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Sample records for association shared endophenotypes

  1. Comorbid Problems in ADHD: Degree of Association, Shared Endophenotypes, and Formation of Distinct Subtypes. Implications for a Future "DSM"

    ERIC Educational Resources Information Center

    Rommelse, Nanda N. J.; Altink, Marieke E.; Fliers, Ellen A.; Martin, Neilson C.; Buschgens, Cathelijne J. M.; Hartman, Catharina A.; Buitelaar, Jan K.; Faraone, Stephen V.; Sergeant, Joseph A.; Oosterlaan, Jaap

    2009-01-01

    We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and…

  2. Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

    PubMed

    Rommelse, Nanda N J; Altink, Marieke E; Fliers, Ellen A; Martin, Neilson C; Buschgens, Cathelijne J M; Hartman, Catharina A; Buitelaar, Jan K; Faraone, Stephen V; Sergeant, Joseph A; Oosterlaan, Jaap

    2009-08-01

    We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)-and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF-and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD-and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF-and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted. PMID:19308723

  3. Linkage and Association Analysis of ADHD Endophenotypes in Extended and Multigenerational Pedigrees from a Genetic Isolate

    PubMed Central

    Martinez, Ariel F.; Lopera, Francisco; Velez, Jorge I.; Palacio, Juan D.; Patel, Hardip; Easteal, Simon; Acosta, Maria T.; Castellanos, F. Xavier

    2015-01-01

    Attention-deficit/ hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, e.g., loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder. PMID:26598068

  4. Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes.

    PubMed

    Vrieze, Scott I; Malone, Stephen M; Pankratz, Nathan; Vaidyanathan, Uma; Miller, Michael B; Kang, Hyun Min; McGue, Matt; Abecasis, Gonçalo; Iacono, William G

    2014-12-01

    We mapped ∼85,000 rare nonsynonymous exonic single nucleotide polymorphisms (SNPs) to 17 psychophysiological endophenotypes in 4,905 individuals, including antisaccade eye movements, resting EEG, P300 amplitude, electrodermal activity, affect-modulated startle eye blink. Nonsynonymous SNPs are predicted to directly change or disrupt proteins encoded by genes and are expected to have significant biological consequences. Most such variants are rare, and new technologies can efficiently assay them on a large scale. We assayed 247,870 mostly rare SNPs on an Illumina exome array. Approximately 85,000 of the SNPs were polymorphic, rare (MAF < .05), and nonsynonymous. Single variant association tests identified a SNP in the PARD3 gene associated with theta resting EEG power. The sequence kernel association test, a gene-based test, identified a gene PNPLA7 associated with pleasant difference startle, the difference in startle magnitude between pleasant and neutral images. No other single nonsynonymous variant, or gene-based group of variants, was strongly associated with any endophenotype. PMID:25387709

  5. Association between AVPR1A, DRD2, and ASPM and Endophenotypes of Communication Disorders

    PubMed Central

    Stein, Catherine M.; Truitt, Barbara; Deng, Fenghua; Ciesla, Allison Avrich; Qiu, Feiyou; Joseph, Peronne; Raghavendra, Rekha; Fondran, Jeremy; Igo, Robert P.; Tag, Jessica; Freebairn, Lisa; Taylor, H. Gerry; Lewis, Barbara A.; Iyengar, Sudha K

    2014-01-01

    Objectives Speech sound disorder (SSD) is one of the most common communication disorders, with prevalence rates of 16% at 3 years of age, and an estimated 3.8% of children still presenting speech difficulties at 6 years of age. Several studies have identified promising associations between communication disorders and genes in brain and neuronal pathways, but there have been few studies focusing on SSD and its associated endophenotypes. Based on the hypothesis that neuronal genes may influence endophenotypes common to communication disorders, we focused on three genes related to brain and central nervous system functioning: dopamine D2 receptor (DRD2), arginine-vassopressin receptor 1a (AVPR1A), and microcephaly gene ASPM. Methods We examined the association of these genes with key endophenotypes of SSD – phonological memory measured by multisyllabic and nonword repetition, vocabulary measured by Expressive One Word Picture Vocabulary Test (EOWPVT) and Peabody Picture Vocabulary Test (PPVT), and reading decoding measured by Woodcock Reading Mastery Tests Revised – as well as the clinical phenotype of SSD. We genotyped tag SNPs in these genes and examined 498 individuals from 180 families. Results These data show several SNPs in all three genes were associated with phonological memory, vocabulary, and reading decoding with p<0.05. Notably, associations in AVPR1A (rs11832266) were significant after multiple testing correction. Gene-level tests showed DRD2 was associated with vocabulary, ASPM with vocabulary and reading decoding, and AVPR1A with all three endophenotypes. Conclusions Endophenotypes common to SSD, language impairment, and reading disability are all associated with these neuronal pathway genes. PMID:24849541

  6. Endophenotyping reveals differential phenotype-genotype correlations between myopia-associated polymorphisms and eye biometric parameters

    PubMed Central

    Chen, Jian Huan; Chen, Haoyu; Huang, Shulan; Lin, Jianwei; Zheng, Yuqian; Xie, Mingliang; Lin, Wenjie; Pang, Chi Pui

    2012-01-01

    Purpose To investigate the association with ocular biometric parameters in myopia-associated single nucleotide polymorphisms (SNPs) of the gap junction protein delta 2 (GJD2), insulin-like growth factor-1 (IGF1) and hepatocyte growth factor (HGF) genes in two geographically different Chinese cohorts. Methods In 814 unrelated Han Chinese individuals aged above 50 years including 362 inland residents and 432 island dwellers, comprehensive ophthalmic examinations were performed. Three SNPs, including GJD2 rs634990, IGF1 rs6214, and HGF rs3735520, were genotyped. Genetic association with ocular biometric parameters was analyzed in individual cohorts, using linear regression controlled for sex and age. Common associations shared by the two cohorts were revealed by meta-analysis. Results Meta-analysis showed that GJD2 rs634990 alone was not associated with any biometric parameters (adjusted p>0.645). The T allele of IGF1 rs6214 was specifically associated with thicker lens (β±SE=0.055±0.022, adjusted p=0.034). The A allele of HGF rs3735520 was associated with longer vitreous chamber depth (β±SE=0.143±0.060, adjusted p=0.050). Significant interaction between HGF rs3735520 and GJD2 rs634990 was found in association with axial length and vitreous chamber depth (adjusted p=0.003 and 0.033, respectively), and possibly with spherical error (adjusted p=0.056). Conclusions Our endophenotyping analysis showed differential association between selected myopia-associated genes and ocular biometric parameters in our Chinese cohorts, which may underline substantial but diversified effects of these genes and their interaction on the development of eye structure and etiology of myopia. PMID:22509107

  7. Electrophysiological Endophenotypes for Schizophrenia.

    PubMed

    Owens, Emily M; 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 GABAergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating data sets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype. PMID:26954597

  8. Working-memory endophenotype and dyslexia-associated genetic variant predict dyslexia phenotype.

    PubMed

    Männel, Claudia; Meyer, Lars; Wilcke, Arndt; Boltze, Johannes; Kirsten, Holger; Friederici, Angela D

    2015-10-01

    Developmental dyslexia, a severe impairment of literacy acquisition, is known to have a neurological basis and a strong genetic background. However, effects of individual genetic variations on dyslexia-associated deficits are only moderate and call for the assessment of the genotype's impact on mediating neuro-endophenotypes by the imaging genetics approach. Using voxel-based morphometry (VBM) in German participants with and without dyslexia, we investigated gray matter changes and their association with impaired phonological processing, such as reduced verbal working memory. These endophenotypical alterations were, together with dyslexia-associated genetic variations, examined on their suitability as potential predictors of dyslexia. We identified two gray matter clusters in the left posterior temporal cortex related to verbal working memory capacity. Regional cluster differences correlated with genetic risk variants in TNFRSF1B. High-genetic-risk participants exhibit a structural predominance of auditory-association areas relative to auditory-sensory areas, which may partly compensate for deficient early auditory-sensory processing stages of verbal working memory. The reverse regional predominance observed in low-genetic-risk participants may in turn reflect reliance on these early auditory-sensory processing stages. Logistic regression analysis further supported that regional gray matter differences and genetic risk interact in the prediction of individuals' diagnostic status: With increasing genetic risk, the working-memory related structural predominance of auditory-association areas relative to auditory-sensory areas classifies participants with dyslexia versus control participants. Focusing on phonological deficits in dyslexia, our findings suggest endophenotypical changes in the left posterior temporal cortex could comprise novel pathomechanisms for verbal working memory-related processes translating TNFRSF1B genotype into the dyslexia phenotype. PMID

  9. 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…

  10. Genomewide Association Analyses of Electrophysiological Endophenotypes for Schizophrenia and Psychotic Bipolar Disorders: A Preliminary Report

    PubMed Central

    Hall, Mei-Hua; Chen, Chia-Yen; Cohen, Bruce M.; Spencer, Kevin M.; Levy, Deborah L.; Öngür, Dost; Smoller, Jordan W.

    2015-01-01

    Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P = 1.27 × 10−9). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude. PMID:25740047

  11. 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

  12. Endophenotype Network Models: Common Core of Complex Diseases.

    PubMed

    Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I; Giulianini, Franco; Wang, Ruisheng; Ricchiuto, Piero; Aikawa, Masanori; Iwata, Hiroshi; Müller, Christian; Zeller, Tania; Sharma, Amitabh; Wild, Philipp; Lackner, Karl; Singh, Sasha; Ridker, Paul M; Blankenberg, Stefan; Barabási, Albert-László; Loscalzo, Joseph

    2016-01-01

    Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease's expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules. PMID:27278246

  13. Endophenotype Network Models: Common Core of Complex Diseases

    PubMed Central

    Ghiassian, Susan Dina; Menche, Jörg; Chasman, Daniel I.; Giulianini, Franco; Wang, Ruisheng; Ricchiuto, Piero; Aikawa, Masanori; Iwata, Hiroshi; Müller, Christian; Zeller, Tania; Sharma, Amitabh; Wild, Philipp; Lackner, Karl; Singh, Sasha; Ridker, Paul M.; Blankenberg, Stefan; Barabási, Albert-László; Loscalzo, Joseph

    2016-01-01

    Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules. PMID:27278246

  14. Endophenotypes for Alcohol Use Disorder: An Update on the Field

    PubMed Central

    Salvatore, Jessica E.; Gottesman, Irving I.; Dick, Danielle M.

    2015-01-01

    The endophenotype concept was first proposed as a strategy to use (purportedly) genetically simpler phenotypes in gene identification studies for psychiatric disorders, and is distinct from the closely related concept of intermediate phenotypes. In the area of alcohol use disorder (AUD) research, two candidate endophenotypes have produced replicable genetic associations: level of response to alcohol and neurophysiology markers (e.g., event-related oscillations and event-related potentials). Additional candidate endophenotypes from the cognitive, sensory, and neuroimaging literatures show promise, although more evidence is needed to fully evaluate their potential utility. Translational approaches to AUD endophenotypes have helped characterize the underlying neurobiology and genetics of AUD endophenotypes and identified relevant pharmacological interventions. Future research that capitalizes on the polygenic nature of endophenotypes and emphasizes endophenotypes that may change across development will enhance the usefulness of this concept to understand the genetically-influenced pathways toward AUD. PMID:26236574

  15. Differences in planning performance, a neurocognitive endophenotype, are associated with a functional variant in PER3 gene.

    PubMed

    González-Giraldo, Yeimy; González-Reyes, Rodrigo E; Mueller, Shane T; Piper, Brian J; Adan, Ana; Forero, Diego A

    2015-06-01

    Performance alterations in executive function have been studied as potential endophenotypes for several neuropsychiatric diseases. Planning is an important component of executive function and has been shown to be affected in diseases such as attention deficit hyperactivity disorder, schizophrenia, obsessive-compulsive disorder and Parkinson's disease. Several genes related to dopaminergic systems, such as COMT, have been explored as candidates for influencing planning performance. The circadian clock gene PERIOD3 (PER3) has been shown to be associated with several complex behaviors in humans and could be involved in different signaling mechanisms. In this study, we evaluated the possible association between a functional polymorphism in the PER3 gene (PER3-VNTR, rs57875989) and performance in a commonly used test of planning (Tower of London, TOL) in 229 healthy subjects from Bogotá, Colombia. PER3-VNTR genotyping was carried out with conventional PCR and all participants completed the TOL test using the computerized Psychology Experiment Building Language (PEBL) battery. A linear regression model was used for the analysis of association with the SNPStats program. We found that 4/4 genotype carriers showed a better performance and made fewer moves, in comparison to 4/5 and 5/5 genotype carriers (p = 0.003). These results appear to be independent from effects of this polymorphism on self-reported average hours of sleep during work days in our sample. This is the first evidence of an association between PER3-VNTR and planning performance in a sample of healthy subjects and our results are consistent from previous findings for alterations in other cognitive domains. Future studies examining additional genes could lead to the identification of novel molecular underpinnings of planning in healthy subjects and in patients with neuropsychiatric disorders. PMID:25798540

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

    PubMed Central

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

    2016-01-01

    Background: 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. Methods: 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: 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

  17. [The endophenotype concept in the neurophysiological studies of schizophrenia].

    PubMed

    Kirenskaia, A V; Storozheva, Z I; Miamlin, V V; Tkachenko, A A

    2013-01-01

    The endophenotype concept is considered as theoretical basis for the study of pathobiological mechanisms of schizophrenia and for the development of the complex of instrumental diagnostic methods. The contemporary state of the problem and the most significant results of the study of three neurophysiological schizophrenia endophenotypes are presented in the review: P50 auditory evoked potential suppression, prepulse inhibition of the startle reflex and antisaccade task. The current understanding of the underlying neurophysiological and neurochemical mechanisms is described for each measure. The results of the association studies of neurophysiological endophenotypes with the relevant to schizophrenia genes' polymorphisms are laid down. High degree of independence of the considered endophenotypes is demonstrated. Taking into account the data on relatively low specificity of each endophenotype to schizophrenia compared to other mental disturbances the authors pay special attention to the model of multivariate endophenotype as a scientific and diagnostic tool. PMID:25464754

  18. [The endophenotype concept in the neurophysiological studies of schizophrenia].

    PubMed

    2013-01-01

    The endophenotype concept is considered as theoretical basis for the study of pathobiological mechanisms of schizophrenia and for the development of the complex of instrumental diagnostic methods. The contemporary state of the problem and the most significant results of the study of three neurophysiological schizophrenia endophenotypes are presented in the review: P50 auditory evoked potential suppression, prepulse inhibition of the startle reflex and antisaccade task. The current understanding of the underlying neurophysiological and neurochemical mechanisms is described for each measure. The results of the association studies of neurophysiological endophenotypes with the relevant to schizophrenia genes' polymorphisms are laid down. High degree of independence of the considered endophenotypes is demonstrated. Taking into account the data on relatively low specificity of each endophenotype to schizophrenia compared to other mental disturbances the authors pay special attention to the model of multivariate endophenotype as a scientific and diagnostic tool. PMID:25508385

  19. Endophenotypes in Schizophrenia for the Perinatal Period: Criteria for Validation

    PubMed Central

    Ross, Randal G.; Freedman, Robert

    2015-01-01

    Endophenotypes are disease-associated phenotypes that are thought to reflect the neurobiological or other mechanisms that underlie the more overt symptoms of a psychiatric illness. Endophenotypes have been critical in understanding the genetics, neurobiology, and treatment of schizophrenia. Because psychiatric illnesses have multiple causes, including both genetic and nongenetic risk factors, an endophenotype linked to one of the mechanisms may be expressed more frequently than the disease itself. However, in schizophrenia research, endophenotypes have almost exclusively been studied in older adolescents or adults who have entered or passed through the age of risk for the disorder. Yet, schizophrenia is a neurodevelopmental disorder where prenatal development starts a cascade of brain changes across the lifespan. Endophenotypes have only minimally been utilized to explore the perinatal development of vulnerability. One major impediment to the development of perinatally-useful endophenotypes has been the established validity criteria. For example, the criterion that the endophenotype be more frequently present in those with disease than those without is difficult to demonstrate when there can be a decades-long period between endophenotype measurement and the age of greatest risk for onset of the disorder. This article proposes changes to the endophenotype validity criteria appropriate to perinatal research and reviews how application of these modified criteria helped identify a perinatally-usable phenotype of risk for schizophrenia, P50 sensory gating, which was then used to propose a novel perinatal primary prevention intervention. PMID:25943124

  20. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism

    PubMed Central

    James, S. Jill; Melnyk, Stepan; Jernigan, Stefanie; Cleves, Mario A.; Halsted, Charles H.; Wong, Donna H.; Cutler, Paul; Bock, Kenneth; Boris, Marvin; Bradstreet, J. Jeffrey; Baker, Sidney M.; Gaylor, David W.

    2008-01-01

    Autism is a behaviorally-defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G>A), transcobalamin II (TCN2 776G>C), catechol-O-methyltransferase (COMT 472G>A), methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C), and GST M1. We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and clinical manifestations of autism. PMID

  1. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.

    PubMed

    James, S Jill; Melnyk, Stepan; Jernigan, Stefanie; Cleves, Mario A; Halsted, Charles H; Wong, Donna H; Cutler, Paul; Bock, Kenneth; Boris, Marvin; Bradstreet, J Jeffrey; Baker, Sidney M; Gaylor, David W

    2006-12-01

    Autism is a behaviorally defined neurodevelopmental disorder usually diagnosed in early childhood that is characterized by impairment in reciprocal communication and speech, repetitive behaviors, and social withdrawal. Although both genetic and environmental factors are thought to be involved, none have been reproducibly identified. The metabolic phenotype of an individual reflects the influence of endogenous and exogenous factors on genotype. As such, it provides a window through which the interactive impact of genes and environment may be viewed and relevant susceptibility factors identified. Although abnormal methionine metabolism has been associated with other neurologic disorders, these pathways and related polymorphisms have not been evaluated in autistic children. Plasma levels of metabolites in methionine transmethylation and transsulfuration pathways were measured in 80 autistic and 73 control children. In addition, common polymorphic variants known to modulate these metabolic pathways were evaluated in 360 autistic children and 205 controls. The metabolic results indicated that plasma methionine and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an indicator of methylation capacity, were significantly decreased in the autistic children relative to age-matched controls. In addition, plasma levels of cysteine, glutathione, and the ratio of reduced to oxidized glutathione, an indication of antioxidant capacity and redox homeostasis, were significantly decreased. Differences in allele frequency and/or significant gene-gene interactions were found for relevant genes encoding the reduced folate carrier (RFC 80G > A), transcobalamin II (TCN2 776G > C), catechol-O-methyltransferase (COMT 472G > A), methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C), and glutathione-S-transferase (GST M1). We propose that an increased vulnerability to oxidative stress (endogenous or environmental) may contribute to the development and

  2. ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila

    PubMed Central

    van der Voet, M; Harich, B; Franke, B; Schenck, A

    2016-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. Here we report a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options. PMID:25962619

  3. ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila.

    PubMed

    van der Voet, M; Harich, B; Franke, B; Schenck, A

    2016-04-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. Here we report a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options. PMID:25962619

  4. 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

  5. Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample

    PubMed Central

    Mobascher, A.; Diaz-Lacava, A.; Wagner, M.; Gallinat, J.; Wienker, T. F.; Drichel, D.; Becker, T.; Steffens, M.; Dahmen, N.; Gründer, G.; Thürauf, N.; Kiefer, F.; Kornhuber, J.; Toliat, M. R.; Thiele, H.; Nürnberg, P.; Steinlein, O.; Winterer, G.

