining RSA indices in depression prediction.

PubMed

Yaroslavsky, Ilya; Rottenberg, Jonathan; Kovacs, Maria

2013-05-01

Depression is associated with protracted despondent mood, blunted emotional reactivity, and dysregulated parasympathetic nervous system (PNS) activity. PNS activity is commonly indexed via cardiac output, using indictors of its level (resting respiratory sinus arrhythmia [RSA]) or fluctuations (RSA reactivity). RSA reactivity can reflect increased or decreased PNS cardiac output (RSA augmentation and RSA withdrawal, respectively). Because a single index of a dynamic physiological system may be inadequate to characterize interindividual differences, we investigated whether the interaction of RSA reactivity and resting RSA is a better predictor of depression. Adult probands with childhood-onset depressive disorder histories (n = 113) and controls with no history of major mental disorders (n = 93) completed a psychophysiology protocol involving assessment of RSA at multiple rest periods and while watching a sad film. When examined independently, resting RSA and RSA reactivity were unrelated to depression, but their interaction predicted latent depression levels and proband status. In the context of high resting RSA, RSA withdrawal from the sad film predicted the lowest levels of depressive symptoms (irrespective of depression histories) and the greatest likelihood of having had no history of major mental disorder (irrespective of current distress). Our findings highlight the utility of combining indices of physiological responses in studying depression; combinations of RSA indices should be given future consideration as reflecting depression endophenotypes. © 2013 American Psychological Association

Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

PubMed

Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

2017-05-30

A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

Gender-specific modulation of neural mechanisms underlying social reward processing by Autism Quotient

PubMed Central

Barman, Adriana; Richter, Sylvia; Soch, Joram; Deibele, Anna; Richter, Anni; Assmann, Anne; Wüstenberg, Torsten; Walter, Henrik; Seidenbecher, Constanze I.

2015-01-01

Autism spectrum disorder refers to a neurodevelopmental condition primarily characterized by deficits in social cognition and behavior. Subclinically, autistic features are supposed to be present in healthy humans and can be quantified using the Autism Quotient (AQ). Here, we investigated a potential relationship between AQ and neural correlates of social and monetary reward processing, using functional magnetic resonance imaging in young, healthy participants. In an incentive delay task with either monetary or social reward, reward anticipation elicited increased ventral striatal activation, which was more pronounced during monetary reward anticipation. Anticipation of social reward elicited activation in the default mode network (DMN), a network previously implicated in social processing. Social reward feedback was associated with bilateral amygdala and fusiform face area activation. The relationship between AQ and neural correlates of social reward processing varied in a gender-dependent manner. In women and, to a lesser extent in men, higher AQ was associated with increased posterior DMN activation during social reward anticipation. During feedback, we observed a negative correlation of AQ and right amygdala activation in men only. Our results suggest that social reward processing might constitute an endophenotype for autism-related traits in healthy humans that manifests in a gender-specific way. PMID:25944965

Working memory activation of neural networks in the elderly as a function of information processing phase and task complexity.

PubMed

Charroud, Céline; Steffener, Jason; Le Bars, Emmanuelle; Deverdun, Jérémy; Bonafe, Alain; Abdennour, Meriem; Portet, Florence; Molino, François; Stern, Yaakov; Ritchie, Karen; Menjot de Champfleur, Nicolas; Akbaraly, Tasnime N

2015-11-01

Changes in working memory are sensitive indicators of both normal and pathological brain aging and associated disability. The present study aims to further understanding of working memory in normal aging using a large cohort of healthy elderly in order to examine three separate phases of information processing in relation to changes in task load activation. Using covariance analysis, increasing and decreasing neural activation was observed on fMRI in response to a delayed item recognition task in 337 cognitively healthy elderly persons as part of the CRESCENDO (Cognitive REServe and Clinical ENDOphenotypes) study. During three phases of the task (stimulation, retention, probe), increased activation was observed with increasing task load in bilateral regions of the prefrontal cortex, parietal lobule, cingulate gyrus, insula and in deep gray matter nuclei, suggesting an involvement of central executive and salience networks. Decreased activation associated with increasing task load was observed during the stimulation phase, in bilateral temporal cortex, parietal lobule, cingulate gyrus and prefrontal cortex. This spatial distribution of decreased activation is suggestive of the default mode network. These findings support the hypothesis of an increased activation in salience and central executive networks and a decreased activation in default mode network concomitant to increasing task load. Copyright © 2015 Elsevier Inc. All rights reserved.

GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.

PubMed

Cruchaga, Carlos; Kauwe, John S K; Harari, Oscar; Jin, Sheng Chih; Cai, Yefei; Karch, Celeste M; Benitez, Bruno A; Jeng, Amanda T; Skorupa, Tara; Carrell, David; Bertelsen, Sarah; Bailey, Matthew; McKean, David; Shulman, Joshua M; De Jager, Philip L; Chibnik, Lori; Bennett, David A; Arnold, Steve E; Harold, Denise; Sims, Rebecca; Gerrish, Amy; Williams, Julie; Van Deerlin, Vivianna M; Lee, Virginia M-Y; Shaw, Leslie M; Trojanowski, John Q; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Schellenberg, Gerard D; Peskind, Elaine R; Galasko, Douglas; Fagan, Anne M; Holtzman, David M; Morris, John C; Goate, Alison M

2013-04-24

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci. Copyright © 2013 Elsevier Inc. All rights reserved.