    2016-01-01

    Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures. PMID:27054571

  6. Association of Common Polymorphisms in the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene with an Electrophysiological Endophenotype in a Large Population-Based Sample.

    PubMed

    Mobascher, A; Diaz-Lacava, A; Wagner, M; Gallinat, J; Wienker, T F; Drichel, D; Becker, T; Steffens, M; Dahmen, N; Gründer, G; Thürauf, N; Kiefer, F; Kornhuber, J; Toliat, M R; Thiele, H; Nürnberg, P; Steinlein, O; Winterer, G

    2016-01-01

    Variation in genes coding for nicotinic acetylcholine receptor (nAChR) subunits affect cognitive processes and may contribute to the genetic architecture of neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in the CHRNA4 gene that codes for the alpha4 subunit of alpha4/beta2-containing receptors have previously been implicated in aspects of (mostly visual) attention and smoking-related behavioral measures. Here we investigated the effects of six synonymous but functional CHRNA4 exon 5 SNPs on the N100 event-related potential (ERP), an electrophysiological endophenotype elicited by a standard auditory oddball. A total of N = 1,705 subjects randomly selected from the general population were studied with electroencephalography (EEG) as part of the German Multicenter Study on nicotine addiction. Two of the six variants, rs1044396 and neighboring rs1044397, were significantly associated with N100 amplitude. This effect was pronounced in females where we also observed an effect on reaction time. Sequencing of the complete exon 5 region in the population sample excluded the existence of additional/functional variants that may be responsible for the observed effects. This is the first large-scale population-based study investigation the effects of CHRNA4 SNPs on brain activity measures related to stimulus processing and attention. Our results provide further evidence that common synonymous CHRNA4 exon 5 SNPs affect cognitive processes and suggest that they also play a role in the auditory system. As N100 amplitude reduction is considered a schizophrenia-related endophenotype the SNPs studied here may also be associated with schizophrenia outcome measures. PMID:27054571

  7. Endophenotypes in bipolar disorder.

    PubMed

    Lenox, Robert H; Gould, Todd D; Manji, Husseini K

    2002-05-01

    The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-beta (GSK-3beta), a known target of lithium. PMID:11992561

  8. Detecting local haplotype sharing and haplotype association.

    PubMed

    Xu, Hanli; Guan, Yongtao

    2014-07-01

    A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype sharing between individuals at each marker. A statistical model was developed to link the local haplotype sharing and phenotypes to test for association. We devised a novel method to fit the LD model, reducing the complexity from putatively quadratic to linear (in the number of ancestral haplotypes). Therefore, the LD model can be fitted to all study samples simultaneously, and, consequently, our method is applicable to big data sets. Compared to existing haplotype association methods, our method integrated out phase uncertainty, avoided arbitrariness in specifying haplotypes, and had the same number of tests as the single-SNP analysis. We applied our method to data from the Wellcome Trust Case Control Consortium and discovered eight novel associations between seven gene regions and five disease phenotypes. Among these, GRIK4, which encodes a protein that belongs to the glutamate-gated ionic channel family, is strongly associated with both coronary artery disease and rheumatoid arthritis. A software package implementing methods described in this article is freely available at http://www.haplotype.org. PMID:24812308

  9. 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…

  10. 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

  11. The feasibility of genetic dissection of endophenotypes.

    PubMed

    Wilhelmsen, Kirk C

    2014-12-01

    Endophenotypes are traits that proceed and predict traits of interest. In this special issue, there are a series of papers on genomic analysis of 17 physiologic traits measured by the Minnesota Center for Twin and Family Research that are thought to be endophenotypes for behavioral clinical traits such as addiction and schizophrenia. Because these 17 traits, which can be precisely defined and measured throughout the life of subjects, display variation in normal subjects and are heritable, it is thought that they may be more tractable to genetic dissection. These articles show that these 17 endophenotypes appear to have a similar architecture to the vast majority of traits with complex modes of inheritance. The study identified several genetic loci that play a role in these endophenotypes. It appears that further progress in understanding the genetics of these 17 endophenotypes can be made with an expanded data set. PMID:25387719

  12. 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. PMID:26597662

  13. Knowns and unknowns for psychophysiological endophenotypes: Integration and response to commentaries

    PubMed Central

    IACONO, WILLIAM G.; VAIDYANATHAN, UMA; VRIEZE, SCOTT I.; MALONE, STEPHEN M.

    2014-01-01

    We review and summarize seven molecular genetic studies of 17 psychophysiological endophenotypes that comprise this special issue of Psychophysiology, address criticisms raised in accompanying Perspective and Commentary pieces, and offer suggestions for future research. Endophenotypes are polygenic, and possibly influenced by rare genetic variants. Because they are not simpler genetically than clinical phenotypes, they are unlikely to assist gene discovery for psychiatric disorder. Once genetic variants for clinical phenotypes are identified, associated endophenotypes are likely to provide valuable insights into the psychological and neural mechanisms important to disorder pathology. This special issue provides a foundation for informed future steps in endophenotype genetics, including the formation of large sample consortia capable of fleshing out the many genetic variants contributing to individual differences in psychophysiological measures. PMID:25387720

  14. Literacy Outcomes of Children with Early Childhood Speech Sound Disorders: Impact of Endophenotypes

    ERIC Educational Resources Information Center

    Lewis, Barbara A.; Avrich, Allison A.; Freebairn, Lisa A.; Hansen, Amy J.; Sucheston, Lara E.; Kuo, Iris; Taylor, H. Gerry; Iyengar, Sudha K.; Stein, Catherine M.

    2011-01-01

    Purpose: To demonstrate that early childhood speech sound disorders (SSD) and later school-age reading, written expression, and spelling skills are influenced by shared endophenotypes that may be in part genetic. Method: Children with SSD and their siblings were assessed at early childhood (ages 4-6 years) and followed at school age (7-12 years).…

  15. Sharing Assessment Data: An Example from a National Professional Association.

    ERIC Educational Resources Information Center

    Bradley, Jama L.; And Others

    Alexander Astin, a pioneer in assessment research, has argued persuasively for building national databases that would permit programs and institutions to share common data and thus compare themselves with peers (1987, 1991). Others have suggested that certain process and outcome data should be collected and shared by disciplinary associations and…

  16. Detecting local haplotype sharing and haplotype association

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A novel haplotype association method is presented, and its power is demonstrated. Relying on a statistical model for linkage disequilibrium (LD), the method first infers ancestral haplotypes and their loadings at each marker for each individual. The loadings are then used to quantify local haplotype...

  17. 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. PMID:27132484

  18. [Schizophrenia and/or bipolar disorder: the neurocognitive endophenotypes].

    PubMed

    Kaladjian, A; Azorin, J-M; Pomietto, P; Corréard, N; Belzeaux, R; Adida, M

    2012-12-01

    Although Kraepelinian dichotomous conceptualization of psychosis was historically beneficial, modern studies do not support the existence of a sub-typing of psychotic illnesses into schizophrenic and affective psychoses. Years of intensive investigation on the genetic bases of schizophrenia and bipolar disorder suggest that these disorders, rather than being wholly distinct disorders, share common genetic risks. However, one of the most serious difficulties for genetic research in these illnesses is their enormous phenotypic heterogeneity. A response to this problem is the use of neurocognitive functions as endophenotypes or intermediate phenotypes. A review of the literature suggests that in both schizophrenia and bipolar disorder, neurocognitive functions are influenced by genetic factors and that there exists neuropsychological deficits in the nonaffected relatives of probands. However, it is unclear whether or not patterns of performance on neurocognitive tasks across probands as well as unaffected family members offer potential for identifying shared and illness-specific neurocognitive phenotypes for schizophrenia and bipolar disorder. Overlapping and unique neurocognitive endophenotypic signatures of the two psychoses are comprehensively described. PMID:23279993

  19. 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. PMID:25006008

  20. 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

  1. First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children.

    PubMed

    Roeske, D; Ludwig, K U; Neuhoff, N; Becker, J; Bartling, J; Bruder, J; Brockschmidt, F F; Warnke, A; Remschmidt, H; Hoffmann, P; Müller-Myhsok, B; Nöthen, M M; Schulte-Körne, G

    2011-01-01

    Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks. PMID:19786962

  2. Evaluation of behavioral impulsivity and aggression tasks as endophenotypes for borderline personality disorder

    PubMed Central

    McCloskey, Michael S.; New, Antonia S.; Siever, Larry J.; Goodman, Marianne; Koenigsberg, Harold W.; Flory, Janine D.; Coccaro, Emil F.

    2010-01-01

    Borderline personality disorder (BPD) is marked by aggression and impulsive, often self-destructive behavior. Despite the severe risks associated with BPD, relatively little is known about the disorder’s etiology. Identification of genetic correlates (endophenotypes) of BPD would improve the prospects of targeted interventions for more homogeneous subsets of borderline patients characterized by specific genetic vulnerabilities. The current study evaluated behavioral measures of aggression and impulsivity as potential endophenotypes for BPD. Subjects with BPD (N = 127), a non cluster B personality disorder (OPD N = 122), or healthy volunteers (HV N = 112) completed self report and behavioral measures of aggression, motor impulsivity and cognitive impulsivity. Results showed that BPD subjects demonstrated more aggression and motor impulsivity than HV (but not OPD) subjects on behavioral tasks. In contrast, BPD subjects self-reported more impulsivity and aggression than either comparison group. Subsequent analyses showed that among BPD subjects behavioral aggression was associated with self-reported aggression, while behavioral and self-report impulsivity measures were more modestly associated. Overall, the results provide partial support for the use of behavioral measures of aggression and motor impulsivity as endophenotypes for BPD, with stronger support for behavioral aggression measures as an endophenotype for aggression within BPD samples. PMID:19232640

  3. In search of rare variants: preliminary results from whole genome sequencing of 1,325 individuals with psychophysiological endophenotypes.

    PubMed

    Vrieze, Scott I; Malone, Stephen M; Vaidyanathan, Uma; Kwong, Alan; Kang, Hyun Min; Zhan, Xiaowei; Flickinger, Matthew; Irons, Daniel; Jun, Goo; Locke, Adam E; Pistis, Giorgio; Porcu, Eleonora; Levy, Shawn; Myers, Richard M; Oetting, William; McGue, Matt; Abecasis, Goncalo; Iacono, William G

    2014-12-01

    Whole genome sequencing was completed on 1,325 individuals from 602 families, identifying 27 million autosomal variants. Genetic association tests were conducted for those individuals who had been assessed for one or more of 17 endophenotypes (N range = 802-1,185). No significant associations were found. These 27 million variants were then imputed into the full sample of individuals with psychophysiological data (N range = 3,088-4,469) and again tested for associations with the 17 endophenotypes. No association was significant. Using a gene-based variable threshold burden test of nonsynonymous variants, we obtained five significant associations. These findings are preliminary and call for additional analysis of this rich sample. We argue that larger samples, alternative study designs, and additional bioinformatics approaches will be necessary to discover associations between these endophenotypes and genomic variation. PMID:25387710

  4. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

    PubMed

    Lu, Yi; Cuellar-Partida, Gabriel; Painter, Jodie N; Nyholt, Dale R; Morris, Andrew P; Fasching, Peter A; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias W; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; Rossing, Mary Anne; Wicklund, Kristine G; Chang-Claude, Jenny; Eilber, Ursula; Rudolph, Anja; Wang-Gohrke, Shan; Goodman, Marc T; Bogdanova, Natalia; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B; Antonenkova, Natalia; Butzow, Ralf; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M; Edwards, Robert P; Kelley, Joseph L; Modugno, Francesmary; Moysich, Kirsten B; Ness, Roberta B; Cannioto, Rikki; Høgdall, Estrid; Jensen, Allan; Giles, Graham G; Bruinsma, Fiona; Kjaer, Susanne K; Hildebrandt, Michelle A T; Liang, Dong; Lu, Karen H; Wu, Xifeng; Bisogna, Maria; Dao, Fanny; Levine, Douglas A; Cramer, Daniel W; Terry, Kathryn L; Tworoger, Shelley S; Missmer, Stacey; Bjorge, Line; Salvesen, Helga B; Kopperud, Reidun K; Bischof, Katharina; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Brooks-Wilson, Angela; Olson, Sara H; McGuire, Valerie; Rothstein, Joseph H; Sieh, Weiva; Whittemore, Alice S; Cook, Linda S; Le, Nhu D; Gilks, C Blake; Gronwald, Jacek; Jakubowska, Anna; Lubiński, Jan; Gawełko, Jan; Song, Honglin; Tyrer, Jonathan P; Wentzensen, Nicolas; Brinton, Louise; Trabert, Britton; Lissowska, Jolanta; Mclaughlin, John R; Narod, Steven A; Phelan, Catherine; Anton-Culver, Hoda; Ziogas, Argyrios; Eccles, Diana; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J; Wu, Anna H; Dansonka-Mieszkowska, Agnieszka; Kupryjanczyk, Jolanta; Timorek, Agnieszka; Szafron, Lukasz; Cunningham, Julie M; Fridley, Brooke L; Winham, Stacey J; Bandera, Elisa V; Poole, Elizabeth M; Morgan, Terry K; Risch, Harvey A; Goode, Ellen L; Schildkraut, Joellen M; Webb, Penelope M; Pearce, Celeste L; Berchuck, Andrew; Pharoah, Paul D P; Montgomery, Grant W; Zondervan, Krina T; Chenevix-Trench, Georgia; MacGregor, Stuart

    2015-10-15

    Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci. PMID:26231222

  5. An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7.

    PubMed

    Gass, Natalia; Weber-Fahr, Wolfgang; Sartorius, Alexander; Becker, Robert; Didriksen, Michael; Stensbøl, Tine Bryan; Bastlund, Jesper Frank; Meyer-Lindenberg, Andreas; Schwarz, Adam J

    2016-07-01

    The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation. PMID:27061851

  6. Molecular Genetics of Alcohol Dependence and Related Endophenotypes

    PubMed Central

    Le Strat, Yann; Ramoz, Nicolas; Schumann, Gunter; Gorwood, Philip

    2008-01-01

    Alcohol dependence is a worldwide public health problem, and involves both environmental and genetic vulnerability factors. The heritability of alcohol dependence is rather high, ranging between 50% and 60%, although alcohol dependence is a polygenic, complex disorder. Genome-wide scans on large cohorts of multiplex families, including the collaborative study on genetics of alcoholism (COGA), emphasized the role of many chromosome regions and some candidate genes. The genes encoding the alcohol-metabolizing enzymes, or those involved in brain reward pathways, have been involved. Since dopamine is the main neurotransmitter in the reward circuit, genes involved in the dopaminergic pathway represent candidates of interest. Furthermore, gamma-amino-butyric acid (GABA) neurotransmitter mediates the acute actions of alcohol and is involved in withdrawal symptomatology. Numerous studies showed an association between variants within GABA receptors genes and the risk of alcohol dependence. In accordance with the complexity of the “alcohol dependence” phenotype, another field of research, related to the concept of endophenotypes, received more recent attention. The role of vulnerability genes in alcohol dependence is therefore re-assessed focusing on different phenotypes and endophenotypes. The latter include brain oscillations, EEG alpha and beta variants and alpha power, and amplitude of P300 amplitude elicited from a visual oddball task. Recent enhancement on global characterizations of the genome by high-throughput approach for genotyping of polymorphisms and studies of transcriptomics and proteomics in alcohol dependence is also reviewed. PMID:19506733

  7. 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

  8. Anonymizing patient genomic data for public sharing association studies.

    PubMed

    Fernandez-Lozano, Carlos; Lopez-Campos, Guillermo; Seoane, Jose A; Lopez-Alonso, Victoria; Dorado, Julian; Martín-Sanchez, Fernando; Pazos, Alejandro

    2013-01-01

    The development of personalized medicine is tightly linked with the correct exploitation of molecular data, especially those associated with the genome sequence along with these use of genomic data there is an increasing demand to share these data for research purposes. Transition of clinical data to research is based in the anonymization of these data so the patient cannot be identified, the use of genomic data poses a great challenge because its nature of identifying data. In this work we have analyzed current methods for genome anonymization and propose a one way encryption method that may enable the process of genomic data sharing accessing only to certain regions of genomes for research purposes. PMID:23920753

  9. An Application of the Elastic Net for an Endophenotype Analysis

    PubMed Central

    Palejev, Dean; Hwang, Wookyeon; Landi, Nicole; Eastman, Maria; Frost, Stephen J.; Fulbright, Robert K.; Kidd, Judith R.; Kidd, Kenneth K.; Mason, Graeme F.; Mencl, W. Einar; Yrigollen, Carolyn; Pugh, Kenneth R.

    2011-01-01

    We provide an illustration of an application of the elastic net to a large number of common genetic variants in the context of the search for the genetic bases of an endophenotype conceivably related to individual differences in learning. GABA concentration in the occipital cortex, a critical area for reading, was obtained in a group (n = 76) of children aged 6–10 years. Two extreme groups, high and low, were selected for genotyping with the 650Y Illumina array chip (Ilmn650Y). An elastic net approach was applied to the resulting SNP dataset; 100 SNPs were identified for each chromosome as “interesting” based on having the highest absolute value coefficients. The analyses highlighted chromosomes 15 and 20, which contained 55 candidate genes. The STRING partner analyses of the associated proteins pointed to a number of related genes, most notably, GABA and NTRK receptors. PMID:21229297

  10. Scale-dependent neighborhood effects: shared doom and associational refuge.

    PubMed

    Emerson, Sara E; Brown, Joel S; Whelan, Christopher J; Schmidt, Kenneth A

    2012-03-01

    A resource's susceptibility to predation may be influenced by its own palatability and the palatability of its neighbors. We tested for effects of plant chemical defenses on seed survival by manipulating the frequency of palatable and less palatable sunflower seeds in food patches subject to harvest by fox squirrels (Sciurus niger) and gray squirrels (Sciurus carolinensis). We varied resource distributions at three scales: among stations (aggregates of patches ca. 50 m apart), among patches immediately adjacent to each other, and within patches. When food patches were segregated into high-palatability and low-palatability stations (Experiment 1), seeds suffered greater mortality at stations with high levels of palatable seeds. In the same experiment, within patches, squirrels selected strongly for palatable seeds over less palatable seeds. When high- and low-palatability food patches were placed together at the same stations (Experiment 2), increasing densities of co-occurring palatable seeds amplified the mortality of less palatable seeds, indicating "shared doom." When palatable and less palatable seeds were partitioned into micropatches (Experiment 3), associational effects disappeared, as predicted. Furthermore, selectivity in less palatable patches increased as the initial densities of palatable seeds increased, and selectivity in palatable patches decreased as the initial densities of less palatable seeds increased. Foraging theory predicts associational effects among prey that vary in palatability. Our results show how the type and magnitude of associational effects emerge from the interplay among the spatial scale of prey heterogeneity, the diet selection strategy, and the scale-dependent foraging responses of the consumer. PMID:21987268

  11. 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

  12. 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. PMID:25387703

  13. The 5-HTTLPR polymorphism, early and recent life stress, and cognitive endophenotypes of depression.

    PubMed

    Kruijt, Anne-Wil; Putman, Peter; Van der Does, Willem

    2014-01-01

    Studies associating interactions of 5-HTTLPR and life adversities with depression have yielded equivocal results. Studying endophenotypes may constitute a more powerful approach. In the current study, it was assessed whether interactions of 5-HTTLPR with childhood emotional abuse (CEA) and recent negative life events (RNLE) affect possible cognitive endophenotypes of depression, namely, attention-allocation bias and the ability to recognise others' mind states in 215 young adults of North-West European descent. The ability to classify others' negative mind states was found to be increased with increasing RNLE in carriers of low-expressing Serotonin Transporter Linked Polymorphic Region (5-HTTLPR) alleles. Carriers of two low-expressing alleles also preferentially oriented attention towards negative information. Gene-environment interactions were not observed for attention allocation bias. No effects involving CEA were observed. These results suggest that low-expressing 5-HTTLPR alleles may confer increased risk for depression through enhanced recognition of negative facial expressions following RNLE. PMID:24433089

  14. 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. PMID:26545630

  15. 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. PMID:26337483

  16. Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer's disease.