CHOLESTEROL-RELATED GENETIC RISK SCORES ARE ASSOCIATED WITH HYPOMETABOLISM IN ALZHEIMER’S-AFFECTED BRAIN REGIONS

PubMed Central

Reiman, Eric M.; Chen, Kewei; Caselli, Richard J.; Alexander, Gene E.; Bandy, Daniel; Adamson, Jennifer L.; Lee, Wendy; Cannon, Ashley; Stephan, Elizabeth A.; Stephan, Dietrich A.; Papassotiropoulos, Andreas

2008-01-01

We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer’s disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person’s risk. In a separate study, we found that apolipoprotein E (APOE) ε4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and non-carriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE ε4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD, and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk. PMID:18280754

Report To The Secretary Of Defense-Task Group On A Culture Of Savings: Implementing Behavior Change In DoD

DTIC Science & Technology

2011-01-01

Shared Services in the Public Sector - Accenture Shared Services in Government - AT Kearney – 2009 Global Shared Services Survey Results - Deloitte... Shared Services - a Benchmark Study - The Johnson Group – Economics of Business Process Outsourcing - Technology Association of Georgia – State of... Shared Services and Business Process Outsourcing - Accenture – Public Sector Outsourcing Surge in 2010 - National Outsourcing Association – Naval

The extent of interorganizational resource sharing among local health departments: the association with organizational characteristics and institutional factors.

PubMed

Vest, Joshua R; Shah, Gulzar H

2012-11-01

Resource sharing, arrangements between local health departments (LHDs) for joint programs or to share staff, is a growing occurrence. The post-9/11 influx of federal funding and new public health preparedness responsibilities dramatically increased the occurrence of these inter-LHD relationships, and several states have pursed more intrastate collaboration. This article describes the current state of resource sharing among LHDs and identifies the factors associated with resource sharing. Using the National Association of County & City Health Officials' 2010 Profile Survey, we determined the self-reported number of shared programmatic activities and the number of shared organizational functions for a sample of LHDs. Negative binomial regression models described the relationships between factors suggested by interorganizational theory and the counts of sharing activities. We examined the extent of resource sharing using 2 different count variables: (1) number of shared programmatic activities and (2) number of shared organizational functions. About one-half of all LHDs are engaged in resource sharing. The extent of sharing was lower for those serving larger populations, with city jurisdictions, or of larger size. Sharing was more extensive for state-governed LHDs, those covering multiple jurisdictions, states with centralized governance, and in instances of financial constraint. Many LHDs are engaged in a greater extent of resource sharing than others. Leaders of LHDs can work within the context of these factors to leverage resource sharing to meet their organizational needs.

Putting the brakes on the "drive to eat": Pilot effects of naltrexone and reward based eating on food cravings among obese women

PubMed Central

Mason, Ashley E.; Laraia, Barbara; Daubenmier, Jennifer; Hecht, Frederick M.; Lustig, Robert H.; Puterman, Eli; Adler, Nancy; Dallman, Mary; Kiernan, Michaela; Gearhardt, Ashley N.; Epel, Elissa S.

2015-01-01

Purpose Obese individuals vary in their experience of food cravings and tendency to engage in reward-driven eating, both of which can be modulated by the neural reward system rather than physiological hunger. We examined two predictions in a sample of obese women: (1) whether opioidergic blockade reduced food-craving intensity, and (2) whether opioidergic blockade reduced an association between food-craving intensity and reward-driven eating, which is a trait-like index of three factors (lack of control over eating, lack of satiation, preoccupation with food). Methods Forty-four obese, pre-menopausal women completed the Reward-based Eating Drive (RED) scale at study start and daily food-craving intensity on 5 days on which they ingested either a pill-placebo (2 days), a 25mg naltrexone dose (1 day), or a standard 50mg naltrexone dose (2 days). Results Craving intensity was similar under naltrexone and placebo doses. The association between food-craving intensity and reward-driven eating significantly differed between placebo and 50mg naltrexone doses. Reward-driven eating and craving intensity were significantly positively associated under both placebo doses. As predicted, opioidergic blockade (for both doses 25mg and 50mg naltrexone) reduced this positive association between reward-driven eating and craving intensity to non-significance. Conclusions Opioidergic blockade did not reduce craving intensity; however, blockade reduced an association between trait-like reward-driven eating and daily food-craving intensity, and may help identify an important endophenotype within obesity. PMID:26164674

Posttraumatic stress disorder symptom severity is associated with reduced default mode network connectivity in individuals with elevated genetic risk for psychopathology.

PubMed

Miller, Danielle R; Logue, Mark W; Wolf, Erika J; Maniates, Hannah; Robinson, Meghan E; Hayes, Jasmeet P; Stone, Annjanette; Schichman, Steven; McGlinchey, Regina E; Milberg, William P; Miller, Mark W

2017-07-01

Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity. Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs. Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD. Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder. © 2017 Wiley Periodicals, Inc.

The folic acid endophenotype and depression in an elderly population.

PubMed

Naumovski, N; Veysey, M; Ng, X; Boyd, L; Dufficy, L; Blades, B; Travers, C; Lewis, P; Sturm, J; Townley-Jones, M; Yates, Z; Roach, P; Lucock, M

2010-12-01

Folate status and/or genes have been linked to depression in a number of studies. This may be via a direct action (or actions) on neuronal membranes or indirect effects through the metabolism of methyl groups involved in neurotransmitter synthesis. This study examines folate and related thiol metabolism that might underpin either phenomenon. Cohort study describing the relationship between several genetic and nutritional aspects of folic acid homeostasis and depression assessed by the HADS psychometric index in an elderly cohort. New South Wales (Australia) retirement village. 118 elderly participants (age 65-90 years). Stepwise multiple regression was used to determine the best statistical model to predict depression; C677T-MTHFR (p=0.0103) was found to be positively associated with depression, while the thiol dipeptide Cys-Gly was negatively associated (p=0.0403). The statistical models used accounted for the major folate related indices (genetic and biochemical) that are most often evaluated in the context of health and disease. When only genetic data were examined for interactions, C677T-MTHFR was found to be negatively associated with the HADS Depression Index Score (p=0.0191). The potential influence of Cys-Gly on this phenotype is novel, and of considerable interest given that it has been linked to altered spontaneous activity and sedation in an animal model. Cys-Gly is a recognised ligand at the N-methyl-D-aspartatic acid (NMDA) subclass of glutamate receptor, a system associated with depression. In addition, the C677T-MTHFR association adds further support to existing findings underscoring the potential role of folate in depression.