    PubMed

    Ertekin-Taner, Nilüfer

    2011-01-01

    Uncovering the underlying genetic component of any disease is key to the understanding of its pathophysiology and may open new avenues for development of therapeutic strategies and biomarkers. In the past several years, there has been an explosion of genome-wide association studies (GWAS) resulting in the discovery of novel candidate genes conferring risk for complex diseases, including neurodegenerative diseases. Despite this success, there still remains a substantial genetic component for many complex traits and conditions that is unexplained by the GWAS findings. Additionally, in many cases, the mechanism of action of the newly discovered disease risk variants is not inherently obvious. Furthermore, a genetic region with multiple genes may be identified via GWAS, making it difficult to discern the true disease risk gene. Several alternative approaches are proposed to overcome these potential shortcomings of GWAS, including the use of quantitative, biologically relevant phenotypes. Gene expression levels represent an important class of endophenotypes. Genetic linkage and association studies that utilize gene expression levels as endophenotypes determined that the expression levels of many genes are under genetic influence. This led to the postulate that there may exist many genetic variants that confer disease risk via modifying gene expression levels. Results from the handful of genetic studies which assess gene expression level endophenotypes in conjunction with disease risk suggest that this combined phenotype approach may both increase the power for gene discovery and lead to an enhanced understanding of their mode of action. This review summarizes the evidence in support of gene expression levels as promising endophenotypes in the discovery and characterization of novel candidate genes for complex diseases, which may also represent a novel approach in the genetic studies of Alzheimer's and other neurodegenerative diseases. PMID:21569597

  17. Genetic covariance between psychopathic traits and anticipatory skin conductance responses to threat: Evidence for a potential endophenotype.

    PubMed

    Wang, Pan; Gao, Yu; Isen, Joshua; Tuvblad, Catherine; Raine, Adrian; Baker, Laura A

    2015-11-01

    The genetic architecture of the association between psychopathic traits and reduced skin conductance responses (SCRs) is poorly understood. By using 752 twins aged 9-10 years, this study investigated the heritability of two SCR measures (anticipatory SCRs to impending aversive stimuli and unconditioned SCRs to the aversive stimuli themselves) in a countdown task. The study also investigated the genetic and environmental sources of the covariance between these SCR measures and two psychopathic personality traits: impulsive/disinhibited (reflecting impulsive-antisocial tendencies) and manipulative/deceitful (reflecting the affective-interpersonal features). For anticipatory SCRs, 27%, 14%, and 59% of the variation was due to genetic, shared environmental, and nonshared environmental effects, respectively, while the percentages for unconditioned SCRs were 44%, 2%, and 54%. The manipulative/deceitful (not impulsive/disinhibited) traits were negatively associated with both anticipatory SCRs (r = -.14, p < .05) and unconditioned SCRs (r = -.17, p < .05) in males only, with the former association significantly accounted for by genetic influences (r g = -.72). Reduced anticipatory SCRs represent a candidate endophenotype for the affective-interpersonal facets of psychopathic traits in males. PMID:26439076

  18. Genetic covariance between psychopathic traits and anticipatory skin conductance responses to threat: Evidence for a potential endophenotype

    PubMed Central

    WANG, PAN; GAO, YU; ISEN, JOSHUA; TUVBLAD, CATHERINE; RAINE, ADRIAN; BAKER, LAURA A.

    2015-01-01

    The genetic architecture of the association between psychopathic traits and reduced skin conductance responses (SCRs) is poorly understood. By using 752 twins aged 9–10 years, this study investigated the heritability of two SCR measures (anticipatory SCRs to impending aversive stimuli and unconditioned SCRs to the aversive stimuli themselves) in a countdown task. The study also investigated the genetic and environmental sources of the covariance between these SCR measures and two psychopathic personality traits: impulsive/disinhibited (reflecting impulsive–antisocial tendencies) and manipulative/deceitful (reflecting the affective–interpersonal features). For anticipatory SCRs, 27%, 14%, and 59% of the variation was due to genetic, shared environmental, and nonshared environmental effects, respectively, while the percentages for unconditioned SCRs were 44%, 2%, and 54%. The manipulative/deceitful (not impulsive/disinhibited) traits were negatively associated with both anticipatory SCRs (r = −.14, p < .05) and unconditioned SCRs (r = −.17, p < .05) in males only, with the former association significantly accounted for by genetic influences (rg = −.72). Reduced anticipatory SCRs represent a candidate endophenotype for the affective–interpersonal facets of psychopathic traits in males. PMID:26439076

  19. Behavioral endophenotypes of drug addiction: Etiological insights from neuroimaging studies.

    PubMed

    Jupp, Bianca; Dalley, Jeffrey W

    2014-01-01

    This article reviews recent advances in the elucidation of neurobehavioral endophenotypes associated with drug addiction made possible by the translational neuroimaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET). Increasingly, these non-invasive imaging approaches have been the catalyst for advancing our understanding of the etiology of drug addiction as a brain disorder involving complex interactions between pre-disposing behavioral traits, environmental influences and neural perturbations arising from the chronic abuse of licit and illicit drugs. In this article we discuss the causal role of trait markers associated with impulsivity and novelty-/sensation-seeking in speeding the development of compulsive drug administration and in facilitating relapse. We also discuss the striking convergence of imaging findings from these behavioural traits and addiction in rats, monkeys and humans with a focus on biomarkers of dopamine neurotransmission, and highlight areas where further research is needed to disambiguate underlying causal mechanisms. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID:23756169

  20. Identification of a circuit-based endophenotype for familial depression

    PubMed Central

    Dubin, Marc; Weissman, Myrna; Xu, Dongrong; Bansal, Ravi; Hao, Xuejun; Liu, Jun; Warner, Virginia; Peterson, Bradley

    2012-01-01

    Frontal and parietal lesions may cause depression, and cortical thinning of the right frontal and parietal lobes have been shown to be a marker of risk for familial major depression. We studied biological offspring within a three-generation cohort, in which risk was defined by the depression status of the first generation, to identify regional volume differences associated with risk for depression throughout the cerebrum. We found reduced frontal and parietal white matter volumes in the high-risk group, including in persons without any personal history of depression, suggesting that hypoplasia of frontal and parietal white matter is an endophenotype for familial depression. In addition, white matter volumes in these regions correlated with current severity of symptoms of depression, inattention, and impulsivity. White matter volumes also correlated strongly with the degree of thinning in the right parietal cortex. These findings support a model of pathogenesis in which hypoplasia within a neural network for attention and emotional processing predisposes to depression. PMID:22516664

  1. Increased Causal Connectivity Related to Anatomical Alterations as Potential Endophenotypes for Schizophrenia

    PubMed Central

    Guo, Wenbin; Liu, Feng; Xiao, Changqing; Yu, Miaoyu; Zhang, Zhikun; Liu, Jianrong; Zhang, Jian; Zhao, Jingping

    2015-01-01

    Abstract Anatomical and functional abnormalities in the cortico-cerebellar-thalamo-cortical circuit have been observed in schizophrenia patients and their unaffected siblings. However, it remains unclear to the relationship between anatomical and functional abnormalities within this circuit in schizophrenia patients and their unaffected siblings, which may serve as potential endophenotypes for schizophrenia. Anatomical and resting-state functional magnetic resonance imaging data were acquired from 49 first-episode, drug-naive schizophrenia patients, 46 unaffected siblings, and 46 healthy controls. Data were analyzed by using voxel-based morphometry and Granger causality analysis. The patients and the siblings shared anatomical deficits in the left middle temporal gyrus (MTG) and increased left MTG–left angular gyrus (AG) connectivity. Moreover, the left MTG–left AG connectivity negatively correlates to the duration of untreated psychosis in the patients. The findings indicate that anatomical deficits in the left MTG and its increased causal connectivity with the left AG may serve as potential endophenotypes for schizophrenia with clinical implications. PMID:26496253

  2. Shared-Reading versus Oral Storytelling: Associations with Preschoolers' Prosocial Skills and Problem Behaviours

    ERIC Educational Resources Information Center

    Curenton, Stephanie M.; Craig, Michelle Jones

    2011-01-01

    Dyadic shared-reading and oral storytelling practices and their association to American preschoolers' (N = 33) prosocial and problem behaviour was examined. The frequency (how often dyads read) and history (the child's age at first reading) were examined within shared-reading; emotion state talk and evaluative judgments were examined in both…

  3. 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

  4. [Early diagnosis of autism: Phenotype-endophenotype].

    PubMed

    Kotsopoulos, S

    2015-01-01

    Autism Spectrum Disorders have for some time been the focus of intense interest for clinicians and researchers because of the high prevalence of the disorders among children in the community (approximately 1%), their severity and pervasiveness. Particular attention has been paid to the early diagnosis of the disorder and to the intensive therapeutic intervention. Currently the best prognosis for autism lays in the early diagnosis and intervention. Postponing the diagnosis and the intervention beyond infancy is considered loss of precious time. The diagnosis of autism, which begins early in life, was until recently considered that could be reliability made at the age of 3 years. Recent follow up studies however on children at risk for autism (children who had an older sibling with autism) have shown that the clinical signs of autism emerge at the end of the first year and become distinct by the end of the second year when the diagnosis can reliably be made. From a clinical perspective it is noted that the early clinical signs of risk for autism are related to social communication (e.g. limited or absent response when calling his/her name and to joint attention), stereotype behaviours and body movements or unusual handling of objects (e.g. intensive observation of objects and stereotype movements of hands and tapping or spinning), incongruent regulation of emotions (reduced positive and increased negative emotion). There is also delay in developmental characteristics such as the language (both receptive and expressive) and motor (particularly in postural control - characteristic is the drop of the head backwards when the infant is held in horizontal position). Studies on various aspects of the endophenotype of certain clinical signs among infants at risk for Autism Spectrum Disorders, such as avoidance of eye contact, delay in verbal communication and increase of the head circumference, may provide useful information and may assist the clinician on follow up in the

  5. 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…

  6. 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

  7. HIV and HCV discordant injecting partners and their association to drug equipment sharing.

    PubMed

    De, Prithwish; Cox, Joseph; Boivin, Jean-Francois; Platt, Robert W; Jolly, Ann M; Alexander, Paul E

    2009-01-01

    Our objective was to examine the association between HIV and HCV discordant infection status and the sharing of drug equipment by injection drug users (IDUs). IDUs were recruited from syringe exchange and methadone treatment programmes in Montreal, Canada. Characteristics of participants and their injecting partners were elicited using a structured questionnaire. Among 159 participants and 245 injecting partners, sharing of syringes and drug preparation equipment did not differ between concordant or discordant partners, although HIV-positive subjects did not share with HIV-negative injectors. Sharing of syringes was positively associated with discordant HIV status (OR=1.85) and negatively with discordant HCV status (OR=0.65), but both results were not statistically significant. Sharing of drug preparation equipment was positively associated with both discordant HIV (OR=1.61) and HCV (OR=1.18) status, but both results were non-significant. Factors such as large injecting networks, frequent mutual injections, younger age, and male gender were stronger predictors of equipment sharing. In conclusion, IDUs do not appear to discriminate drug equipment sharing partners based at least on their HCV infection status. The results warrant greater screening to raise awareness of infection status, post-test counselling to promote status disclosure among partners, and skill-building to avoid equipment sharing between discordant partners. PMID:19172434

  8. Testing for association in case-control genome-wide association studies with shared controls.

    PubMed

    Chen, Zhongxue; Huang, Hanwen; Ng, Hon Keung Tony

    2016-04-01

    The statistical analysis of genome-wide association studies (GWASs) with multiple diseases and shared controls (SCs) is discussed. The usual method for analyzing data from these studies is to compare each individual disease with either the SCs or the pooled controls which include other diseases. We observed that applying individual association tests can be problematic because these tests may suffer from power loss in detecting significant associations between diseases and single-nucleotide polymorphism or copy number variant. We propose here a two-stage procedure wherein we first apply an overall chi-square test for multiple diseases with SCs; if the overall test is rejected, then individual tests using the chi-square partition method will be applied to each disease against SCs. A real GWAS data set with SCs and a Monte Carlo simulation study are used to demonstrate that the proposed method is more effective and preferable than other existing methods for analyzing data from GWASs with multiple diseases and SCs. PMID:23376960

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

    PubMed Central

    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.

    2015-01-01

    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. PMID:26150519

  10. Steroid sulfatase-deficient mice exhibit endophenotypes relevant to Attention Deficit Hyperactivity Disorder

    PubMed Central

    Trent, Simon; Dennehy, Alison; Richardson, Heather; Ojarikre, Obah A.; Burgoyne, Paul S.; Humby, Trevor; Davies, William

    2012-01-01

    Summary Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterised by inattention, impulsivity and hyperactivity; it is frequently co-morbid with anxiety and conduct disorders, sleep perturbation and abnormal consummatory behaviours. Recent studies have implicated the neurosteroid-modulating enzyme steroid sulfatase (STS) as a modulator of ADHD-related endophenotypes. The effects of steroid sulfatase deficiency on homecage activity, feeding/drinking behaviours, anxiety-related behaviours (assayed in light-dark box and open field paradigms), social dominance and serum steroid hormone levels were determined by comparing 40,XY and 39,XY*O mice. Subsequently, mice administered the steroid sulfatase inhibitor COUMATE acutely were compared to vehicle-treated mice on behavioural tasks sensitive to enzyme deficiency to dissociate between its developmental and ongoing effects. 39,XY*O mice exhibited heightened reactivity to a novel environment, hyperactivity in the active phase, and increased water (but not food) consumption relative to 40,XY mice during a 24 h period; the former group also demonstrated evidence for heightened emotional reactivity. There was no difference in social dominance between the 40,XY and 39,XY*O mice. COUMATE administration had no effect on homecage activity, water consumption or anxiety measures in the open field. 39,XY*O mice exhibited significantly lower dehydroepiandrosterone (DHEA) serum levels than 40,XY mice, but equivalent corticosterone levels. Together with previous data, the present results suggest that steroid sulfatase may influence core and associated ADHD behavioural endophenotypes via both developmental and ongoing mechanisms, and that the 39,XY*O model may represent a useful tool for elucidating the neurobiological basis of these endophenotypes. PMID:21723668

  11. 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. PMID:26150519

  12. 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

  13. 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

  14. Neuroanatomical Abnormalities and Cognitive Impairments Are Shared by Adults with Attention-Deficit/Hyperactivity Disorder and Their Unaffected First-Degree Relatives

    PubMed Central

    Pironti, Valentino Antonio; Lai, Meng-Chuan; Müller, Ulrich; Dodds, Chris Martin; Suckling, John; Bullmore, Edward Thomas; Sahakian, Barbara Jacquelyn

    2014-01-01

    Background Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, yet the search for genes with a definitive role in its etiology has been elusive. Deconstructing the disorder in its endophenotypic traits, where the variance is thought to be associated with a fewer number of genes, should boost the statistical power of molecular genetic studies and clarify the pathophysiology of ADHD. In this study, we tested for neuroanatomical and cognitive endophenotypes in a group of adults with ADHD, their unaffected first-degree relatives, and typically developing control subjects. Methods Sixty participants, comprising 20 adults with ADHD, 20 unaffected first-degree relatives, and 20 typically developing control subjects matched for age and gender undertook structural magnetic resonance imaging scans. Voxel-based morphometry with DARTEL was performed to obtain regional gray and white matter volumes. General linear analyses of the volumes of brain regions, adjusting for age and total intracranial volume, were used to compare groups. Sustained attention and response inhibition were also investigated as cognitive endophenotypes. Results Neuroanatomical abnormalities in gray matter volume in the right inferior frontal gyrus and white matter volume in the caudal portion of the right inferior fronto-occipital fasciculus were shared between ADHD probands and their unaffected first-degree relatives. In addition, impairments in sustained attention were also found to be shared between ADHD patients and their relatives. Conclusions Cognitive impairments in sustained attention and neuroanatomical abnormalities in the right inferior frontal gyrus and the posterior part of right inferior fronto-occipital fasciculus are putative neurocognitive endophenotypes in adult ADHD. PMID:24199662

  15. Principal Component Analysis Characterizes Shared Pathogenetics from Genome-Wide Association Studies

    PubMed Central

    Chang, Diana; Keinan, Alon

    2014-01-01

    Genome-wide association studies (GWASs) have recently revealed many genetic associations that are shared between different diseases. We propose a method, disPCA, for genome-wide characterization of shared and distinct risk factors between and within disease classes. It flips the conventional GWAS paradigm by analyzing the diseases themselves, across GWAS datasets, to explore their “shared pathogenetics”. The method applies principal component analysis (PCA) to gene-level significance scores across all genes and across GWASs, thereby revealing shared pathogenetics between diseases in an unsupervised fashion. Importantly, it adjusts for potential sources of heterogeneity present between GWAS which can confound investigation of shared disease etiology. We applied disPCA to 31 GWASs, including autoimmune diseases, cancers, psychiatric disorders, and neurological disorders. The leading principal components separate these disease classes, as well as inflammatory bowel diseases from other autoimmune diseases. Generally, distinct diseases from the same class tend to be less separated, which is in line with their increased shared etiology. Enrichment analysis of genes contributing to leading principal components revealed pathways that are implicated in the immune system, while also pointing to pathways that have yet to be explored before in this context. Our results point to the potential of disPCA in going beyond epidemiological findings of the co-occurrence of distinct diseases, to highlighting novel genes and pathways that unsupervised learning suggest to be key players in the variability across diseases. PMID:25211452

  16. Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease

    PubMed Central

    Cruchaga, Carlos; Kauwe, John S.K.; Nowotny, Petra; Bales, Kelly; Pickering, Eve H.; Mayo, Kevin; Bertelsen, Sarah; Hinrichs, Anthony; Fagan, Anne M.; Holtzman, David M.; Morris, John C.; Goate, Alison M.