Distinct cortical correlates of autistic versus antisocial traits in a longitudinal sample of typically developing youth

PubMed Central

Wallace, Gregory L.; Shaw, Philip; Lee, Nancy Raitano; Clasen, Liv S.; Raznahan, Armin; Lenroot, Rhoshel K.; Martin, Alex; Giedd, Jay N.

2012-01-01

In humans, behaviors associated with autism and antisociality, disorders characterized by distinct social impairments, can be viewed as quantitative traits that range from frank impairment to normal variation, as found in the general population. Neuroimaging investigations of autism and antisociality demonstrate diagnostically specific aberrant cortical brain structure. However, little is known about structural brain correlates of social behavior in non-clinical populations. Therefore, we sought to determine if autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. 323 typically developing youth (age at first scan: mean=10.63, SD=3.71 years) underwent anatomic magnetic resonance imaging (1–6 scans each; total=742 scans), and provided ratings of autistic and antisocial traits. Higher autistic trait ratings were associated with thinner cortex most prominently in right superior temporal sulcus while higher antisocial trait ratings were associated with thinner cortex in primarily bilateral anterior prefrontal cortices. There was no interaction with age, indicating that these brain-behavior associations were stable across development. Using assessments of both subclinical autistic and subclinical antisocial traits within a large longitudinal sample of typically developing youth, we demonstrate dissociable neuroanatomic correlations that parallel those found in the frank clinical disorders of autism (e.g., superior temporal cortex) and antisociality (e.g., anterior prefrontal cortex). Moreover, these correlations appear to be established in early childhood and remain fixed into early adulthood. These results support the dimensional view of psychopathology and provide neural signatures that can serve as informative endophenotypes for future genetic studies. PMID:22492041

Biological indicators of illness risk in offspring of bipolar parents: targeting the hypothalamic-pituitary-adrenal axis and immune system.

PubMed

Duffy, Anne; Lewitzka, Ute; Doucette, Sarah; Andreazza, Ana; Grof, Paul

2012-05-01

The study aims to provide a selective review of the literature pertaining to the hypothalamic-pituitary-adrenal (HPA) axis and immune abnormalities as informative biological indicators of vulnerability in bipolar disorder (BD). We summarize key findings relating to HPA axis and immunological abnormalities in bipolar patients and their high-risk offspring. Findings derive from a review of selected original papers published in the literature, and supplemented by papers identified through bibliography review. Neurobiological findings are discussed in the context of emergent BD in those at genetic risk and synthesized into a neurodevelopmental model of illness onset and progression. BD is associated with a number of genetic and possibly epigenetic abnormalities associated with neurotransmitter, hormonal and immunologically mediated neurobiological pathways. Data from clinical and high-risk studies implicate HPA axis and immune system abnormalities, which may represent inherited vulnerabilities important for the transition to illness onset. Post-mortem and clinical studies implicate intracellular signal transduction processes and disturbance in energy metabolism associated with established BD. Specifically, long-standing maladaptive alterations such as changes in neuronal systems may be mediated through changes in intracellular signalling pathways, oxidative stress, cellular energy metabolism and apoptosis associated with substantial burden of illness. Prospective longitudinal studies of endophenotypes and biomarkers such as HPA axis and immune abnormalities in high-risk offspring will be helpful to understand genetically mediated biological pathways associated with illness onset and progression. A clinical staging model describing emergent illness in those at genetic risk should facilitate this line of investigation. © 2011 Blackwell Publishing Asia Pty Ltd.

Distinct cortical correlates of autistic versus antisocial traits in a longitudinal sample of typically developing youth.

PubMed

Wallace, Gregory L; Shaw, Philip; Lee, Nancy Raitano; Clasen, Liv S; Raznahan, Armin; Lenroot, Rhoshel K; Martin, Alex; Giedd, Jay N

2012-04-04

In humans, behaviors associated with autism and antisociality, disorders characterized by distinct social impairments, can be viewed as quantitative traits that range from frank impairment to normal variation, as found in the general population. Neuroimaging investigations of autism and antisociality demonstrate diagnostically specific aberrant cortical brain structure. However, little is known about structural brain correlates of social behavior in nonclinical populations. Therefore, we sought to determine whether autistic and antisocial traits exhibit dissociable cortical correlates and whether these associations are stable across development among typically developing youth. Three hundred twenty-three typically developing youth (age at first scan: mean = 10.63, SD = 3.71 years) underwent anatomic magnetic resonance imaging (1-6 scans each; total = 742 scans), and provided ratings of autistic and antisocial traits. Higher autistic trait ratings were associated with thinner cortex most prominently in right superior temporal sulcus while higher antisocial trait ratings were associated with thinner cortex in primarily bilateral anterior prefrontal cortices. There was no interaction with age, indicating that these brain-behavior associations were stable across development. Using assessments of both subclinical autistic and subclinical antisocial traits within a large longitudinal sample of typically developing youth, we demonstrate dissociable neuroanatomic correlations that parallel those found in the frank clinical disorders of autism (e.g., superior temporal cortex) and antisociality (e.g., anterior prefrontal cortex). Moreover, these correlations appear to be established in early childhood and remain fixed into early adulthood. These results support the dimensional view of psychopathology and provide neural signatures that can serve as informative endophenotypes for future genetic studies.