    2012-01-01

    The apolipoprotein E (APOE) genotype is the major genetic risk factor for Alzheimer's disease (AD). We have access to cerebrospinal fluid (CSF) and plasma APOE protein levels from 641 individuals and genome-wide genotyped data from 570 of these samples. The aim of this study was to test whether CSF or plasma APOE levels could be a useful endophenotype for AD and to identify genetic variants associated with APOE levels. We found that CSF (P = 8.15 × 10−4) but not plasma (P = 0.071) APOE protein levels are significantly associated with CSF Aβ42 levels. We used Mendelian randomization and genetic variants as instrumental variables to confirm that the association of CSF APOE with CSF Aβ42 levels and clinical dementia rating (CDR) is not because of a reverse causation or confounding effect. In addition the association of CSF APOE with Aβ42 levels was independent of the APOE ɛ4 genotype, suggesting that APOE levels in CSF may be a useful endophenotype for AD. We performed a genome-wide association study to identify genetic variants associated with CSF APOE levels: the APOE ɛ4 genotype was the strongest single-genetic factor associated with CSF APOE protein levels (P = 6.9 × 10−13). In aggregate, the Illumina chip single nucleotide polymorphisms explain 72% of the variability in CSF APOE protein levels, whereas the APOE ɛ4 genotype alone explains 8% of the variability. No other genetic variant reached the genome-wide significance threshold, but nine additional variants exhibited a P-value <10−6. Pathway mining analysis indicated that these nine additional loci are involved in lipid metabolism (P = 4.49 × 10−9). PMID:22821396

  17. 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. PMID:24942138

  18. Who Shares? Who Doesn't? Factors Associated with Openly Archiving Raw Research Data

    PubMed Central

    Piwowar, Heather A.

    2011-01-01

    Many initiatives encourage investigators to share their raw datasets in hopes of increasing research efficiency and quality. Despite these investments of time and money, we do not have a firm grasp of who openly shares raw research data, who doesn't, and which initiatives are correlated with high rates of data sharing. In this analysis I use bibliometric methods to identify patterns in the frequency with which investigators openly archive their raw gene expression microarray datasets after study publication. Automated methods identified 11,603 articles published between 2000 and 2009 that describe the creation of gene expression microarray data. Associated datasets in best-practice repositories were found for 25% of these articles, increasing from less than 5% in 2001 to 30%–35% in 2007–2009. Accounting for sensitivity of the automated methods, approximately 45% of recent gene expression studies made their data publicly available. First-order factor analysis on 124 diverse bibliometric attributes of the data creation articles revealed 15 factors describing authorship, funding, institution, publication, and domain environments. In multivariate regression, authors were most likely to share data if they had prior experience sharing or reusing data, if their study was published in an open access journal or a journal with a relatively strong data sharing policy, or if the study was funded by a large number of NIH grants. Authors of studies on cancer and human subjects were least likely to make their datasets available. These results suggest research data sharing levels are still low and increasing only slowly, and data is least available in areas where it could make the biggest impact. Let's learn from those with high rates of sharing to embrace the full potential of our research output. PMID:21765886

  19. Who shares? Who doesn't? Factors associated with openly archiving raw research data.

    PubMed

    Piwowar, Heather A

    2011-01-01

    Many initiatives encourage investigators to share their raw datasets in hopes of increasing research efficiency and quality. Despite these investments of time and money, we do not have a firm grasp of who openly shares raw research data, who doesn't, and which initiatives are correlated with high rates of data sharing. In this analysis I use bibliometric methods to identify patterns in the frequency with which investigators openly archive their raw gene expression microarray datasets after study publication. Automated methods identified 11,603 articles published between 2000 and 2009 that describe the creation of gene expression microarray data. Associated datasets in best-practice repositories were found for 25% of these articles, increasing from less than 5% in 2001 to 30%-35% in 2007-2009. Accounting for sensitivity of the automated methods, approximately 45% of recent gene expression studies made their data publicly available. First-order factor analysis on 124 diverse bibliometric attributes of the data creation articles revealed 15 factors describing authorship, funding, institution, publication, and domain environments. In multivariate regression, authors were most likely to share data if they had prior experience sharing or reusing data, if their study was published in an open access journal or a journal with a relatively strong data sharing policy, or if the study was funded by a large number of NIH grants. Authors of studies on cancer and human subjects were least likely to make their datasets available. These results suggest research data sharing levels are still low and increasing only slowly, and data is least available in areas where it could make the biggest impact. Let's learn from those with high rates of sharing to embrace the full potential of our research output. PMID:21765886

  20. Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions.

    PubMed

    Meshi, Dar; Mamerow, Loreen; Kirilina, Evgeniya; Morawetz, Carmen; Margulies, Daniel S; Heekeren, Hauke R

    2016-01-01

    Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting-state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants' degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants' degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain's intrinsic functional organization relates to individual differences in the sharing of self-related information. PMID:26948055

  1. Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions

    PubMed Central

    Meshi, Dar; Mamerow, Loreen; Kirilina, Evgeniya; Morawetz, Carmen; Margulies, Daniel S.; Heekeren, Hauke R.

    2016-01-01

    Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting-state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants’ degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants’ degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain’s intrinsic functional organization relates to individual differences in the sharing of self-related information. PMID:26948055

  2. Oxytocin and vasopressin hormone genes in children's externalizing problems: A cognitive endophenotype approach.

    PubMed

    Wade, Mark; Hoffmann, Thomas J; Knafo-Noam, Ariel; O'Connor, Thomas G; Jenkins, Jennifer M

    2016-06-01

    Externalizing problems are among the most common mental health problems of children. Research suggests that these problems are heritable, yet little is known about the specific genes involved in their pathophysiology. The current study examined a genotype-endophenotype-phenotype model of externalizing problems in 320 preschool-aged children. Markers of the oxytocin (OXT) and arginine vasopressin (AVP) hormone genes were selected as candidates owing to their known association with psychopathology in other domains. We tested whether OXT and AVP variants were related to children's externalizing problems, as well as two cognitive endophenotypes presumed to underlie these problems: theory of mind (ToM) and executive functioning (EF). Externalizing problems were assessed at age 4.5 using a previously-validated rating scale. ToM and EF were measured with age-appropriate tasks. Using a family-based association design and controlling for non-genomic confounds, support was found for an association between a two-marker OXT haplotype (rs2740210-rs2770378) and a two-marker AVP haplotype (rs1887854-rs3761249) and externalizing problems. Specific associations of these haplotypes with ToM and EF were also observed. Further, ToM and EF were shown to independently and jointly predict externalizing problems, and to partially mediate the effects of OXT and AVP on externalizing problems. This study provides the first evidence that genetic variation in OXT and AVP may contribute to individual differences in childhood externalizing problems, and that these effects may operate through emerging neurocognitive abilities in the preschool period. PMID:27155104

  3. Deconstructing Schizophrenia: An Overview of the Use of Endophenotypes in Order to Understand a Complex Disorder

    PubMed Central

    Braff, David L.; Freedman, Robert; Schork, Nicholas J.; Gottesman, Irving I.

    2007-01-01

    The genetics of schizophrenia has been approached utilizing a variety of methods. One emerging strategy is the use of endophenotypes in order to understand and identify the functional importance of genetically transmitted, brain-based deficits across schizophrenia kindreds. The endophenotype strategy is a topic of this issue of Schizophrenia Bulletin. Endophenotypes are quantitative, heritable, trait-related deficits typically assessed by laboratory-based methods rather than clinical observation. Endophenotypes are seen as closer to genetic variation than are clinical symptoms of schizophrenia, and are therefore closely linked to heritable risk factors. There has been a broad expansion of opportunities available to psychiatric neuroscientists who use the endophenotype strategy to understand the genetic basis of schizophrenia. In this context, genetic variation such as single nucleotide polymorphisms (SNPs) induces abnormalities in endophenotypic domains such as neurocognition, neurodevelopment, metabolism, and neurophysiology. This article discusses the challenges that abound in genetic research of schizophrenia, including issues in ascertainment, epistasis, ethnic diversity, and the potentially normalizing effects of second-generation antipsychotic medications on neurocognitive and neurophysiological measures. Robust strategies for meeting these challenges are discussed in this review and the subsequent articles in this issue. This article summarizes conceptual advances and progress in the measurement and use of endophenotypes in schizophrenia that form the basis of the multisite National Institute of Mental Health Consortium on the Genetics of Schizophrenia. The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia. PMID:17088422

  4. 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…

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

    PubMed

    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

  6. 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

  7. Syringe possession arrests are associated with receptive syringe sharing in two Mexico-US border cities

    PubMed Central

    Pollini, Robin A.; Brouwer, Kimberly C.; Lozada, Remedios M.; Ramos, Rebeca; Cruz, Michelle F.; Magis-Rodriguez, Carlos; Case, Patricia; Burris, Scott; Pu, Minya; Frost, Simon D. W.; Palinkas, Lawrence A.; Miller, Cari; Strathdee, Steffanie A.

    2008-01-01

    Aims To identify factors associated with receptive syringe sharing among injection drug users (IDUs) and elucidate the association between syringe possession arrests and syringe sharing. Design Cross-sectional study. Setting Mexican border cities of Tijuana, Baja California and Ciudad Juarez, Chihuahua. Participants IDUs in Tijuana (n = 222) and Ciudad Juarez (n = 206) were recruited using respondent-driven sampling (RDS). IDUs were ≥18 years and had injected illicit drugs in the past month. Measurements An interviewer-administered survey was used to collect quantitative data on socio-demographic, behavioral and contextual characteristics, including self-reported syringe sharing and arrests for syringe possession. Associations with receptive syringe sharing were investigated using logistic regression with RDS adjustment. Findings Overall, 48% of participants reported ever being arrested for carrying an unused/sterile syringe, even though syringe purchase and possession is legal in Mexico. Arrest for possessing unused/sterile syringes was associated independently with receptive syringe sharing [adjusted odds ratio (AOR) = 2.05; 95% confidence interval (CI): 1.26, 3.35], as was injecting in a shooting gallery (AOR = 3.60; 95% CI: 2.21, 5.87), injecting in the street (AOR = 2.05; 95% CI: 1.18, 3.54) and injecting methamphetamine (AOR = 2.77; 95% CI: 1.41, 5.47) or cocaine (AOR = 1.96; 95% CI: 1.15, 3.36). More than half of participants (57%) had been arrested for possessing a used syringe; in a second model, arrest for used syringe possession was also associated independently with receptive sharing (AOR = 2.87; 95% CI: 1.76, 4.69). Conclusions We documented high levels of syringe-related arrests in two Mexican–US border cities and an independent association between these arrests and risky injection practices. Public health collaborations with law enforcement to modify the risk environment in which drug use occurs are essential to facilitate safer injection

  8. The error-related negativity (ERN) and psychopathology: Toward an Endophenotype

    PubMed Central

    Olvet, Doreen M.; Hajcak, Greg

    2008-01-01

    The ERN is a negative deflection in the event-related potential that peaks approximately 50 ms after the commission of an error. The ERN is thought to reflect early error-processing activity of the anterior cingulate cortex (ACC). First, we review current functional, neurobiological, and developmental data on the ERN. Next, the ERN is discussed in terms of three psychiatric disorders characterized by abnormal response monitoring: anxiety disorders, depression, and substance abuse. These data indicate that increased and decreased error-related brain activity is associated with the internalizing and externalizing dimensions of psychopathology, respectively. Recent data further suggest that abnormal error-processing indexed by the ERN indexes trait- but not state-related symptoms, especially related to anxiety. Overall, these data point to utility of ERN in studying risk for psychiatric disorders, and are discussed in terms of the endophenotype construct. PMID:18694617

  9. Bicycling injury hospitalisation rates in Canadian jurisdictions: analyses examining associations with helmet legislation and mode share

    PubMed Central

    Teschke, Kay; Koehoorn, Mieke; Shen, Hui; Dennis, Jessica

    2015-01-01

    Objectives The purpose of this study was to calculate exposure-based bicycling hospitalisation rates in Canadian jurisdictions with different helmet legislation and bicycling mode shares, and to examine whether the rates were related to these differences. Methods Administrative data on hospital stays for bicycling injuries to 10 body region groups and national survey data on bicycling trips were used to calculate hospitalisation rates. Rates were calculated for 44 sex, age and jurisdiction strata for all injury causes and 22 age and jurisdiction strata for traffic-related injury causes. Inferential analyses examined associations between hospitalisation rates and sex, age group, helmet legislation and bicycling mode share. Results In Canada, over the study period 2006–2011, there was an average of 3690 hospitalisations per year and an estimated 593 million annual trips by bicycle among people 12 years of age and older, for a cycling hospitalisation rate of 622 per 100 million trips (95% CI 611 to 633). Hospitalisation rates varied substantially across the jurisdiction, age and sex strata, but only two characteristics explained this variability. For all injury causes, sex was associated with hospitalisation rates; females had rates consistently lower than males. For traffic-related injury causes, higher cycling mode share was consistently associated with lower hospitalisation rates. Helmet legislation was not associated with hospitalisation rates for brain, head, scalp, skull, face or neck injuries. Conclusions These results suggest that transportation and health policymakers who aim to reduce bicycling injury rates in the population should focus on factors related to increased cycling mode share and female cycling choices. Bicycling routes designed to be physically separated from traffic or along quiet streets fit both these criteria and are associated with lower relative risks of injury. PMID:26525719

  10. Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers

    PubMed Central

    Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L.; Swofford, Ross; Frantz, Aric M.; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C.; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S.; Karlsson, Elinor K.; Azuma, Chieko

    2015-01-01

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers. PMID:25642983

  11. Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.

    PubMed

    Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L; Swofford, Ross; Frantz, Aric M; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S; Karlsson, Elinor K; Azuma, Chieko; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin

    2015-02-01

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers. PMID:25642983

  12. [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. PMID:23167137

  13. Continuing HIV Risk in New York City Injection Drug Users: The Association of Syringe Source and Syringe Sharing

    PubMed Central

    Jenness, Samuel M.; Hagan, Holly; Liu, Kai-Lih; Wendel, Travis; Murrill, Christopher S.

    2016-01-01

    Sterile syringe access is an important means to reduce HIV risk, but many injection drug users (IDU) who obtain syringes from sterile sources continue to share syringes. We examined the factors associated with continuing syringe sharing in New York City. We recruited 500 active IDU in 2005 through respondent-driven sampling. In multiple logistic regression, not obtaining all syringes in the past year exclusively from sterile sources was associated with increased syringe sharing. Ensuring adequate syringe availability as well as engaging and retaining nonusers and inconsistent users in sterile syringe services may increase sterile syringe access and decrease syringe sharing. PMID:21303239

  14. The "nuts and bolts" of implementing shared medical appointments: the Harvard Vanguard Medical Associates experience.

    PubMed

    Berger-Fiffy, Jill

    2012-01-01

    Harvard Vanguard Medical Associates (Harvard Vanguard) decided to develop a Shared Medical Appointment (SMA) program in 2007 for a variety of reasons. The program has launched 86 SMAs in 17 specialties at 12 sites and has exceeded 13 000 patient visits. Currently, the practice offers 54 SMAs and is believed to be the largest program in the country. This article provides an overview regarding staffing, space and equipment, project planning, promotional materials, training programs, workflow development, and the use of quality improvement (ie, LEAN) tools used to monitor the work to be completed and the metrics to date. PMID:22668614

  15. Sharing milk but not messages: campylobacteriosis associated with consumption of raw milk from a cow-share program in Alaska, 2011.

    PubMed

    Castrodale, L J; Gerlach, R F; Xavier, C M; Smith, B J; Cooper, M P; McLaughlin, J B

    2013-05-01

    Alaska public and environmental health authorities investigated a cluster of campylobacteriosis cases among people who had consumed raw, unpasteurized milk obtained from a cow-share program in Alaska. Although raw milk is not permitted by law to be offered commercially, consumers can enter into cow-share agreements whereby they contribute funds for the upkeep of cows and in turn receive a share of the milk for their personal use. Laboratory testing of stool specimens collected from ill persons and from cows on the farm revealed an indistinguishable strain of Campylobacter. In this outbreak, numerous confirmed and suspected cases were not among cow shareholders; therefore, these individuals had not been advised of the potential health hazards associated with consumption of raw milk nor were they informed of the outbreak developments. PMID:23643114

  16. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

    PubMed Central

    Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.; Farlow, Martin R.; Grafman, Jordan; Huey, Edward D.; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T.; Kretzschmar, Hans A.; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L.; Vonsattel, Jean Paul G.; Van Deerlin, Vivianna M.; Grossman, Murray; Hurtig, Howard I.; Gross, Rachel G.; Arnold, Steven E.; Trojanowski, John Q.; Lee, Virginia M.; Wenning, Gregor K.; White, Charles L.; Höglinger, Günter U.; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I.; Crook, Julia; Parisi, Joseph E.; Boeve, Bradley F.; Josephs, Keith A.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Graff-Radford, Neill R.; Litvan, Irene; Younkin, Steven G.; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D.; Dickson, Dennis W.

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  17. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.

    PubMed

    Kouri, Naomi; Ross, Owen A; Dombroski, Beth; Younkin, Curtis S; Serie, Daniel J; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B; Farlow, Martin R; Grafman, Jordan; Huey, Edward D; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T; Kretzschmar, Hans A; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L; Vonsattel, Jean Paul G; Van Deerlin, Vivianna M; Grossman, Murray; Hurtig, Howard I; Gross, Rachel G; Arnold, Steven E; Trojanowski, John Q; Lee, Virginia M; Wenning, Gregor K; White, Charles L; Höglinger, Günter U; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I; Crook, Julia; Parisi, Joseph E; Boeve, Bradley F; Josephs, Keith A; Wszolek, Zbigniew K; Uitti, Ryan J; Graff-Radford, Neill R; Litvan, Irene; Younkin, Steven G; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D; Dickson, Dennis W

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  18. Drug Addiction Endophenotypes: Impulsive Versus Sensation-Seeking Personality Traits

    PubMed Central

    Ersche, Karen D.; Turton, Abigail J.; Pradhan, Shachi; Bullmore, Edward T.; Robbins, Trevor W.

    2010-01-01

    Background Genetic factors have been implicated in the development of substance abuse disorders, but the role of pre-existing vulnerability in addiction is still poorly understood. Personality traits of impulsivity and sensation-seeking are highly prevalent in chronic drug users and have been linked with an increased risk for substance abuse. However, it has not been clear whether these personality traits are a cause or an effect of stimulant drug dependence. Method We compared self-reported levels of impulsivity and sensation-seeking between 30 sibling pairs of stimulant-dependent individuals and their biological brothers/sisters who did not have a significant drug-taking history and 30 unrelated, nondrug-taking control volunteers. Results Siblings of chronic stimulant users reported significantly higher levels of trait-impulsivity than control volunteers but did not differ from control volunteers with regard to sensation-seeking traits. Stimulant-dependent individuals reported significantly higher levels of impulsivity and sensation-seeking compared with both their siblings and control volunteers. Conclusions These data indicate that impulsivity is a behavioral endophenotype mediating risk for stimulant dependence that may be exacerbated by chronic drug exposure, whereas abnormal sensation-seeking is more likely to be an effect of stimulant drug abuse. PMID:20678754

  19. Sharing and re-use of phylogenetic trees (and associated data) to facilitate synthesis

    PubMed Central

    2012-01-01

    Background Recently, various evolution-related journals adopted policies to encourage or require archiving of phylogenetic trees and associated data. Such attention to practices that promote sharing of data reflects rapidly improving information technology, and rapidly expanding potential to use this technology to aggregate and link data from previously published research. Nevertheless, little is known about current practices, or best practices, for publishing trees and associated data so as to promote re-use. Findings Here we summarize results of an ongoing analysis of current practices for archiving phylogenetic trees and associated data, current practices of re-use, and current barriers to re-use. We find that the technical infrastructure is available to support rudimentary archiving, but the frequency of archiving is low. Currently, most phylogenetic knowledge is not easily re-used due to a lack of archiving, lack of awareness of best practices, and lack of community-wide standards for formatting data, naming entities, and annotating data. Most attempts at data re-use seem to end in disappointment. Nevertheless, we find many positive examples of data re-use, particularly those that involve customized species trees generated by grafting to, and pruning from, a much larger tree. Conclusions The technologies and practices that facilitate data re-use can catalyze synthetic and integrative research. However, success will require engagement from various stakeholders including individual scientists who produce or consume shareable data, publishers, policy-makers, technology developers and resource-providers. The critical challenges for facilitating re-use of phylogenetic trees and associated data, we suggest, include: a broader commitment to public archiving; more extensive use of globally meaningful identifiers; development of user-friendly technology for annotating, submitting, searching, and retrieving data and their metadata; and development of a minimum reporting

  20. Genome-wide association study of shared components of reading disability and language impairment.

    PubMed

    Eicher, J D; Powers, N R; Miller, L L; Akshoomoff, N; Amaral, D G; Bloss, C S; Libiger, O; Schork, N J; Darst, B F; Casey, B J; Chang, L; Ernst, T; Frazier, J; Kaufmann, W E; Keating, B; Kenet, T; Kennedy, D; Mostofsky, S; Murray, S S; Sowell, E R; Bartsch, H; Kuperman, J M; Brown, T T; Hagler, D J; Dale, A M; Jernigan, T L; St Pourcain, B; Davey Smith, G; Ring, S M; Gruen, J R

    2013-11-01

    Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language. PMID:24024963

  1. WORKING MEMORY IMPAIRMENT AS AN ENDOPHENOTYPIC MARKER OF A SCHIZOPHRENIA DIATHESIS

    PubMed Central

    Park, Sohee; Gooding, Diane C.