Cohort Profile Update: The TRacking Adolescents’ Individual Lives Survey (TRAILS)

PubMed Central

Oldehinkel, Albertine J; Rosmalen, Judith GM; Buitelaar, Jan K; Hoek, Hans W; Ormel, Johan; Raven, Dennis; Reijneveld, Sijmen A; Veenstra, René; Verhulst, Frank C; Vollebergh, Wilma AM; Hartman, Catharina A

2015-01-01

TRAILS consists of a population cohort (N = 2230) and a clinical cohort (N = 543), both of which were followed from about age 11 years onwards. To date, the population cohort has been assessed five times over a period of 11 years, with retention rates ranging between 80% and 96%. The clinical cohort has been assessed four times over a period of 8 years, with retention rates ranging between 77% and 85%. Since the IJE published a cohort profile on the TRAILS in 2008, the participants have matured from adolescents into young adults. The focus shifted from parents and school to entry into the labour market and family formation, including offspring. Furthermore, psychiatric diagnostic interviews were administered, the database was linked to a Psychiatric Case Registry, and the availability of genome-wide SNP variations opened the door to genome-wide association studies regarding a wide range of (endo)phenotypes. With some delay, TRAILS data are available to researchers outside the TRAILS consortium without costs; access can be obtained by submitting a publication proposal (see www.trails.nl). PMID:25431468

Impaired ability to organize information in individuals with autism spectrum disorders and their siblings.

PubMed

Sumiyoshi, Chika; Kawakubo, Yuki; Suga, Motomu; Sumiyoshi, Tomiki; Kasai, Kiyoto

2011-03-01

Despite rigorous research on disturbances of executive function and social cognition in autism spectrum disorders (ASD), little information has been available concerning higher cognitive functions, such as the ability to focus and associate relevant features to form categories, or 'organizing of information'. The purpose of this study was to investigate this issue by using the Wisconsin Card Sorting Test (WCST) and the Verbal Learning Task (VLT). Cognitive assessments were conducted in 22 individuals with ASD, 14 non-affected siblings, and 15 age-matched control subjects. Overall, individuals with ASD performed significantly worse on the WCST and VLT compared to their siblings and normal control subjects. Although siblings performed generally well on both tasks, they exhibited similar degree of perseverative responses in the WCST compared to the probands. A linear increase of the memory organization score in the VLT was also absent in siblings as well as the ASD group. These results suggest an impaired ability to organize information is one of the cognitive endophenotypes for ASD. Copyright © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Temperament and its Association with Autism Symptoms in a High-risk Population.

PubMed

Garon, Nancy; Zwaigenbaum, Lonnie; Bryson, Susan; Smith, Isabel M; Brian, Jessica; Roncadin, Caroline; Vaillancourt, Tracy; Armstrong, Vickie; Sacrey, Lori-Ann R; Roberts, Wendy

2016-05-01

Temperament was investigated in a group of high-risk infants (N = 383; 45 % girls) who had an older sibling with autism spectrum disorder (ASD), and in community control infants (N = 162; 46 % girls) with no family history of ASD (low-risk). The infants were assessed at age 12 months using the Infant Behavior Questionnaire, and at 24 months using the Toddler Behavior Assessment Questionnaire. At 36 months, an independent blind diagnostic assessment for ASD was conducted using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). The results indicate not only differences in temperament traits between the high- and low-risk groups, but also differences in the structure of higher-order temperament factors. The results support the importance of early reactive temperament in the development of Effortful Control in the high-risk sample. Furthermore, Effortful Control at 24 months appears to play a critical role in predicting later ASD symptoms (at 36 months). Taken together, these findings support the use of early temperament as an endophenotype for ASD.

The Mediating Effect of Prefrontal Asymmetry on the Relationship between the COMT Val158Met SNP and Trait Consummatory Positive Affect

PubMed Central

Katz, Andrea C.; Sarapas, Casey; Bishop, Jeffrey R.; Patel, Shitalben R.; Shankman, Stewart A.

2014-01-01

The Val158Met rs4680 polymorphism in the COMT gene regulates dopamine catabolism in the prefrontal cortex (PFC). Dopamine’s involvement in reward experience suggests those with the Met variant may exhibit trait-level sensitivity to reward due to more post-synaptic dopamine in the PFC. A physiological mediator of this association may be greater relative left asymmetry in the PFC, a putative biomarker for trait positive emotionality. Electroencephalograms of 120 participants were measured during a task that assesses two aspects of reward processing: pre-reward anticipation and post-reward consummatory affect. Participants provided genetics samples and completed the Temporal Experience of Pleasure Scale, which assesses trait-level anticipatory and consummatory positive affect. Met carriers had higher TEPS-Consummatory scores. This effect was mediated by greater relative left activation in the post-reward phase of the task. No effects were observed for the pre-reward phase. Results suggest that frontal asymmetry is an endophenotype between COMT genotype and trait reward responsivity. PMID:25195915

Facial affect recognition deficit as a marker of genetic vulnerability to schizophrenia.

PubMed

Alfimova, Margarita V; Abramova, Lilia I; Barhatova, Aleksandra I; Yumatova, Polina E; Lyachenko, Galina L; Golimbet, Vera E

2009-05-01

The aim of this study was to investigate the possibility that affect recognition impairments are associated with genetic liability to schizophrenia. In a group of 55 unaffected relatives of schizophrenia patients (parents and siblings) we examined the capacity to detect facially expressed emotions and its relationship to schizotypal personality, neurocognitive functioning, and the subject's actual emotional state. The relatives were compared with 103 schizophrenia patients and 99 healthy subjects without any family history of psychoses. Emotional stimuli were nine black-and-white photos of actors, who portrayed six basic emotions as well as interest, contempt, and shame. The results evidenced the affect recognition deficit in relatives, though milder than that in patients themselves. No correlation between the deficit and schizotypal personality measured with SPQ was detected in the group of relatives. Neither cognitive functioning, including attention, verbal memory and linguistic ability, nor actual emotional states accounted for their affect recognition impairments. The results suggest that the facial affect recognition deficit in schizophrenia may be related to genetic predisposition to the disorder and may serve as an endophenotype in molecular-genetic studies.

Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke–Korsakoff syndrome

PubMed Central

Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

2016-01-01

Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation. PMID:27576603

Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

PubMed

Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

2016-12-01

Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

Animal models of speech and vocal communication deficits associated with psychiatric disorders

PubMed Central

Konopka, Genevieve; Roberts, Todd F.