    2014-01-01

    This chapter focuses on the viability of working memory impairment as an endophenotypic marker of a schizophrenia diathesis. It begins with an introduction of the construct of working memory. It follows with a review of the operational criteria for defining an endophenotype. Research findings regarding the working memory performance of schizophrenia and schizophrenia-spectrum patients, first-degree relatives of schizophrenia patients and healthy controls, are reviewed in terms of the criteria for being considered an endophenotypic marker. Special attention is paid to specific components of the working memory deficit (namely, encoding, maintenance, and manipulation), in terms of which aspects are likely to be the best candidates for endophenotypes. We consider the extant literature regarding working memory performance in bipolar disorder and major depression in order to address the issue of relative specificity to schizophrenia. Despite some unresolved issues, it appears that working memory impairment is a very promising candidate for an endophenotypic marker of a schizophrenia diathesis but not for mood disorders. Throughout this chapter, we identify future directions for research in this exciting and dynamic area of research and evaluate the contribution of working memory research to our understanding of schizophrenia. PMID:25414816

  2. 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

  3. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype.

    PubMed

    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

    2007-11-01

    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

  4. Spatiotemporal Molecular Approach of in utero Electroporation to Functionally Decipher Endophenotypes in Neurodevelopmental Disorders

    PubMed Central

    Kolk, Sharon Margriet; de Mooij-Malsen, Annetrude Johanne; Martens, Gerard Julianus Maria

    2011-01-01

    We have only just begun to decipher the complexity of our brain, including its maturation. Correct brain development and communication among brain areas are crucial for proper cognitive behavior. Brain area-specific genes expressed within a particular time window direct neurodevelopmental events such as proliferation, migration, axon guidance, dendritic arborization, and synaptogenesis. These genes can pose as susceptibility factors in neurodevelopmental disorders eventually resulting in area-specific cognitive deficits. Therefore, in utero electroporation (IUE)-mediated gene transfer can aid in creating valuable animal models in which the regionality and time of expression can be restricted for the targeted gene(s). Moreover, through the use of cell-type-specific molecular constructs, expression can be altered in a particular neuronal subset within a distinct area such that we are now able to causally link the function of that gene in that brain region to the etiology of the disorder. Thus, IUE-mediated gene transfer is an attractive molecular technique to spatiotemporally address the developmental aspects of gene function in relation to neurodevelopmental disorder-associated endophenotypes. PMID:22065947

  5. Is rheumatoid arthritis in Indians associated with HLA antigens sharing a DR beta 1 epitope?

    PubMed Central

    Ollier, W E; Stephens, C; Awad, J; Carthy, D; Gupta, A; Perry, D; Jawad, A; Festenstein, H

    1991-01-01

    HLA class II antigens were identified in a group of 44 patients with rheumatoid arthritis (RA) originating largely from the north or northeast of the Indian subcontinent and resident now in east London. Compared with 67 locally typed east London Asian controls, the prevalence of three HLA-DR antigens was raised in the patients: DR1 18.2% v 6.0% chi 2 = 3.99, DR4 20.5% v 11.9% chi 2 = 1.48, and DRw10 27.3% v 8.9% chi 2 = 6.56. These differences were also found when the patients with RA were compared with a larger control group of 110 northern Indians: DR1 18.2% v 7.2% chi 2 = 4.02, DR4 20.5% v 7.2% chi 2 = 5.56, and DRw10 27.3% v 8.1% chi 2 = 9.7. Twenty five (57%) of the patients expressed at least one of these antigens. All patients were also characterised for HLA-Dw types by mixed lymphocyte culture typing. The prevalence of the HLA-DR4 associated Dw types in the patients was: Dw4 2.3%, Dw10 0%, Dw14 11.4%, and Dw15 6.8%. The DR beta 1 chains of DR1 and DRw10 together with the Dw types of DR4 other than Dw10 share amino acid residues in a region of the third hypervariable region considered to be critical in antigen presentation. It is concluded that RA in Indians is associated with these HLA antigens, and data from this study support the hypothesis of a cross reactive epitope common to HLA specificities associated with RA. PMID:1710441

  6. Promoting Physical Activity Through the Shared Use of School Recreational Spaces: A Policy Statement From the American Heart Association

    PubMed Central

    Young, Deborah R.; Spengler, John O.; Frost, Natasha; Evenson, Kelly R.; Vincent, Jeffrey M.; Whitsel, Laurie

    2014-01-01

    Most Americans are not sufficiently physically active, even though regular physical activity improves health and reduces the risk of many chronic diseases. Those living in rural, non-White, and lower-income communities often have insufficient access to places to be active, which can contribute to their lower level of physical activity. The shared use of school recreational facilities can provide safe and affordable places for communities. Studies suggest that challenges to shared use include additional cost, liability protection, communication among constituencies interested in sharing space, and decision-making about scheduling and space allocation. This American Heart Association policy statement has provided recommendations for federal, state, and local decision-makers to support and expand opportunities for physical activity in communities through the shared use of school spaces. PMID:24134355

  7. Cellulolytic Streptomyces Strains Associated with Herbivorous Insects Share a Phylogenetically Linked Capacity To Degrade Lignocellulose

    PubMed Central

    Book, Adam J.; Lewin, Gina R.; McDonald, Bradon R.; Takasuka, Taichi E.; Doering, Drew T.; Adams, Aaron S.; Blodgett, Joshua A. V.; Clardy, Jon; Raffa, Kenneth F.; Fox, Brian G.

    2014-01-01

    Actinobacteria in the genus Streptomyces are critical players in microbial communities that decompose complex carbohydrates in the soil, and these bacteria have recently been implicated in the deconstruction of plant polysaccharides for some herbivorous insects. Despite the importance of Streptomyces to carbon cycling, the extent of their plant biomass-degrading ability remains largely unknown. In this study, we compared four strains of Streptomyces isolated from insect herbivores that attack pine trees: DpondAA-B6 (SDPB6) from the mountain pine beetle, SPB74 from the southern pine beetle, and SirexAA-E (SACTE) and SirexAA-G from the woodwasp, Sirex noctilio. Biochemical analysis of secreted enzymes demonstrated that only two of these strains, SACTE and SDPB6, were efficient at degrading plant biomass. Genomic analyses indicated that SACTE and SDPB6 are closely related and that they share similar compositions of carbohydrate-active enzymes. Genome-wide proteomic and transcriptomic analyses revealed that the major exocellulases (GH6 and GH48), lytic polysaccharide monooxygenases (AA10), and mannanases (GH5) were conserved and secreted by both organisms, while the secreted endocellulases (GH5 and GH9 versus GH9 and GH12) were from diverged enzyme families. Together, these data identify two phylogenetically related insect-associated Streptomyces strains with high biomass-degrading activity and characterize key enzymatic similarities and differences used by these organisms to deconstruct plant biomass. PMID:24837391

  8. [18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies.

    PubMed

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

    2006-04-01

    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 3 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

  9. [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

  10. 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

  11. Genome-wide scans of genetic variants for psychophysiological endophenotypes: introduction to this special issue of Psychophysiology.

    PubMed

    Iacono, William G

    2014-12-01

    This special issue addresses the heritability and molecular genetic basis of 17 putative endophenotypes involving resting EEG power, P300 event-related potential amplitude, electrodermal orienting and habituation, antisaccade eye tracking, and affective modulation of the startle eye blink. These measures were collected from approximately 4,900 twins and parents who provided DNA samples through their participation in the Minnesota Twin Family Study. Included are papers that detail the methodology followed, genome-wide association analyses of single nucleotide polymorphisms and genes, analysis of rare variants in the human exome, and a whole genome sequencing study. Also included are 11 articles by leading experts in psychophysiology and genetics that provide perspective and commentary. A final integrative report summarizes findings and addresses issues raised. This introduction provides an overview of the aims and rationale behind these studies. PMID:25387700

  12. 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

  13. 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 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK INSURANCE...

  14. The Association between Attitude towards the Implementation of Staff Development Training and the Practice of Knowledge Sharing among Lecturers

    ERIC Educational Resources Information Center

    Kassim, Abd. Latif; Raman, Arumugam; Don, Yahya; Daud, Yaakob; Omar, Mohd Sofian

    2015-01-01

    This study was aimed to identify the association of teachers' attitude towards the implementation of Staff Development Training with Knowledge Sharing Practices among the lecturers of the Teacher Training Institution (TTI). In addition, this study was also to examine the differences in attitudes towards the implementation of Staff Development…

  15. 31 CFR 50.36 - Allocation of premium income associated with entities that do share profits and losses with...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance: Treasury 1 2014-07-01 2014-07-01 false Allocation of premium income associated with entities that do share profits and losses with private sector insurers. 50.36 Section 50.36 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK INSURANCE...

  16. 31 CFR 50.36 - Allocation of premium income associated with entities that do share profits and losses with...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance: Treasury 1 2012-07-01 2012-07-01 false Allocation of premium income associated with entities that do share profits and losses with private sector insurers. 50.36 Section 50.36 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK INSURANCE...

  17. 31 CFR 50.36 - Allocation of premium income associated with entities that do share profits and losses with...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance: Treasury 1 2011-07-01 2011-07-01 false Allocation of premium income associated with entities that do share profits and losses with private sector insurers. 50.36 Section 50.36 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK INSURANCE...

  18. 31 CFR 50.36 - Allocation of premium income associated with entities that do share profits and losses with...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance: Treasury 1 2013-07-01 2013-07-01 false Allocation of premium income associated with entities that do share profits and losses with private sector insurers. 50.36 Section 50.36 Money and Finance: Treasury Office of the Secretary of the Treasury TERRORISM RISK INSURANCE...

  19. 12 CFR 563b.505 - May my directors, officers, and their associates freely trade shares?

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... OF THE TREASURY CONVERSIONS FROM MUTUAL TO STOCK FORM Standard Conversions Post-Conversion § 563b.505... the event of the death of the officer or director, the successor in interest may sell the shares....

  20. Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases: Erratum.

    PubMed

    2015-02-01

    [In the article "Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases", which appeared in Volume 93, Issue 27 of Medicine, one of Orietta M. Borghi's affiliations was omitted. The article should have stated that Orietta M. Borghi is associated with the IRCCS Istituto Auxologico Italiano, Milano, Italy as well as the Dipartimento di Scienze Cliniche e di Comunità, Università di Milano.]. PMID:25803365

  1. 13 CFR 120.222 - Fees which the Lender or Associate may not collect from the Borrower or share with third parties.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... may not collect from the Borrower or share with third parties. 120.222 Section 120.222 Business Credit... Guaranteed Loans § 120.222 Fees which the Lender or Associate may not collect from the Borrower or share with... or add-on interest; (d) Share any premium received from the sale of an SBA guaranteed loan in...

  2. Determination of Emotional Endophenotypes: A Validation of the Affective Neuroscience Personality Scales and Further Perspectives

    ERIC Educational Resources Information Center

    Pingault, Jean-Baptiste; Pouga, Lydia; Grezes, Julie; Berthoz, Sylvie

    2012-01-01

    The study of endophenotypes, notably with configured self-reports, represents a promising research pathway to overcome the limits of a syndromal approach of psychiatric diseases. The Affective Neuroscience Personality Scales (ANPS) is a self-report questionnaire, based on neuroethological considerations, that could help to assess emotional…

  3. 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…

  4. 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…

  5. The Association Between Law Enforcement Encounters and Syringe Sharing Among IDUs on Skid Row: A Mixed Methods Analysis

    PubMed Central

    Simon-Freeman, Rebecca; Bluthenthal, Ricky N.

    2013-01-01

    The legal environment is one factor that influences injection drug users' (IDUs) risk for HIV and other bloodborne pathogens such as hepatitis C virus (HCV). We examined the association between law enforcement encounters (i.e., arrests and citations) and receptive syringe sharing among IDUs in the context of an intensified policing effort. We conducted a mixed methods analysis of 30 qualitative and 187 quantitative interviews with IDUs accessing services at a Los Angeles, CA syringe exchange program from 2008 to 2009. Qualitative findings illustrate concerns related to visibility, drug withdrawal, and previous history of arrest/incarceration. In quantitative analysis, the number of citations received, current homelessness, and perceiving that being arrested would be a “big problem” were independently associated with recent syringe sharing. Findings illustrate some of the unintended public health consequences associated with intensified street-level policing, including risk for HIV and HCV transmission. PMID:23620243

  6. The association between law enforcement encounters and syringe sharing among IDUs on skid row: a mixed methods analysis.

    PubMed

    Wagner, Karla D; Simon-Freeman, Rebecca; Bluthenthal, Ricky N

    2013-10-01

    The legal environment is one factor that influences injection drug users' (IDUs) risk for HIV and other bloodborne pathogens such as hepatitis C virus (HCV). We examined the association between law enforcement encounters (i.e., arrests and citations) and receptive syringe sharing among IDUs in the context of an intensified policing effort. We conducted a mixed methods analysis of 30 qualitative and 187 quantitative interviews with IDUs accessing services at a Los Angeles, CA syringe exchange program from 2008 to 2009. Qualitative findings illustrate concerns related to visibility, drug withdrawal, and previous history of arrest/incarceration. In quantitative analysis, the number of citations received, current homelessness, and perceiving that being arrested would be a "big problem" were independently associated with recent syringe sharing. Findings illustrate some of the unintended public health consequences associated with intensified street-level policing, including risk for HIV and HCV transmission. PMID:23620243

  7. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.

    PubMed

    Ellinghaus, David; Ellinghaus, Eva; Nair, Rajan P; Stuart, Philip E; Esko, Tõnu; Metspalu, Andres; Debrus, Sophie; Raelson, John V; Tejasvi, Trilokraj; Belouchi, Majid; West, Sarah L; Barker, Jonathan N; Kõks, Sulev; Kingo, Külli; Balschun, Tobias; Palmieri, Orazio; Annese, Vito; Gieger, Christian; Wichmann, H Erich; Kabesch, Michael; Trembath, Richard C; Mathew, Christopher G; Abecasis, Gonçalo R; Weidinger, Stephan; Nikolaus, Susanna; Schreiber, Stefan; Elder, James T; Weichenthal, Michael; Nothnagel, Michael; Franke, Andre

    2012-04-01

    Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci. PMID:22482804

  8. 12 CFR 563b.505 - May my directors, officers, and their associates freely trade shares?

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... certificate of stock that a director or officer purchases during the conversion or receives in connection with a stock dividend, stock split, or otherwise with respect to such restricted shares. (c) You must..., DEPARTMENT OF THE TREASURY CONVERSIONS FROM MUTUAL TO STOCK FORM Standard Conversions Post-Conversion §...

  9. Untangling the Effects of Shared Book Reading: Multiple Factors and Their Associations with Preschool Literacy Outcomes

    ERIC Educational Resources Information Center

    Hindman, Annemarie H.; Connor, Carol M.; Jewkes, Abigail M.; Morrison, Frederick J.

    2008-01-01

    Evidence strongly suggests that shared book reading at home and in preschool is important for young children's development of the foundational skills required for the eventual mastery of decoding and comprehension. Yet the nuances of how learning from book reading might vary across these contexts and with children's skills are not well understood.…

  10. Constitutive genetic deletion of the growth regulator Nogo-A induces schizophrenia-related endophenotypes.

    PubMed

    Willi, Roman; Weinmann, Oliver; Winter, Christine; Klein, Julia; Sohr, Reinhard; Schnell, Lisa; Yee, Benjamin K; Feldon, Joram; Schwab, Martin E

    2010-01-13

    The membrane protein Nogo-A, which is predominantly expressed by oligodendrocytes in the adult CNS and by neurons mainly during development, is well known for limiting neurite outgrowth and regeneration in the injured mammalian CNS. In addition, it has recently been proposed that abnormal Nogo-A expression or Nogo receptor (NgR) mutations may confer genetic risks for neuropsychiatric disorders of presumed neurodevelopmental origin, such as schizophrenia. We therefore evaluated whether Nogo-A deletion may lead to schizophrenia-like abnormalities in a mouse model of genetic Nogo-A deficiency. Here, we show that systemic, lifelong knock-out of the Nogo-A gene can lead to specific behavioral abnormalities resembling schizophrenia-related endophenotypes: deficient sensorimotor gating, disrupted latent inhibition, perseverative behavior, and increased sensitivity to the locomotor stimulating effects of amphetamine. These behavioral phenotypes were accompanied by altered monoaminergic transmitter levels in specific striatal and limbic structures, as well as changes in dopamine D2 receptor expression in the same brain regions. Nogo-A deletion was further associated with elevated expression of growth-related markers. In contrast, acute antibody-mediated Nogo-A neutralization in adult wild-type mice failed to produce such phenotypes, suggesting that the phenotypes observed in the knock-out mice might be of developmental origin, and that Nogo-A normally subserves critical functions in neurodevelopment. This study provides the first experimental demonstration that Nogo-A bears neuropsychiatric relevance, and alterations in its expression may be one etiological factor in schizophrenia and related disorders. PMID:20071518

  11. Trends and Factors Associated with Bed-Sharing: The National Infant Sleep Position Study (NISP) 1993–2010

    PubMed Central

    Colson, Eve R.; Willinger, Marian; Rybin, Denis; Heeren, Timothy; Smith, Lauren A.; Lister, George; Corwin, Michael J.