2015-01-01

Disruptions in speech, language and vocal communication are hallmarks of several neuropsychiatric disorders, most notably autism spectrum disorders. Historically, the use of animal models to dissect molecular pathways and connect them to behavioral endophenotypes in cognitive disorders has proven to be an effective approach for developing and testing disease-relevant therapeutics. The unique aspects of human language when compared to vocal behaviors in other animals make such an approach potentially more challenging. However, the study of vocal learning in species with analogous brain circuits to humans may provide entry points for understanding this human-specific phenotype and diseases. Here, we review animal models of vocal learning and vocal communication, and specifically link phenotypes of psychiatric disorders to relevant model systems. Evolutionary constraints in the organization of neural circuits and synaptic plasticity result in similarities in the brain mechanisms for vocal learning and vocal communication. Comparative approaches and careful consideration of the behavioral limitations among different animal models can provide critical avenues for dissecting the molecular pathways underlying cognitive disorders that disrupt speech, language and vocal communication. PMID:26232298

Parent-adolescent dyads: association of parental autonomy support and parent-adolescent shared diabetes care responsibility.

PubMed

Hanna, K M; Dashiff, C J; Stump, T E; Weaver, M T

2013-09-01

Parent-adolescent shared responsibility for diabetes care is advocated by experts to achieve beneficial diabetes and psychosocial outcomes for adolescents with type 1 diabetes. Parental autonomy support may be a way to facilitate this sharing. In this dyadic study, we examined parental diabetes-specific autonomy support experienced by adolescents with type 1 diabetes and their parents (n = 89 dyads), and its association with their experience of shared diabetes care responsibility. Path analysis was used to test an Actor-Partner Interdependence Model for parental autonomy support effects on shared responsibility. This was a secondary analysis of data from 89 parent-early/mid-adolescent dyads. Actor effects were identified. Parents' and adolescents' perceptions of parental autonomy support were associated with their respective reports of shared diabetes care responsibility. One partner effect was identified. Adolescents' reports of parental autonomy support were associated with parents' reports of shared responsibility. Parents and adolescents held similar views of autonomy support but discrepant views of shared responsibility. Older adolescents perceived less parental autonomy support. Increasing parental autonomy support may facilitate parent-adolescent sharing of diabetes care responsibility. Adolescent and parent perceptions influence each other and need to be considered when working with them to strengthen parental autonomy support. © 2012 John Wiley & Sons Ltd.

Bed-sharing, breastfeeding and maternal moods in Barbados.

PubMed

Galler, Janina R; Harrison, Robert H; Ramsey, Frank

2006-12-01

Bed-sharing among Barbadian mothers and infants was studied in relationship to maternal and infant characteristics. This prospective study followed 226 healthy, well-nourished mother-infant dyads at birth, 7 weeks, 3 months, and 6 months postpartum. At each age, approximately half of the infants shared the same beds as their mothers. Bed-sharing was associated with demographic characteristics, especially fewer home conveniences, and also maternal characteristics, including less information seeking by the mother and younger maternal age at first pregnancy. Bed-sharing was also associated with lower infant birth weights. Maternal moods were significantly correlated with bed-sharing, such that mothers who reported having more despair and anxiety were also more likely to sleep with their infants. Bed-sharing was also significantly associated with increased breastfeeding at all infant ages, but this relationship was no longer significant once the effects of maternal moods were controlled. This study emphasizes the importance of assessing maternal moods in studies evaluating the risk and benefits of bed-sharing.

Gating Deficits are More Heritable and Correlate with Increased Clinical Severity in Schizophrenia Patients with a Positive versus Negative Family History

PubMed Central

Greenwood, Tiffany A.; Light, Gregory A.; Swerdlow, Neal R.; Calkins, Monica E.; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Stone, William S.; Sugar, Catherine A.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Freedman, Robert; Braff, David L.

2016-01-01

Objective The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here we investigated whether gating measures were more heritable in multiply affected families with a positive family history vs. families with only a single affected proband (singleton). Method A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons. Results Both PPI and P50 gating displayed significantly increased heritability in the 97 multiply affected families (47% and 36%, respectively), compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those derived from singleton families. Conclusions PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, which provides further support for the commonality of genes underlying both schizophrenia and gating measures. PMID:26441157

Proteomics and metabolomics in ageing research: from biomarkers to systems biology.

PubMed

Hoffman, Jessica M; Lyu, Yang; Pletcher, Scott D; Promislow, Daniel E L

2017-07-15

Age is the single greatest risk factor for a wide range of diseases, and as the mean age of human populations grows steadily older, the impact of this risk factor grows as well. Laboratory studies on the basic biology of ageing have shed light on numerous genetic pathways that have strong effects on lifespan. However, we still do not know the degree to which the pathways that affect ageing in the lab also influence variation in rates of ageing and age-related disease in human populations. Similarly, despite considerable effort, we have yet to identify reliable and reproducible 'biomarkers', which are predictors of one's biological as opposed to chronological age. One challenge lies in the enormous mechanistic distance between genotype and downstream ageing phenotypes. Here, we consider the power of studying 'endophenotypes' in the context of ageing. Endophenotypes are the various molecular domains that exist at intermediate levels of organization between the genotype and phenotype. We focus our attention specifically on proteins and metabolites. Proteomic and metabolomic profiling has the potential to help identify the underlying causal mechanisms that link genotype to phenotype. We present a brief review of proteomics and metabolomics in ageing research with a focus on the potential of a systems biology and network-centric perspective in geroscience. While network analyses to study ageing utilizing proteomics and metabolomics are in their infancy, they may be the powerful model needed to discover underlying biological processes that influence natural variation in ageing, age-related disease, and longevity. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review

PubMed Central

Fineberg, Naomi A; Potenza, Marc N; Chamberlain, Samuel R; Berlin, Heather A; Menzies, Lara; Bechara, Antoine; Sahakian, Barbara J; Robbins, Trevor W; Bullmore, Edward T; Hollander, Eric

2010-01-01

Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field. PMID:19940844

Convergence and divergence of neurocognitive patterns in schizophrenia and depression.