    2013-01-01

    Objective Determine trends and factors associated with bed-sharing. Design National Infant Sleep Position Study: Annual telephone surveys. Setting 48 contiguous United States. Participants Nighttime caregivers of infants born within the last 7 months between 1993 and 2010. Approximately 1000 interviews annually. Main Outcome Measure Infant usually bed-sharing. Results Of 18,986 participants, 11% reported usually bed-sharing. Bed-sharing increased between 1993 (6.0%) and 2010 (13.5%). While there was an increase for Whites from 1993 to 2000 (p<0.001), there was no significant increase from 2001 to 2010 (p=0.48). Blacks and Hispanics showed increase in bed-sharing throughout the period 1993 to 2010, with no difference between the two time periods (p=0.63 and 0.77, respectively). After accounting for study year, factors associated with increase in usually bed-sharing included: compared to college or more, maternal education less than high school (AOR = 1.4; 95% CI, 1.1–1.8), compared to White race, maternal race or ethnicity Black (AOR = 3.5; 95% CI, 3.0–4.1), Hispanic (AOR = 1.3; 95% CI, 1.1–1.6) and Other (AOR 2.5; 95% CI, 2.0–3.0), compared to household income ≥$50,000, less than $20 000 (AOR = 1.7; 95% CI, 1.4–2.0) and $20–$50,000 (AOR=1.3; 95%CI 1.1–1.5), compared with living in the Midwest, living in the West (AOR=1.6; 95%CI 1.4–1.9) or South (AOR=1.5; 95% CI=1.3–1.7), compared with infant age ≥16 weeks, less than 8 weeks (AOR = 1.5; 95%CI 1.2–1.7 and 8–15 weeks (AOR-1.3; 95% CI=1.2–1.5) and being born prematurely (AOR = 1.4; 95% CI, 1.2–1.6). Thirty-six percent of the participants reported talking to a doctor about bed-sharing. Compared with those who did not talk to a doctor, those who reported their doctors had a negative attitude were less likely to bed-share (AOR 0.66 (95% 0.53, 0.82), whereas a neutral attitude was associated with increased bed-sharing. (AOR 1.4; 95%CI 1.1–1.8). Conclusion Our findings of the continual

  12. Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia.

    PubMed

    Costas, J; Carrera, N; Alonso, P; Gurriarán, X; Segalàs, C; Real, E; López-Solà, C; Mas, S; Gassó, P; Domènech, L; Morell, M; Quintela, I; Lázaro, L; Menchón, J M; Estivill, X; Carracedo, Á

    2016-01-01

    Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10(-5)), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10(-6), explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications. PMID:27023174

  13. Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia

    PubMed Central

    Costas, J; Carrera, N; Alonso, P; Gurriarán, X; Segalàs, C; Real, E; López-Solà, C; Mas, S; Gassó, P; Domènech, L; Morell, M; Quintela, I; Lázaro, L; Menchón, J M; Estivill, X; Carracedo, Á

    2016-01-01

    Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10−5), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10−6, explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications. PMID:27023174

  14. Phenylthiocarbamide (PTC) perception in ultra-high risk for psychosis participants who develop schizophrenia: testing the evidence for an endophenotypic marker

    PubMed Central

    Brewer, Warrick J; Lin, Ashleigh; Moberg, Paul J; Smutzer, Gregory; Nelson, Barnaby; Yung, Alison R; Pantelis, Christos; McGorry, Patrick D; Turetsky, Bruce I; Wood, Stephen J.

    2012-01-01

    Reports suggesting that schizophrenia participants are more likely to be phenylthiocarbamide (PTC) non-tasters when compared to controls have recently been controversial. If supported, a genetic-based phenotypic variation in PTC taster status is implicated, suggesting a greater illness risk for those participants with recessive alleles for the TAS2R38 receptor. Should PTC insensitivity be a schizophrenia endophenotype, then it would be expected in follow-up of ultra high-risk for psychosis participants who later develop schizophrenia (UHR-S). UHR-S were hypothesised to show reduced PTC sensitivity compared to those who were previously at risk, but did not transition (UHR-NP). PTC perception was assessed in 219 UHR participants at long-term follow-up, of whom 53 had transitioned to psychosis (UHR-P) during the follow-up period. Fifteen of the 219 participants were diagnosed with schizophrenia. Seventy-eight had a family history of psychotic disorder. No differences in PTC taster status were found in UHR participants based upon transition to psychosis status, schizophrenia diagnosis, or family history of schizophrenia. This report indicates that schizophrenia development among UHR participants is not associated with PTC tasting deficits and fails to support previous findings that inability to detect the bitter taste of PTC is a schizophrenia endophenotype. PMID:22503356

  15. [Electrophysiology and schizophrenic vulnerability: the N400 component as endophenotype candidate?].

    PubMed

    Cermolacce, M; Micoulaud-Franchi, J-A; Faugere, M; Naudin, J; Besson, M; Vion-Dury, J

    2013-04-01

    Research on early stages of schizophrenia aims to provide early, objective, and stable markers of vulnerability. In this review, we first briefly describe the notion of such markers, or endophenotypes, notably in terms of stability, specificity and heritability. Among other empirical approaches, event-related potentials (ERPs) have been recently considered as putative endophenotypes. The N400 component is an event-related brain potential classically elicited during semantic processing, as suggested by a growing body of empirical studies with a large variety of paradigms. We provide here a short account of its typical descriptions and the interpretations of its functional significance. Then we describe the main current results about schizophrenic alterations of the N400 component. Two levels of semantic processing (automatic spreading and controlled mechanisms) are disturbed in schizophrenia, even if the underlying mechanisms remain unclear or discussed. Several controversial issues may also need further research, such as the influence of symptomatology and evolution of schizophrenia. Another crucial topic concerns the putative schizophrenic specificity, and only little is known about possible alterations of N400 in affective disorders. We discuss the notion of heritability, mainly explored in current literature among people with schizotypal personality. Finally, even if N400 studies contribute to a better understanding of linguistic disturbances in schizophrenia, it appears difficult to consider the N400 component as a relevant schizophrenic endophenotype, given the current paucity of results on its stability, its heritability (clinical and genetic vulnerability) and its schizophrenic specificity. PMID:23540257

  16. An Indian experience of neurocognitive endophenotypic markers in unaffected first-degree relatives of schizophrenia patients

    PubMed Central

    Solanki, Ram Kumar; Kumar, Ashok; Satija, Yogesh; Gupta, Suresh; Singh, Paramjeet

    2016-01-01

    Context: Multiple vulnerability genes interact with environmental factors to develop a range of phenotypes in the schizophrenia spectrum. Endophenotypes can help characterize the impact of risk genes by providing genetically relevant traits that are more complaisant than the behavioral symptoms that classify mental illness. Aims: We aimed to investigate the neurocognitive endophenotypic markers for schizophrenia in Indian population. Settings and Design: In a cross-sectional study, we assessed neurocognitive functioning in 40 unaffected first-degree relatives (FDR) of schizophrenia patients with an equal number of healthy controls. Materials and Methods: FDR schizophrenia group was compared with the control group on measures of short-term memory, verbal working memory, auditory verbal memory on indices of immediate recall and recognition, visuospatial working memory, visual attention, and executive functions. Results: The study found that FDR schizophrenia scored poorly on all tested measures of neurocognition except visual attention. On calculating composite score, we found that composite neurocognitive score better discriminated the FDR schizophrenia from the control group. Conclusions: Neurocognitive measures of short-term memory, verbal working memory, auditory verbal memory, visuospatial working memory, and executive functions significantly differentiate FDR of patients with schizophrenia from controls and can be considered as endophenotypic markers of schizophrenia in non-Caucasian population. The exactitude of this approach can be increased by calculating a composite neurocognitive score which combines various neurocognitive measures. PMID:26985100

  17. Neuropsychological, electrophysiological and neurological impairments in patients with obsessive compulsive disorder, their healthy siblings and healthy controls: Identifying potential endophenotype(s).

    PubMed

    Ozcan, Halil; Ozer, Suzan; Yagcioglu, Suha

    2016-06-30

    The etiology of obsessive-compulsive disorder (OCD) has not been clarified. This study aimed to investigate the cognitive, neurological, electrophysiological functions which are reflected in executive functions, memory, visuospatial integration; neurological examination and auditory event related potentials (AERP) (N100, N200, P200 and P300) in patients with OCD, their siblings, and control subjects and to determine potential endophenotypic markers. Thirty-three patients with OCD, 18 siblings and 21 controls; matched for age, gender and years of education were included. Yale Brown Obsessive Compulsive Symptoms Checklist Scale, Hamilton Depression-Rating Scale, an exhaustive neuropscyhological test battery and Neurological Evaluation Scale were administered. Their AERP recordings were obtained. Executive functions and visuospatial integration were highly impaired in patients and slightly in their siblings compared to controls. P200 amplitude was sorted as siblings>patients>controls. P300 amplitude was sorted as patientsendophenotypes of OCD. PMID:27100062

  18. Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects.

    PubMed

    Zhou, Yang; Kaiser, Tobias; Monteiro, Patrícia; Zhang, Xiangyu; Van der Goes, Marie S; Wang, Dongqing; Barak, Boaz; Zeng, Menglong; Li, Chenchen; Lu, Congyi; Wells, Michael; Amaya, Aldo; Nguyen, Shannon; Lewis, Michael; Sanjana, Neville; Zhou, Yongdi; Zhang, Mingjie; Zhang, Feng; Fu, Zhanyan; Feng, Guoping

    2016-01-01

    Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients. PMID:26687841

  19. The association between kinematic risky driving among parents and their teenage children: Moderation by shared personality characteristics

    PubMed Central

    Ehsani, Johnathon P.; Simons-Morton, Bruce; Xie, Yunlong; Klauer, Sheila G.; Albert, Paul S.

    2014-01-01

    This study examined the driving behavior of 42 parent–teenager dyads for 18 months, under naturalistic driving conditions. At baseline participants’ personality characteristics were assessed. Objective risky driving measures (kinematic risky driving) were captured by accelerometers for the duration of the study. To estimate teenage and parent correlations in kinematic risky driving, separate Poisson regression models were fit for teenagers and parents. Standardized residuals were computed for each trip for each individual. Correlations were obtained by estimating the Spearman rank correlations of the individual average residuals across teenagers and parents. The bootstrap technique was used to estimate the standard errors associated with the parent–teenager correlations. The overall correlation between teenage and parent kinematic risky driving for the 18-month study period was positive, but weak (r = 0.18). When the association between parent and teenagers’ risky driving was adjusted for shared personality characteristics, the correlation reduced to 0.09. Although interesting, the 95% confidence intervals on the difference between these two estimates overlapped zero. We conclude that the weak similarity in parent–teen kinematic risky driving was partly explained by shared personality characteristics. PMID:24745931

  20. Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes.

    PubMed

    Sepúlveda, Maria; Armangue, Thaís; Martinez-Hernandez, Eugenia; Arrambide, Georgina; Sola-Valls, Nuria; Sabater, Lidia; Téllez, Nieves; Midaglia, Luciana; Ariño, Helena; Peschl, Patrick; Reindl, Markus; Rovira, Alex; Montalban, Xavier; Blanco, Yolanda; Dalmau, Josep; Graus, Francesc; Saiz, Albert

    2016-07-01

    The aim of this study was to report the clinical spectrum associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) in adult patients, and to assess whether phenotypic variants are dependent on recognition of rodent MOG epitopes. We retrospectively analyzed the features, course and outcome of 56 patients whose samples were investigated by brain tissue immunohistochemistry and cell-based assays using human and rodent MOG. The median age at symptom onset was 37 years (range 18-70); 35 patients (63 %) were female. After a median follow-up of 43 months (range 4-554), only 14 patients (25 %) developed a neuromyelitis optica spectrum disorder (NMOSD), 27 patients (47 %) retained the initial diagnosis of isolated optic neuritis, 7 (12 %) of longitudinally extensive transverse myelitis, and 2 (4 %) of acute disseminated encephalomyelitis; 6 patients (11 %) developed atypical demyelinating syndromes (4 had relapsing episodes of short myelitis lesions which in one occurred with optic neuritis; 1 had relapsing brainstem symptoms, and 1 relapsing demyelinating encephalomyelitis). The course was frequently associated with relapses (71 %) and good outcome. Twenty-seven patients (49 %) had antibodies that recognized rodent MOG epitopes, and 9 of them (16 %) showed a myelin staining pattern in rodent tissue. Only the myelin staining pattern was linked to NMOSD (p = 0.005). In conclusion, MOG autoimmunity in adult patients associates with a clinical spectrum wider than the one expected for patients with suspected NMOSD and overall good outcome. Antibodies to rodent MOG epitopes do not associate with any phenotypic variant. PMID:27147513

  1. Associative-memory representations emerge as shared spatial patterns of theta activity spanning the primate temporal cortex.

    PubMed

    Nakahara, Kiyoshi; Adachi, Ken; Kawasaki, Keisuke; Matsuo, Takeshi; Sawahata, Hirohito; Majima, Kei; Takeda, Masaki; Sugiyama, Sayaka; Nakata, Ryota; Iijima, Atsuhiko; Tanigawa, Hisashi; Suzuki, Takafumi; Kamitani, Yukiyasu; Hasegawa, Isao

    2016-01-01

    Highly localized neuronal spikes in primate temporal cortex can encode associative memory; however, whether memory formation involves area-wide reorganization of ensemble activity, which often accompanies rhythmicity, or just local microcircuit-level plasticity, remains elusive. Using high-density electrocorticography, we capture local-field potentials spanning the monkey temporal lobes, and show that the visual pair-association (PA) memory is encoded in spatial patterns of theta activity in areas TE, 36, and, partially, in the parahippocampal cortex, but not in the entorhinal cortex. The theta patterns elicited by learned paired associates are distinct between pairs, but similar within pairs. This pattern similarity, emerging through novel PA learning, allows a machine-learning decoder trained on theta patterns elicited by a particular visual item to correctly predict the identity of those elicited by its paired associate. Our results suggest that the formation and sharing of widespread cortical theta patterns via learning-induced reorganization are involved in the mechanisms of associative memory representation. PMID:27282247

  2. Associative-memory representations emerge as shared spatial patterns of theta activity spanning the primate temporal cortex

    PubMed Central

    Nakahara, Kiyoshi; Adachi, Ken; Kawasaki, Keisuke; Matsuo, Takeshi; Sawahata, Hirohito; Majima, Kei; Takeda, Masaki; Sugiyama, Sayaka; Nakata, Ryota; Iijima, Atsuhiko; Tanigawa, Hisashi; Suzuki, Takafumi; Kamitani, Yukiyasu; Hasegawa, Isao

    2016-01-01

    Highly localized neuronal spikes in primate temporal cortex can encode associative memory; however, whether memory formation involves area-wide reorganization of ensemble activity, which often accompanies rhythmicity, or just local microcircuit-level plasticity, remains elusive. Using high-density electrocorticography, we capture local-field potentials spanning the monkey temporal lobes, and show that the visual pair-association (PA) memory is encoded in spatial patterns of theta activity in areas TE, 36, and, partially, in the parahippocampal cortex, but not in the entorhinal cortex. The theta patterns elicited by learned paired associates are distinct between pairs, but similar within pairs. This pattern similarity, emerging through novel PA learning, allows a machine-learning decoder trained on theta patterns elicited by a particular visual item to correctly predict the identity of those elicited by its paired associate. Our results suggest that the formation and sharing of widespread cortical theta patterns via learning-induced reorganization are involved in the mechanisms of associative memory representation. PMID:27282247

  3. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.

    PubMed

    2007-06-01

    There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a

  4. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

    PubMed Central

    2009-01-01

    There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined ~2,000 individuals for each of 7 major diseases and a shared set of ~3,000 controls. Case-control comparisons identified 24 independent association signals at P<5×10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn’s disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5×10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics

  5. 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

  6. Type VI secretion apparatus and phage tail-associated protein complexes share a common evolutionary origin

    SciTech Connect

    Leiman, Petr G.; Basler, Marek; Ramagopal, Udupi A.; Bonanno, Jeffrey B.; Sauder, J. Michael; Pukatzki, Stefan; Burley, Stephen K.; Almo, Steven C.; Mekalanos, John J.

    2009-04-22

    Protein secretion is a common property of pathogenic microbes. Gram-negative bacterial pathogens use at least 6 distinct extracellular protein secretion systems to export proteins through their multilayered cell envelope and in some cases into host cells. Among the most widespread is the newly recognized Type VI secretion system (T6SS) which is composed of 15--20 proteins whose biochemical functions are not well understood. Using crystallographic, biochemical, and bioinformatic analyses, we identified 3 T6SS components, which are homologous to bacteriophage tail proteins. These include the tail tube protein; the membrane-penetrating needle, situated at the distal end of the tube; and another protein associated with the needle and tube. We propose that T6SS is a multicomponent structure whose extracellular part resembles both structurally and functionally a bacteriophage tail, an efficient machine that translocates proteins and DNA across lipid membranes into cells.

  7. The importance of genetic and shared environmental factors for the associations between job demands, control, support and burnout.

    PubMed

    Blom, Victoria; Bodin, Lennart; Bergström, Gunnar; Hallsten, Lennart; Svedberg, Pia

    2013-01-01

    Within occupational health research, one of the most influential models is the Job Demands-Control-Support model. Numerous studies have applied the model to different domains, with both physical and psychological health outcomes, such as burnout. The twin design provides a unique and powerful research methodology for examining the effects of environmental risk factors on burnout while taking familial factors (genetic and shared environment) into account. The aim of the present study was to investigate the impact of familial factors on the associations of burnout with job demands, control and support. A total of 14,516 individuals from the Swedish Twin Registry, who were born between 1959 and 1986, and who participated in the Study of Twin Adults: Genes and Environment (STAGE) by responding to a web-based questionnaire in 2005, were included in the analyses. Of these, there were 5108 individuals in complete same-sex twin pairs. Co-twin control analyses were performed using linear mixed modeling, comparing between-pairs effects and within-pair effects, stratified also by zygosity and sex. The results indicate that familial factors are of importance in the association between support and burnout in both women and men, but not between job demands and burnout. There are also tendencies towards familial factors being involved in the association between control and burnout in men. These results offer increased understanding of the mechanisms involved in the associations between work stress and burnout. PMID:24086520

  8. Shared Genetic Background for Regulation of Mood and Sleep: Association of GRIA3 with Sleep Duration in Healthy Finnish Women

    PubMed Central

    Utge, Siddheshwar; Kronholm, Erkki; Partonen, Timo; Soronen, Pia; Ollila, Hanna M.; Loukola, Anu; Perola, Markus; Salomaa, Veikko; Porkka-Heiskanen, Tarja; Paunio, Tiina

    2011-01-01

    Study Objectives: Sleeping 7 to 8 hours per night appears to be optimal, since both shorter and longer sleep times are related to increased morbidity and mortality. Depressive disorder is almost invariably accompanied by disturbed sleep, leading to decreased sleep duration, and disturbed sleep may be a precipitating factor in the initiation of depressive illness. Here, we examined whether, in healthy individuals, sleep duration is associated with genes that we earlier found to be associated with depressive disorder. Design: Population-based molecular genetic study. Setting: Regression analysis of 23 risk variants for depressive disorder from 12 genes to sleep duration in healthy individuals. Participants: Three thousand, one hundred, forty-seven individuals (25–75 y) from population-based Health 2000 and FINRISK 2007 samples. Measurements and Results: We found a significant association of rs687577 from GRIA3 on the X-chromosome with sleep duration in women (permutation-based corrected empirical P = 0.00001, β = 0.27; Bonferroni corrected P = 0.0052; f = 0.11). The frequency of C/C genotype previously found to increase risk for depression in women was highest among those who slept for 8 hours or less in all age groups younger than 70 years. Its frequency decreased with the lengthening of sleep duration, and those who slept for 9 to 10 hours showed a higher frequency of C/A or A/A genotypes, when compared with the midrange sleepers (7-8 hours) (permutation-based corrected empirical P = 0.0003, OR = 1.81). Conclusions: The GRIA3 polymorphism that was previously found to be associated with depressive disorder in women showed an association with sleep duration in healthy women. Mood disorders and short sleep may share a common genetic background and biologic mechanisms that involve glutamatergic neurotransmission. Citation: Utge S; Kronholm E; Partonen T; Soronen P; Ollila HM; Loukola A; Perola M; Salomaa V; Porkka-Heiskanen T; Paunio T. Shared genetic background for

  9. Scalable Privacy-Preserving Data Sharing Methodology for Genome-Wide Association Studies

    PubMed Central

    Yu, Fei; Fienberg, Stephen E.; Slavković, Aleksandra; Uhler, Caroline

    2014-01-01

    The protection of privacy of individual-level information in genome-wide association study (GWAS) databases has been a major concern of researchers following the publication of “an attack” on GWAS data by Homer et al. [1]. Traditional statistical methods for confidentiality and privacy protection of statistical databases do not scale well to deal with GWAS data, especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach that provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, Uhler et al. [2] proposed new methods to release aggregate GWAS data without compromising an individual's privacy. We extend the methods developed in [2] for releasing differentially-private χ2-statistics by allowing for arbitrary number of cases and controls, and for releasing differentially-private allelic test statistics. We also provide a new interpretation by assuming the controls’ data are known, which is a realistic assumption because some GWAS use publicly available data as controls. We assess the performance of the proposed methods through a risk-utility analysis on a real data set consisting of DNA samples collected by the Wellcome Trust Case Control Consortium and compare the methods with the differentially-private release mechanism proposed by Johnson and Shmatikov [3]. PMID:24509073

  10. A narrative review of binge eating and addictive behaviors: shared associations with seasonality and personality factors.