PubMed

Liang, Sugai; Brown, Matthew R G; Deng, Wei; Wang, Qiang; Ma, Xiaohong; Li, Mingli; Hu, Xun; Juhas, Michal; Li, Xinmin; Greiner, Russell; Greenshaw, Andrew J; Li, Tao

2018-02-01

Neurocognitive impairments are frequently observed in schizophrenia and major depressive disorder (MDD). However, it remains unclear whether reported neurocognitive abnormalities could objectively identify an individual as having schizophrenia or MDD. The current study included 220 first-episode patients with schizophrenia, 110 patients with MDD and 240 demographically matched healthy controls (HC). All participants performed the short version of the Wechsler Adult Intelligence Scale-Revised in China; the immediate and delayed logical memory of the Wechsler Memory Scale-Revised in China; and seven tests from the computerized Cambridge Neurocognitive Test Automated Battery to evaluate neurocognitive performance. The three-class AdaBoost tree-based ensemble algorithm was employed to identify neurocognitive endophenotypes that may distinguish between subjects in the categories of schizophrenia, depression and HC. Hierarchical cluster analysis was applied to further explore the neurocognitive patterns in each group. The AdaBoost algorithm identified individual's diagnostic class with an average accuracy of 77.73% (80.81% for schizophrenia, 53.49% for depression and 86.21% for HC). The average area under ROC curve was 0.92 (0.96 in schizophrenia, 0.86 in depression and 0.92 in HC). Hierarchical cluster analysis revealed for MDD and schizophrenia, convergent altered neurocognition patterns related to shifting, sustained attention, planning, working memory and visual memory. Divergent neurocognition patterns for MDD and schizophrenia related to motor speed, general intelligence, perceptual sensitivity and reversal learning were identified. Neurocognitive abnormalities could predict whether the individual has schizophrenia, depression or neither with relatively high accuracy. Additionally, the neurocognitive features showed promise as endophenotypes for discriminating between schizophrenia and depression. Copyright © 2017 Elsevier B.V. All rights reserved.

[Temperamental endophenotypes].

PubMed

Azorin, J-M; Fakra, E; Adida, M; Belzeaux, R; Cermolacce, M; Mazzola, P; Corréard, N; Dubois, M; Pringuey, D; Sokolowsky, M; Kaladjian, A

2012-12-01

Temperament has been defined as the heritable biologically determined core of personality that remains stable throughout the life span and establishes the baseline level of reactivity, mood, and energy of a person. If the link between temperament and mental disorder goes back to the Greco-Roman medicine, Kraepelin was among the first authors to pay attention to the temperamental bases of bipolar disorder. He proposed four temperamental types that he described in the premorbid histories of the majority of manic-depressive patients, and found overrepresented in the biologic relatives of these patients. Building on this ancestry, Akiskal formulated the modern concept of affective temperament, and described five temperaments: depressive, hyperthymic, cyclothymic, irritable, and anxious. According to Akiskal's model, bipolar disorder lies along a continuum from temperament to full-blown episodes of affective illness. A series of recent studies have shown the role played by temperaments in the outbreak of bipolar episodes, their clinical presentation, as well as the illness course and comorbidities. Furthermore modern familial and genetic studies have confirmed the first observations of Kraepelin. It has been recently proposed that affective temperaments may carry distinct evolutionary advantages on the individual or a group level, so that affective disorders would be genetic reservoirs for adaptative temperaments and the price to be paid for the chance of exceptionality. Apart from these theoretical perspectives, paying attention to temperamental components may have important implications for the treatment of bipolar disorder. Finally recent studies confirmed as well, that the concept of affective temperament fulfilled the criteria required to be considered as an endophenotype. Copyright © 2012 L’Encéphale. Published by Elsevier Masson SAS.. All rights reserved.

National Evidence on the Use of Shared Decision Making in Prostate-Specific Antigen Screening

PubMed Central

Han, Paul K. J.; Kobrin, Sarah; Breen, Nancy; Joseph, Djenaba A.; Li, Jun; Frosch, Dominick L.; Klabunde, Carrie N.

2013-01-01

PURPOSE Recent clinical practice guidelines on prostate cancer screening using the prostate-specific antigen (PSA) test (PSA screening) have recommended that clinicians practice shared decision making—a process involving clinician-patient discussion of the pros, cons, and uncertainties of screening. We undertook a study to determine the prevalence of shared decision making in both PSA screening and nonscreening, as well as patient characteristics associated with shared decision making. METHODS A nationally representative sample of 3,427 men aged 50 to 74 years participating in the 2010 National Health Interview Survey responded to questions on the extent of shared decision making (past physician-patient discussion of advantages, disadvantages, and scientific uncertainty associated with PSA screening), PSA screening intensity (tests in past 5 years), and sociodemographic and health-related characteristics. RESULTS Nearly two-thirds (64.3%) of men reported no past physician-patient discussion of advantages, disadvantages, or scientific uncertainty (no shared decision making); 27.8% reported discussion of 1 to 2 elements only (partial shared decision making); 8.0% reported discussion of all 3 elements (full shared decision making). Nearly one-half (44.2%) reported no PSA screening, 27.8% reported low-intensity (less-than-annual) screening, and 25.1% reported high-intensity (nearly annual) screening. Absence of shared decision making was more prevalent in men who were not screened; 88% (95% CI, 86.2%–90.1%) of nonscreened men reported no shared decision making compared with 39% (95% CI, 35.0%–43.3%) of men undergoing high-intensity screening. Extent of shared decision making was associated with black race, Hispanic ethnicity, higher education, health insurance, and physician recommendation. Screening intensity was associated with older age, higher education, usual source of medical care, and physician recommendation, as well as with partial vs no or full shared decision making. CONCLUSIONS Most US men report little shared decision making in PSA screening, and the lack of shared decision making is more prevalent in nonscreened than in screened men. Screening intensity is greatest with partial shared decision making, and different elements of shared decision making are associated with distinct patient characteristics. Shared decision making needs to be improved in decisions for and against PSA screening. PMID:23835816

How Patient Cost-Sharing Trends Affect Adherence and Outcomes

PubMed Central

Eaddy, Michael T.; Cook, Christopher L.; O’Day, Ken; Burch, Steven P.; Cantrell, C. Ron

2012-01-01

Objective We sought to assess the relationship between patient cost sharing; medication adherence; and clinical, utilization, and economic outcomes. Methodology: We conducted a literature review of articles and abstracts published from January 1974 to May 2008. Articles were identified using PubMed, Ovid, medline, Web of Science, and Google Scholar databases. The following terms were used in the search: adherence, compliance, copay, cost sharing, costs, noncompliance, outcomes, hospitalization, utilization, economics, income, and persistence. Results: We identified and included 160 articles in the review. Although the types of interventions, measures, and populations studied varied widely, we were able to identify relatively clear relationships between cost sharing, adherence, and outcomes. Of the articles that evaluated the relationship between changes in cost sharing and adherence, 85% showed that an increasing patient share of medication costs was significantly associated with a decrease in adherence. For articles that investigated the relationship between adherence and outcomes, the majority noted that increased adherence was associated with a statistically significant improvement in outcomes. Conclusion: Increasing patient cost sharing was associated with declines in medication adherence, which in turn was associated with poorer health outcomes. PMID:22346336

31 CFR 50.36 - Allocation of premium income associated with entities that do share profits and losses with...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Allocation of premium income associated with entities that do share profits and losses with private sector insurers. 50.36 Section 50.36... income associated with entities that do share profits and losses with private sector insurers. (a...

Practicing what we preach: developing a data sharing policy for the Journal of the Medical Library Association.

PubMed

Read, Kevin B; Amos, Liz; Federer, Lisa M; Logan, Ayaba; Plutchak, T Scott; Akers, Katherine G

2018-04-01

Providing access to the data underlying research results in published literature allows others to reproduce those results or analyze the data in new ways. Health sciences librarians and information professionals have long been advocates of data sharing. It is time for us to practice what we preach and share the data associated with our published research. This editorial describes the activity of a working group charged with developing a research data sharing policy for the Journal of the Medical Library Association.

Practicing what we preach: developing a data sharing policy for the Journal of the Medical Library Association

PubMed Central

Read, Kevin B.; Amos, Liz; Federer, Lisa M.; Logan, Ayaba; Plutchak, T. Scott; Akers, Katherine G.

2018-01-01

Providing access to the data underlying research results in published literature allows others to reproduce those results or analyze the data in new ways. Health sciences librarians and information professionals have long been advocates of data sharing. It is time for us to practice what we preach and share the data associated with our published research. This editorial describes the activity of a working group charged with developing a research data sharing policy for the Journal of the Medical Library Association. PMID:29632437

"Latent" infection with Toxoplasma gondii: association with trait aggression and impulsivity in healthy adults.

PubMed

Cook, Thomas B; Brenner, Lisa A; Cloninger, C Robert; Langenberg, Patricia; Igbide, Ajirioghene; Giegling, Ina; Hartmann, Annette M; Konte, Bettina; Friedl, Marion; Brundin, Lena; Groer, Maureen W; Can, Adem; Rujescu, Dan; Postolache, Teodor T

2015-01-01

Latent chronic infection with Toxoplasma gondii (T. gondii), a common neurotropic pathogen, has been previously linked with suicidal self-directed violence (SSDV). We sought to determine if latent infection with T. gondii is associated with trait aggression and impulsivity, intermediate phenotypes for suicidal behavior, in psychiatrically healthy adults. Traits of aggression and impulsivity were analyzed in relationship to IgG antibody seropositivity for T. gondii and two other latent neurotropic infections, herpes simplex virus 1 (HSV1) and cytomegalovirus (CMV). One thousand community-residing adults residing in the Munich metropolitan area with no Axis I or II conditions by SCID for DSM-IV (510 men, 490 women, mean age 53.6 ± 15.8, range 20-74). Plasma samples were tested for IgG antibodies to T. gondii, HSV-1 and CMV by ELISA. Self-reported ratings of trait aggression scores (Questionnaire for Measuring Factors of Aggression [FAF]) and trait impulsivity (Sensation-Seeking Scale-V [SSS-V]) were analyzed using linear multivariate methods. T. gondii IgG seropositivity was significantly associated with higher trait reactive aggression scores among women (p < .01), but not among men. T. gondii-positivity was also associated with higher impulsive sensation-seeking (SSS-V Disinhibition) among younger men (p < .01) aged 20-59 years old (median age = 60). All associations with HSV-1 and CMV were not significant. Aggression and impulsivity, personality traits considered as endophenotypes for SSDV, are associated with latent T. gondii infection in a gender and age-specific manner, and could be further investigated as prognostic and treatment targets in T. gondii-positive individuals at risk for SSDV. Published by Elsevier Ltd.

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression.

PubMed

Lintas, C; Sacco, R; Garbett, K; Mirnics, K; Militerni, R; Bravaccio, C; Curatolo, P; Manzi, B; Schneider, C; Melmed, R; Elia, M; Pascucci, T; Puglisi-Allegra, S; Reichelt, K-L; Persico, A M

2009-07-01

Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and betaII isoenzymes result from the alternative splicing of the PKCbeta gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P<0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P<0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P<0.01 and <0.05, respectively) according to qPCR. Protein amounts measured for the PKCbetaII isoform were similarly decreased by 35% (P=0.05). Decreased gene expression characterized patients carrying the 'normal' PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKCbeta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCbeta roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKCbeta roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.

Image Sharing in Radiology-A Primer.