    PubMed

    Davis, Caroline

    2013-01-01

    Binge-eating disorder and seasonal affective disorder were first described as clinically relevant conditions in very close temporal proximity a few decades ago. Both disorders have a higher prevalence rate in woman than in men, are characterized by a high proneness-to-stress and manifest heightened responsiveness to high-calorie, hyper-palatable foods. In recent years, a compelling body of evidence suggests that foods high in sugar and fat have the potential to alter brain reward circuitry in a manner similar to that seen when addictive drugs like alcohol and heroin are consumed in excess. These findings have led to suggestions that some cases of compulsive overeating may be understood as an addiction to sweet, fatty, and salty foods. In this paper, it is proposed that high seasonality is a risk factor for binge eating, especially in those characterized by anxious and impulsive personality traits - associations that could only occur in an environment with a superfluity of, and easy access to, rich and tasty foods. Given the well-established links between binge eating and addiction disorders [Ref. (1-3) for reviews], it is also suggested that seasonality, together with the same high-risk psychological profile, exacerbates the likelihood of engaging in a broad range of addictive behaviors. Data from a community sample (n = 412) of adults tested these models using linear regression procedures. Results confirmed that symptoms of binge eating and other addictive behaviors were significantly inter-correlated, and that seasonality, gender, and addictive personality traits were strong statistical predictors of the variance in binge-eating scores. Seasonality and addictive personality traits also accounted for a significant proportion of the variance in the measure of addictive behaviors. Conclusions are discussed in the context of brain reward mechanisms, motivational alternations in response to chronic over-consumption, and their relevance for the treatment of

  11. A Narrative Review of Binge Eating and Addictive Behaviors: Shared Associations with Seasonality and Personality Factors

    PubMed Central

    Davis, Caroline

    2013-01-01

    Binge-eating disorder and seasonal affective disorder were first described as clinically relevant conditions in very close temporal proximity a few decades ago. Both disorders have a higher prevalence rate in woman than in men, are characterized by a high proneness-to-stress and manifest heightened responsiveness to high-calorie, hyper-palatable foods. In recent years, a compelling body of evidence suggests that foods high in sugar and fat have the potential to alter brain reward circuitry in a manner similar to that seen when addictive drugs like alcohol and heroin are consumed in excess. These findings have led to suggestions that some cases of compulsive overeating may be understood as an addiction to sweet, fatty, and salty foods. In this paper, it is proposed that high seasonality is a risk factor for binge eating, especially in those characterized by anxious and impulsive personality traits – associations that could only occur in an environment with a superfluity of, and easy access to, rich and tasty foods. Given the well-established links between binge eating and addiction disorders [Ref. (1–3) for reviews], it is also suggested that seasonality, together with the same high-risk psychological profile, exacerbates the likelihood of engaging in a broad range of addictive behaviors. Data from a community sample (n = 412) of adults tested these models using linear regression procedures. Results confirmed that symptoms of binge eating and other addictive behaviors were significantly inter-correlated, and that seasonality, gender, and addictive personality traits were strong statistical predictors of the variance in binge-eating scores. Seasonality and addictive personality traits also accounted for a significant proportion of the variance in the measure of addictive behaviors. Conclusions are discussed in the context of brain reward mechanisms, motivational alternations in response to chronic over-consumption, and their relevance for the treatment of

  12. Discriminating Risk and Resilience Endophenotypes From Lifetime Illness Effects in Familial Major Depressive Disorder

    PubMed Central

    Peterson, Bradley S.; Wang, Zhishun; Horga, Guillermo; Warner, Virginia; Rutherford, Bret; Klahr, Kristin W.; Graniello, Barbara; Wickramaratne, Priya; Garcia, Felix; Yu, Shan; Hao, Xuejun; Adams, Phillip B.; Qian, Ming; Liu, Jun; Gerber, Andrew; Weissman, Myrna M.

    2014-01-01

    IMPORTANCE The neural systems that confer risk or vulnerability for developing familial depression, and those that protect against or confer resilience to becoming ill, can be disentangled from the effects of prior illness by comparing brain imaging measures in previously ill and never ill persons who have either a high or low familial risk for depression. OBJECTIVE To distinguish risk and resilience endophenotypes for major depression from the effects of prior lifetime illness. DESIGN, SETTING, AND PARTICIPANTS We used functional magnetic resonance imaging to measure and compare brain function during performance of an attentional, self-regulatory task across a large sample of multigenerational families ascertained specifically to be at either high or low risk for developing major depression. Study procedures were performed in a university setting. A total of 143 community participants were followed up prospectively for more than 20 years in a university setting. The sample was enriched with persons who were at higher or lower familial risk for developing depression based on being biological offspring of either a clinical sample of persons with major depression or a community control sample of persons with no discernible lifetime illness. MAIN OUTCOMES AND MEASURES Task-related change in blood oxygen level–dependent functional magnetic resonance imaging signal. RESULTS A risk endophenotype included greater activation of cortical attention circuits. A resilience endophenotype included greater activation of the dorsal anterior cingulate cortex. The effects of prior lifetime illness were common to both risk groups and included greater deactivation of default-mode circuits. CONCLUSIONS AND RELEVANCE These findings identify neural systems that increase risk for depression, those that protect from illness, and those that endure following illness onset, and they suggest circuits to target for developing novel preventive and therapeutic interventions. PMID:24369340

  13. New parasitoid-predator associations: female parasitoids do not avoid competition with generalist predators when sharing invasive prey

    NASA Astrophysics Data System (ADS)

    Chailleux, Anaïs; Wajnberg, Eric; Zhou, Yuxiang; Amiens-Desneux, Edwige; Desneux, Nicolas

    2014-12-01

    Optimal habitat selection is essential for species survival in ecosystems, and interspecific competition is a key ecological mechanism for many observed species association patterns. Specialized animal species are commonly affected by resource and interference competition with generalist and/or omnivorous competitors, so avoidance behavior could be expected. We hypothesize that specialist species may exploit broad range cues from such potential resource competitors (i.e., cues possibly common to various generalist and/or omnivorous predators) to avoid costly competition regarding food or reproduction, even in new species associations. We tested this hypothesis by studying short-term interactions between a native larval parasitoid and a native generalist omnivorous predator recently sharing the same invasive host/prey, the leaf miner Tuta absoluta. We observed a strong negative effect of kleptoparasitism (food resource stealing) instead of classical intraguild predation on immature parasitoids. There was no evidence that parasitoid females avoided the omnivorous predator when searching for oviposition sites, although we studied both long- and short-range known detection mechanisms. Therefore, we conclude that broad range cue avoidance may not exist in our biological system, probably because it would lead to too much oviposition site avoidance which would not be an efficient and, thus, beneficial strategy. If confirmed in other parasitoids or specialist predators, our findings may have implications for population dynamics, especially in the current context of increasing invasive species and the resulting creation of many new species associations.

  14. Quantitative linkage analysis to the autism endophenotype social responsiveness identifies genome-wide significant linkage to two regions on chromosome 8

    PubMed Central

    Lowe, Jennifer K.; Werling, Donna M.; Constantino, John N.; Cantor, Rita M.; Geschwind, Daniel H.

    2015-01-01

    Objective Autism Spectrum Disorder (ASD) is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, we adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for ASD. Method Linkage analyses using scores from the Social Responsiveness Scale (SRS) were performed in 590 families from AGRE, a largely multiplex ASD cohort. Regional and genome-wide association analyses were performed to search for common variants contributing to social responsiveness. Results SRS is unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in females. In correlated analyses differing by SRS respondent, genome-wide significant linkage for social responsiveness was identified at chr8p21.3 (multi-point LOD=4.11; teacher/parent scores) and chr8q24.22 (multi-point LOD=4.54; parent-only scores), respectively. Genome-wide or linkage-directed association analyses did not detect common variants contributing to social responsiveness. Conclusions The sex-differential distributions of SRS in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to ASD among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as ASD. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of ASD. PMID:25727539

  15. Association of PTPN22 1858C→T polymorphism, HLA-DRB1 shared epitope and autoantibodies with rheumatoid arthritis.

    PubMed

    Raslan, Hala M; Attia, Hanaa R; Salama, Iman; Ibrahim, Mona Hamed; Hassan, Eman Mahmoud; El Hussieny, Mohamed S; El Menyawi, Manal M; Amr, Khalda S

    2016-08-01

    To assess impact of PTPN22 1858C→T polymorphism, HLA shared epitope and autoantibodies on susceptibility and severity of rheumatoid arthritis (RA). A total of 150 RA patients and 150 controls were included in the study. Anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor isotypes (IgG, IgM and IgA) were assayed by ELISA. PTPN22 1858C→T polymorphism was performed by RFLP analysis and HLA-DRB1 genotyping by PCR-SSP analysis. Single-view, anteroposterior radiographs of the hands and feet were obtained on all RA patients. The results showed association of PTPN22 1858 T allele with RA (OR = 2.3, 95 % CI 1.5-3.5) and bone erosion (OR = 2.9, 95 % CI 1.1-7.6). The associations increased with the combination of positive autoantibodies, HLA-DRB1 SE with PTPN22 1858 T allele carriage. The highest association was with the combination with anti-CCP antibodies (OR = 47.3, 95 % CI 10.9-204.4 for RA and OR = 69.4, 95 % CI 15.8-305.5 for erosion p < 0.001). Combination of PTPN22 1858 T allele carriage with negative RF isotypes or with absence HLA-DRB1 SE showed no significant association with RA. The presence of PTPN22 1858C→T polymorphism with HLA SE and autoantibodies increases risk of RA development and erosive disease. PMID:27324632

  16. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

    PubMed

    Cheng, Ching-Yu; Schache, Maria; Ikram, M Kamran; Young, Terri L; Guggenheim, Jeremy A; Vitart, Veronique; MacGregor, Stuart; Verhoeven, Virginie J M; Barathi, Veluchamy A; Liao, Jiemin; Hysi, Pirro G; Bailey-Wilson, Joan E; St Pourcain, Beate; Kemp, John P; McMahon, George; Timpson, Nicholas J; Evans, David M; Montgomery, Grant W; Mishra, Aniket; Wang, Ya Xing; Wang, Jie Jin; Rochtchina, Elena; Polasek, Ozren; Wright, Alan F; Amin, Najaf; van Leeuwen, Elisabeth M; Wilson, James F; Pennell, Craig E; van Duijn, Cornelia M; de Jong, Paulus T V M; Vingerling, Johannes R; Zhou, Xin; Chen, Peng; Li, Ruoying; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Burdon, Kathryn P; Craig, Jamie E; Iyengar, Sudha K; Igo, Robert P; Lass, Jonathan H; Chew, Emily Y; Haller, Toomas; Mihailov, Evelin; Metspalu, Andres; Wedenoja, Juho; Simpson, Claire L; Wojciechowski, Robert; Höhn, René; Mirshahi, Alireza; Zeller, Tanja; Pfeiffer, Norbert; Lackner, Karl J; Bettecken, Thomas; Meitinger, Thomas; Oexle, Konrad; Pirastu, Mario; Portas, Laura; Nag, Abhishek; Williams, Katie M; Yonova-Doing, Ekaterina; Klein, Ronald; Klein, Barbara E; Hosseini, S Mohsen; Paterson, Andrew D; Makela, Kari-Matti; Lehtimaki, Terho; Kahonen, Mika; Raitakari, Olli; Yoshimura, Nagahisa; Matsuda, Fumihiko; Chen, Li Jia; Pang, Chi Pui; Yip, Shea Ping; Yap, Maurice K H; Meguro, Akira; Mizuki, Nobuhisa; Inoko, Hidetoshi; Foster, Paul J; Zhao, Jing Hua; Vithana, Eranga; Tai, E-Shyong; Fan, Qiao; Xu, Liang; Campbell, Harry; Fleck, Brian; Rudan, Igor; Aung, Tin; Hofman, Albert; Uitterlinden, André G; Bencic, Goran; Khor, Chiea-Chuen; Forward, Hannah; Pärssinen, Olavi; Mitchell, Paul; Rivadeneira, Fernando; Hewitt, Alex W; Williams, Cathy; Oostra, Ben A; Teo, Yik-Ying; Hammond, Christopher J; Stambolian, Dwight; Mackey, David A; Klaver, Caroline C W; Wong, Tien-Yin; Saw, Seang-Mei; Baird, Paul N

    2013-08-01

    Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. PMID:24144296

  17. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

    PubMed Central

    Cheng, Ching-Yu; Schache, Maria; Ikram, M. Kamran; Young, Terri L.; Guggenheim, Jeremy A.; Vitart, Veronique; MacGregor, Stuart; Verhoeven, Virginie J.M.; Barathi, Veluchamy A.; Liao, Jiemin; Hysi, Pirro G.; Bailey-Wilson, Joan E.; St. Pourcain, Beate; Kemp, John P.; McMahon, George; Timpson, Nicholas J.; Evans, David M.; Montgomery, Grant W.; Mishra, Aniket; Wang, Ya Xing; Wang, Jie Jin; Rochtchina, Elena; Polasek, Ozren; Wright, Alan F.; Amin, Najaf; van Leeuwen, Elisabeth M.; Wilson, James F.; Pennell, Craig E.; van Duijn, Cornelia M.; de Jong, Paulus T.V.M.; Vingerling, Johannes R.; Zhou, Xin; Chen, Peng; Li, Ruoying; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Rahi, Jugnoo S.; Hysi, Pirro G.; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Delcourt, Cécile; Maubaret, Cecilia; Williams, Cathy; Guggenheim, Jeremy A.; Northstone, Kate; Ring, Susan M.; Davey-Smith, George; Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Stambolian, Dwight; Wilson, Joan E. Bailey; MacGregor, Stuart; Lu, Yi; Jonas, Jost B.; Xu, Liang; Saw, Seang-Mei; Baird, Paul N.; Rochtchina, Elena; Mitchell, Paul; Wang, Jie Jin; Jonas, Jost B.; Nangia, Vinay; Hayward, Caroline; Wright, Alan F.; Vitart, Veronique; Polasek, Ozren; Campbell, Harry; Vitart, Veronique; Rudan, Igor; Vatavuk, Zoran; Vitart, Veronique; Paterson, Andrew D.; Hosseini, S. Mohsen; Iyengar, Sudha K.; Igo, Robert P.; Fondran, Jeremy R.; Young, Terri L.; Feng, Sheng; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Metspalu, Andres; Haller, Toomas; Mihailov, Evelin; Pärssinen, Olavi; Wedenoja, Juho; Wilson, Joan E. Bailey; Wojciechowski, Robert; Baird, Paul N.; Schache, Maria; Pfeiffer, Norbert; Höhn, René; Pang, Chi Pui; Chen, Peng; Meitinger, Thomas; Oexle, Konrad; Wegner, Aharon; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Pärssinen, Olavi; Yip, Shea Ping; Ho, Daniel W.H.; Pirastu, Mario; Murgia, Federico; Portas, Laura; Biino, Genevra; Wilson, James F.; Fleck, Brian; Vitart, Veronique; Stambolian, Dwight; Wilson, Joan E. Bailey; Hewitt, Alex W.; Ang, Wei; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Tai, E-Shyong; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Mackey, David A.; MacGregor, Stuart; Hammond, Christopher J.; Hysi, Pirro G.; Deangelis, Margaret M.; Morrison, Margaux; Zhou, Xiangtian; Chen, Wei; Paterson, Andrew D.; Hosseini, S. Mohsen; Mizuki, Nobuhisa; Meguro, Akira; Lehtimäki, Terho; Mäkelä, Kari-Matti; Raitakari, Olli; Kähönen, Mika; Burdon, Kathryn P.; Craig, Jamie E.; Iyengar, Sudha K.; Igo, Robert P.; Lass, Jonathan H.; Reinhart, William; Belin, Michael W.; Schultze, Robert L.; Morason, Todd; Sugar, Alan; Mian, Shahzad; Soong, Hunson Kaz; Colby, Kathryn; Jurkunas, Ula; Yee, Richard; Vital, Mark; Alfonso, Eduardo; Karp, Carol; Lee, Yunhee; Yoo, Sonia; Hammersmith, Kristin; Cohen, Elisabeth; Laibson, Peter; Rapuano, Christopher; Ayres, Brandon; Croasdale, Christopher; Caudill, James; Patel, Sanjay; Baratz, Keith; Bourne, William; Maguire, Leo; Sugar, Joel; Tu, Elmer; Djalilian, Ali; Mootha, Vinod; McCulley, James; Bowman, Wayne; Cavanaugh, H. Dwight; Verity, Steven; Verdier, David; Renucci, Ann; Oliva, Matt; Rotkis, Walter; Hardten, David R.; Fahmy, Ahmad; Brown, Marlene; Reeves, Sherman; Davis, Elizabeth A.; Lindstrom, Richard; Hauswirth, Scott; Hamilton, Stephen; Lee, W. Barry; Price, Francis; Price, Marianne; Kelly, Kathleen; Peters, Faye; Shaughnessy, Michael; Steinemann, Thomas; Dupps, B.J.; Meisler, David M.; Mifflin, Mark; Olson, Randal; Aldave, Anthony; Holland, Gary; Mondino, Bartly J.; Rosenwasser, George; Gorovoy, Mark; Dunn, Steven P.; Heidemann, David G.; Terry, Mark; Shamie, Neda; Rosenfeld, Steven I.; Suedekum, Brandon; Hwang, David

    2013-01-01

    Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. PMID:24144296

  18. Taxol shares the ability of bacterial lipopolysaccharide to induce tyrosine phosphorylation of microtubule-associated protein kinase.