PubMed

Chatterjee, Arindam R; Stalcup, Seth; Sharma, Arjun; Sato, T Shawn; Gupta, Pushpender; Lee, Yueh Z; Malone, Christopher; McBee, Morgan; Hotaling, Elise L; Kansagra, Akash P

2017-03-01

By virtue of its information technology-oriented infrastructure, the specialty of radiology is uniquely positioned to be at the forefront of efforts to promote data sharing across the healthcare enterprise, including particularly image sharing. The potential benefits of image sharing for clinical, research, and educational applications in radiology are immense. In this work, our group-the Association of University Radiologists (AUR) Radiology Research Alliance Task Force on Image Sharing-reviews the benefits of implementing image sharing capability, introduces current image sharing platforms and details their unique requirements, and presents emerging platforms that may see greater adoption in the future. By understanding this complex ecosystem of image sharing solutions, radiologists can become important advocates for the successful implementation of these powerful image sharing resources. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Sharing information about cancer with one's family is associated with improved quality of life.

PubMed

Lai, Carlo; Borrelli, Beatrice; Ciurluini, Paola; Aceto, Paola

2017-10-01

The aim of this study was to investigate the association between cancer patients' ability to share information about their illness with their social network and attachment style dimensions, alexithymia, and quality of life. We hypothesised that ability to share information about one's cancer with family, friends, and medical teams would be positively associated with quality of life and secure attachment and negatively associated with alexithymia. Forty-five cancer patients were recruited from the Psycho-oncology Unit of the San Camillo-Forlanini Hospital in Rome. We collected anamnestic data and self-report data on social sharing ability, quality of life, alexithymia, and attachment. Sharing with family (B = 4.66; SE = 1.82; β = .52; SE = 0.20; t(41) = 2.6; P = .0143) was the only predictor of global health status, and attachment security was the only predictor of mean social sharing (B = 0.25; SE = 0.06; β = .63; SE = 0.14; t(41) = 4.4; P < .0001). Encouraging patients to share information about their experience of cancer may help to improve their quality of life. Attachment security seems to promote social sharing. Psychological assessments of cancer patients should cover both ability to share information about one's cancer with family and attachment security. Copyright © 2016 John Wiley & Sons, Ltd.

Factors associated with bed-sharing for African American and White mothers in Wisconsin.

PubMed

Salm Ward, Trina C; Ngui, Emmanuel M

2015-04-01

Mother-infant bed-sharing has been associated with a higher risk of sleep-related infant deaths, which affects African Americans at a disproportionately higher rate. Although "separate but proximate sleep surfaces" for infants has been recommended since 2005, bed-sharing remains a common practice, especially among African Americans. This study examined factors associated with bed-sharing among African American and White mothers. Separate logistic regression models were constructed for African American and White respondents to the 2007-2010 Wisconsin Pregnancy Risk Assessment and Monitoring System. The sample consisted of 806 African Americans and 1,680 Whites (N = 2,486). A significantly larger proportion of African Americans (70.6 %) reported bed-sharing than Whites (53.4 %). For both races, partner-related stress was significantly associated with bed-sharing; no significant differences were found between the two racial groups. For African Americans, partner stress (OR 1.8: 1.2-2.6) and maternal education of 13-15 years (OR 2.0: 1.2-3.4) or ≥16 years (OR 2.7: 1.1-6.3) was associated with increased odds of bed-sharing. For Whites, partner stress (OR 1.3: 1-1.8), breastfeeding (OR 2.5: 1.9-3.1), income of $35,000-$49,999 (OR 1.6: 1.2-2.3), being unmarried (OR 1.5: 1.1-2.2), needing money for food (OR 1.6: 1.1-2.3), and non-supine sleep (OR 1.8: 1.2-2.6) were associated with increased odds of bed-sharing. Differences were found in bed-sharing factors between racial groups which suggests a need for culturally-relevant, tailored safe infant sleep interventions. Providers should ask families about their infant's sleeping environment and address safety issues within that environment. More research is needed on the context and reasons for bed-sharing.

Mine or Yours? Development of Sharing in Toddlers in Relation to Ownership Understanding

PubMed Central

Brownell, Celia A.; Iesue, Stephanie S.; Nichols, Sara R.; Svetlova, Margarita

2012-01-01

To examine early developments in other-oriented resource sharing, fifty-one 18- and 24-month-old children were administered six tasks with toys or food that could be shared with an adult playmate who had none. On each task the playmate communicated her desire for the items in a series of progressively more explicit cues. Twenty-four-month-olds shared frequently and spontaneously. Eighteen-month-olds shared when given multiple opportunities and when the partner provided enough communicative support. Younger children engaged in self-focused and hypothesis-testing behavior in lieu of sharing more often than did older children. Ownership understanding, separately assessed, was positively associated with sharing and negatively associated with non-sharing behavior, independent of age and language ability. PMID:23145536

A comparative analysis of moral principles and behavioral norms in eight ethical codes relevant to health sciences librarianship, medical informatics, and the health professions.

PubMed

Byrd, Gary D; Winkelstein, Peter

2014-10-01

Based on the authors' shared interest in the interprofessional challenges surrounding health information management, this study explores the degree to which librarians, informatics professionals, and core health professionals in medicine, nursing, and public health share common ethical behavior norms grounded in moral principles. Using the "Principlism" framework from a widely cited textbook of biomedical ethics, the authors analyze the statements in the ethical codes for associations of librarians (Medical Library Association [MLA], American Library Association, and Special Libraries Association), informatics professionals (American Medical Informatics Association [AMIA] and American Health Information Management Association), and core health professionals (American Medical Association, American Nurses Association, and American Public Health Association). This analysis focuses on whether and how the statements in these eight codes specify core moral norms (Autonomy, Beneficence, Non-Maleficence, and Justice), core behavioral norms (Veracity, Privacy, Confidentiality, and Fidelity), and other norms that are empirically derived from the code statements. These eight ethical codes share a large number of common behavioral norms based most frequently on the principle of Beneficence, then on Autonomy and Justice, but rarely on Non-Maleficence. The MLA and AMIA codes share the largest number of common behavioral norms, and these two associations also share many norms with the other six associations. The shared core of behavioral norms among these professions, all grounded in core moral principles, point to many opportunities for building effective interprofessional communication and collaboration regarding the development, management, and use of health information resources and technologies.