    PubMed

    Ding, A; Sanchez, E; Nathan, C F

    1993-11-15

    Microtubule-associated proteins may mediate the activation of macrophages by bacterial LPS. Three lines of evidence support this hypothesis: a) Taxol, a microtubule-binding diterpene, mimics the ability of LPS to induce cytokines and down-regulate receptors for TNF-alpha. In recombinant inbred mouse strains differing at the Lps gene, responsiveness to these effects of Taxol co-segregates with responsiveness to LPS. b) In vitro, LPS binds specifically to MT and preferentially to beta-tubulin. c) LPS activates microtubule-associated protein-2 kinase (MAPK). The present studies bring together and extend these lines of evidence. a) Taxol, like LPS, rapidly induces tyrosine phosphorylation of MAPK in mouse macrophages, and triggers MAPK to phosphorylate an exogenous substrate. b) Tyrosine phosphorylation of MAPK is an extremely rapid cellular response both to taxol and LPS. c) Macrophages from C3H/HeJ mice, which carry a defective Lps gene, fail to activate MAPK in response to taxol or LPS, although they activate MAPK in response to insulin or IFN-gamma. These results suggest that tyrosine phosphorylation of MAPK is among the earliest known response of macrophages to LPS. Taxol mimics LPS with respect to immediate MAPK activation, later transcriptional events, and the genetic control of both sets of responses. LPS and taxol thus appear to share an early step in a functionally important signal transduction pathway that may involve MT. PMID:7901279

  19. Cognitive Endophenotypes Inform Genome-Wide Expression Profiling in Schizophrenia

    PubMed Central

    Zheutlin, Amanda B.; Viehman, Rachael W.; Fortgang, Rebecca; Borg, Jacqueline; Smith, Desmond J.; Suvisaari, Jaana; Therman, Sebastian; Hultman, Christina M.; Cannon, Tyrone D.

    2015-01-01

    OBJECTIVE We performed a whole-genome expression study to clarify the nature of the biological processes mediating between inherited genetic variations and cognitive dysfunction in schizophrenia. METHOD Gene expression was assayed from peripheral blood mononuclear cells using Illumina Human WG6 v3.0 chips in twins discordant for schizophrenia or bipolar disorder and control twins. After quality control, expression levels of 18,559 genes were screened for association with California Verbal Learning Test (CVLT) performance, and any memory-related probes were then evaluated for variation by diagnostic status in the discovery sample (N = 190), and in an independent replication sample (N = 73). Heritability of gene expression using the twin design was also assessed. RESULTS After Bonferroni correction (p < 2.69 × 10−6), CVLT performance was significantly related to expression levels for 76 genes, 43 of which were differentially expressed in schizophrenia patients, with comparable effect sizes in the same direction in the replication sample. For 41 of these 43 transcripts, expression levels were heritable. Nearly all identified genes contain common or de novo mutations associated with schizophrenia in prior studies. CONCLUSION Genes increasing risk for schizophrenia appear to do so in part via effects on signaling cascades influencing memory. The genes implicated in these processes are enriched for those related to RNA processing and DNA replication and include genes influencing G-protein coupled signal transduction, cytokine signaling, and oligodendrocyte function. PMID:26710095

  20. Revisiting the suitability of antisaccade performance as an endophenotype in schizophrenia.

    PubMed

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

    2011-11-01

    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 patients and relatives, and sought to establish whether antisaccade measures could differentiate between two patients clusters identified in the Western Australian Family Study of Schizophrenia with either pervasive cognitive deficits (CD) or cognitively spared (CS). Ninety-three patients (CD=47, CS=46), 99 relatives and 62 healthy controls carried out a standard antisaccade task. Results showed: (i) significantly greater error rate, and prolonged latencies to correct responses and self-correction saccades in patients compared with controls; (ii) high error rates in relatives of poorly performing patients; (iii) longer latencies of self-correction saccades in relatives compared to controls; and (iv) higher error rate and longer latencies of self-correction saccades in the CD subgroup compared with CS. Unaffected relatives as a group were unimpaired in error rate as compared to healthy controls. These findings suggest that the antisaccade error rate and latency of self-correction saccades are useful measures in specific applications of genetic research in schizophrenia, without fully meeting endophenotype co-familiality requirements. PMID:21924537

  1. Comprehensive Neurocognitive Endophenotyping Strategies for Mouse Models of Genetic Disorders

    PubMed Central

    Hunsaker, Michael R.

    2012-01-01

    There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species. PMID:22266125

  2. S-SCAM, A Rare Copy Number Variation Gene, Induces Schizophrenia-Related Endophenotypes in Transgenic Mouse Model

    PubMed Central

    Zhang, Nanyan; Zhong, Peng; Shin, Seung Min; Metallo, Jacob; Danielson, Eric; Olsen, Christopher M.; Liu, Qing-song

    2015-01-01

    Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis. PMID:25653350

  3. S-SCAM, a rare copy number variation gene, induces schizophrenia-related endophenotypes in transgenic mouse model.

    PubMed

    Zhang, Nanyan; Zhong, Peng; Shin, Seung Min; Metallo, Jacob; Danielson, Eric; Olsen, Christopher M; Liu, Qing-song; Lee, Sang H

    2015-02-01

    Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis. PMID:25653350

  4. Collaboratively Sharing Scientific Data

    NASA Astrophysics Data System (ADS)

    Wang, Fusheng; Vergara-Niedermayr, Cristobal

    Scientific research becomes increasingly reliant on multi-disciplinary, multi-institutional collaboration through sharing experimental data. Indeed, data sharing is mandatory by government research agencies such as NIH. The major hurdles for data sharing come from: i) the lack of data sharing infrastructure to make data sharing convenient for users; ii) users’ fear of losing control of their data; iii) difficulty on sharing schemas and incompatible data from sharing partners; and iv) inconsistent data under schema evolution. In this paper, we develop a collaborative data sharing system SciPort, to support consistency preserved data sharing among multiple distributed organizations. The system first provides Central Server based lightweight data integration architecture, so data and schemas can be conveniently shared across multiple organizations. Through distributed schema management, schema sharing and evolution is made possible, while data consistency is maintained and data compatibility is enforced. With this data sharing system, distributed sites can now consistently share their research data and their associated schemas with much convenience and flexibility. SciPort has been successfully used for data sharing in biomedical research, clinical trials and large scale research collaboration.

  5. 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,…

  6. 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…

  7. A Transient Receptor Potential Ion Channel in Chlamydomonas Shares Key Features with Sensory Transduction-Associated TRP Channels in Mammals

    PubMed Central

    Arias-Darraz, Luis; Cabezas, Deny; Colenso, Charlotte K.; Alegría-Arcos, Melissa; Bravo-Moraga, Felipe; Varas-Concha, Ignacio; Almonacid, Daniel E.; Madrid, Rodolfo; Brauchi, Sebastian

    2015-01-01

    Sensory modalities are essential for navigating through an ever-changing environment. From insects to mammals, transient receptor potential (TRP) channels are known mediators for cellular sensing. Chlamydomonas reinhardtii is a motile single-celled freshwater green alga that is guided by photosensory, mechanosensory, and chemosensory cues. In this type of alga, sensory input is first detected by membrane receptors located in the cell body and then transduced to the beating cilia by membrane depolarization. Although TRP channels seem to be absent in plants, C. reinhardtii possesses genomic sequences encoding TRP proteins. Here, we describe the cloning and characterization of a C. reinhardtii version of a TRP channel sharing key features present in mammalian TRP channels associated with sensory transduction. In silico sequence-structure analysis unveiled the modular design of TRP channels, and electrophysiological experiments conducted on Human Embryonic Kidney-293T cells expressing the Cr-TRP1 clone showed that many of the core functional features of metazoan TRP channels are present in Cr-TRP1, suggesting that basic TRP channel gating characteristics evolved early in the history of eukaryotes. PMID:25595824

  8. Understanding Neuropsychiatric Diseases, Analyzing the Peptide Sharing between Infectious Agents and the Language-Associated NMDA 2A Protein

    PubMed Central

    Lucchese, Guglielmo

    2016-01-01

    Language disorders and infections may occur together and often concur, to a different extent and via different modalities, in characterizing brain pathologies, such as schizophrenia, autism, epilepsies, bipolar disorders, frontotemporal neurodegeneration, and encephalitis, inter alia. The biological mechanism(s) that might channel language dysfunctions and infections into etiological pathways connected to neuropathologic sequelae are unclear. Searching for molecular link(s) between language disorders and infections, the present study explores the language-associated NMDA 2A subunit for peptide sharing with pathogens that have been described in concomitance with neuropsychiatric diseases. It was found that a vast peptide commonality links the human glutamate ionotropic receptor NMDA 2A subunit to infectious agents. Such a link expands to and interfaces with neuropsychiatric disorders in light of the specific allocation of NMDA 2A gene expression in brain areas related to language functions. The data hint at a possible pathologic scenario based on anti-pathogen immune responses cross-reacting with NMDA 2A in the brain. PMID:27148089

  9. Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens

    PubMed Central

    Xu, Jun; Saunders, Charles W.; Hu, Ping; Grant, Raymond A.; Boekhout, Teun; Kuramae, Eiko E.; Kronstad, James W.; DeAngelis, Yvonne M.; Reeder, Nancy L.; Johnstone, Kevin R.; Leland, Meredith; Fieno, Angela M.; Begley, William M.; Sun, Yiping; Lacey, Martin P.; Chaudhary, Tanuja; Keough, Thomas; Chu, Lien; Sears, Russell; Yuan, Bo; Dawson, Thomas L.

    2007-01-01

    Fungi in the genus Malassezia are ubiquitous skin residents of humans and other warm-blooded animals. Malassezia are involved in disorders including dandruff and seborrheic dermatitis, which together affect >50% of humans. Despite the importance of Malassezia in common skin diseases, remarkably little is known at the molecular level. We describe the genome, secretory proteome, and expression of selected genes of Malassezia globosa. Further, we report a comparative survey of the genome and secretory proteome of Malassezia restricta, a close relative implicated in similar skin disorders. Adaptation to the skin environment and associated pathogenicity may be due to unique metabolic limitations and capabilities. For example, the lipid dependence of M. globosa can be explained by the apparent absence of a fatty acid synthase gene. The inability to synthesize fatty acids may be complemented by the presence of multiple secreted lipases to aid in harvesting host lipids. In addition, an abundance of genes encoding secreted hydrolases (e.g., lipases, phospholipases, aspartyl proteases, and acid sphingomyelinases) was found in the M. globosa genome. In contrast, the phylogenetically closely related plant pathogen Ustilago maydis encodes a different arsenal of extracellular hydrolases with more copies of glycosyl hydrolase genes. M. globosa shares a similar arsenal of extracellular hydrolases with the phylogenetically distant human pathogen, Candida albicans, which occupies a similar niche, indicating the importance of host-specific adaptation. The M. globosa genome sequence also revealed the presence of mating-type genes, providing an indication that Malassezia may be capable of sex. PMID:18000048

  10. Neurological soft signs might be endophenotype candidates for patients with deficit syndrome schizophrenia

    PubMed Central

    Albayrak, Yakup; Akyol, Esra Soydaş; Beyazyüz, Murat; Baykal, Saliha; Kuloglu, Murat

    2015-01-01

    Background Schizophrenia is a chronic, disabling, disorder that affects approximately 1% of the population. The nature of schizophrenia is heterogeneous, and unsuccessful efforts to subtype this disorder have been made. Deficit syndrome schizophrenia (DS) is a clinical diagnosis that has not been placed in main diagnostic manuals. In this study, we aimed to investigate and compare neurological soft signs (NSS) in DS patients, non-deficit schizophrenia (NDS) patients, and healthy controls (HCs). We suggest that NSS might be an endophenotype candidate for DS patients. Methods Sixty-six patients with schizophrenia and 30 HCs were enrolled in accordance with our inclusion and exclusion criteria. The patients were sub-typed as DS (n=24) and NDS (n=42) according to the Schedule for the Deficit Syndrome. The three groups were compared in terms of sociodemographic and clinical variables and total scores and subscores on the Physical and Neurological Examination for Soft Signs (PANESS). Following the comparison, a regression analysis was performed for predictability of total PANESS score and its subscales in the diagnosis of DS and NDS. Results The groups were similar in terms of age, sex, and smoking status. The results of our study indicated that the total PANESS score was significantly higher in the DS group compared to the NDS and HC groups, and all PANESS subscales were significantly higher in the DS group than in the HC group. The diagnosis of DS was predicted significantly by total PANESS score (P<0.001, odds ratio =9.48, 95% confidence interval: 0.00–4.56); the synergy, graphesthesia, stereognosis, motor tasks, and ability to maintain posture subscales were found to be significant predictors. Conclusion This study confirms that NSS were higher in patients with DS. In addition, we suggest that our results might support the notion of DS as a different and distinct type of schizophrenia. NSS might also be a promising candidate as an endophenotype for DS. However

  11. Meaning-Related and Print-Related Interactions between Preschoolers and Parents during Shared Book Reading and Their Associations with Emergent Literacy Skills

    ERIC Educational Resources Information Center

    Han, Jisu; Neuharth-Pritchett, Stacey

    2015-01-01

    This study examined interactions between preschool children and parents during shared book reading by analyzing parental self-report data. Using confirmatory factor analytic procedures and structural equation modeling, this study developed a scale measuring meaning-related and print-related reading interactions and examined their associations with…

  12. Contribution of neurophysiological endophenotype, individual frequency of EEG alpha oscillations, to mechanisms of emotional reactivity.

    PubMed

    Tumyalis, A V; Aftanas, L I

    2014-04-01

    We studied the relationship between individual alpha frequency (IAF) of EEG (neurophysiological endophenotype reflecting individual predisposition to efficacious cognitive and creative activity) and individual emotional reactivity. The psychophysiological study included healthy men in two models of evoked emotions - anxious apprehension (awaiting of inescapable aversive punishment) and discrete (opposite) emotions. Analysis of self-report, multichannel EEG, galvanic skin response, and cardiovascular reactivity showed that individuals with high IAF are characterized by predominance of parasympathetic influences in autonomic regulation circuit, proactive strategies of coping with inescapable threat, higher activity of positive emotional attitude and availability of memory traces about positive experience. Individuals with low IAF demonstrate predominance of sympathetic influences and maladaptive avoidance-like coping with inescapable threat and insufficiency of positive emotional activation mechanisms. It is suggested that IAF participates in the formation of individual emotional space and strategies of coping with emotional challenges. PMID:24824678

  13. Research review: crossing syndrome boundaries in the search for brain endophenotypes.

    PubMed

    Levy, Yonata; Ebstein, Richard P

    2009-06-01

    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 the biological level, a rather urgent task facing behavioral scientists involves a reconsideration of the role that clinical syndromes play in psychological theorizing, as well as in research into the biological basis of cognition and personality. Syndrome heterogeneity, cross-syndrome similarities and syndrome comorbidities question the relevance of syndromes to biological research. It is suggested that the search for brain endophenotypes, intermediate between genes and behavior, should be based on cross-syndrome, trait classification. Cohort selection should rest on behavioral homogeneity, enabling, when necessary, syndrome heterogeneity. PMID:19175806

  14. The Autism-Spectrum Quotient and Visual Search: Shallow and Deep Autistic Endophenotypes.

    PubMed

    Gregory, B L; Plaisted-Grant, K C

    2016-05-01

    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 performance on perceptual tasks in high-AQ individuals as observed in autism. We question whether the similarity in performance by high-AQ individuals and autistics reflects the same underlying perceptual cause in the context of two visual search tasks administered to a large sample of typical individuals assessed for AQ. Our results indicate otherwise and that deploying the AQ as a proxy for autism introduces unsubstantiated assumptions about high-AQ individuals, the endophenotypes they express, and their relationship to Autistic Spectrum Conditions (ASC) individuals. PMID:24077740

  15. 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. PMID:26972967

  16. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

    PubMed Central

    Yamasaki, Nobuyuki; Maekawa, Motoko; Kobayashi, Katsunori; Kajii, Yasushi; Maeda, Jun; Soma, Miho; Takao, Keizo; Tanda, Koichi; Ohira, Koji; Toyama, Keiko; Kanzaki, Kouji; Fukunaga, Kohji; Sudo, Yusuke; Ichinose, Hiroshi; Ikeda, Masashi; Iwata, Nakao; Ozaki, Norio; Suzuki, Hidenori; Higuchi, Makoto; Suhara, Tetsuya; Yuasa, Shigeki; Miyakawa, Tsuyoshi

    2008-01-01

    Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising

  17. Association of implementation of a public bicycle share program with intention and self-efficacy: The moderating role of socioeconomic status.

    PubMed

    Bélanger-Gravel, Ariane; Gauvin, Lise; Fuller, Daniel; Drouin, Louis

    2016-06-01

    This natural experiment examines the effect of a public bicycle share program on cognitions and investigates the moderating influence of socioeconomic status on this effect. Two cross-sectional population-based surveys were conducted. Intention and self-efficacy to use the public bicycle share program were assessed by questionnaire. A difference-in-differences approach was adopted using logistic regression analyses. A significant effect of the public bicycle share program was observed on intention (exposure × time; odds ratio = 3.41; 95% confidence interval: 1.50-7.73) and self-efficacy (exposure; odds ratio = 1.61; 95% confidence interval: 1.28-2.01). A positive effect on intention was observed among individuals with low income (exposure × time; odds ratio = 27.85; 95% confidence interval: 2.51-309.25). Implementing a public bicycle share program is associated with increases in intention and self-efficacy for public bicycle share use, although some social inequalities persist. PMID:25104776

  18. You Say Potato, I Say Potato: Problems Associated with the Lack of Shared Meaning in Instruction and Learning.

    ERIC Educational Resources Information Center

    Stork, Steve; Sanders, Stephen W.

    2000-01-01

    Physical educators and their students often perceive physical education differently. Lack of shared meaning can negatively affect instruction, participation, and learning. Teachers often incorrectly assume that differing responses to instruction reflect off-task behavior. The paper examines the issue, presents implications for teaching and teacher…

  19. Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part I: Neurophysiology.

    PubMed

    Thibaut, Florence; Boutros, Nash N; Jarema, Marek; Oranje, Bob; Hasan, Alkomiet; Daskalakis, Zafiris Jeffrey; Wichniak, Adam; Schmitt, Andrea; Riederer, Peter; Falkai, Peter

    2015-01-01

    The neurophysiological components that have been proposed as biomarkers or as endophenotypes for schizophrenia can be measured through electroencephalography (EEG) and magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), polysomnography (PSG), registration of event-related potentials (ERPs), assessment of smooth pursuit eye movements (SPEM) and antisaccade paradigms. Most of them demonstrate deficits in schizophrenia, show at least moderate stability over time and do not depend on clinical status, which means that they fulfil the criteria as valid endophenotypes for genetic studies. Deficits in cortical inhibition and plasticity measured using non-invasive brain stimulation techniques seem promising markers of outcome and prognosis. However the utility of these markers as biomarkers for predicting conversion to psychosis, response to treatments, or for tracking disease progression needs to be further studied. PMID:26213111

  20. Performance of Verbal Fluency as an Endophenotype in Patients with Familial versus Sporadic Schizophrenia and Their Parents

    PubMed Central

    Liang, Sugai; Deng, Wei; Wang, Qiang; Ma, Xiaohong; Li, Mingli; Brown, Matthew R. G.; Hu, Xun; Li, Xinmin; Greenshaw, Andrew J.; Li, Tao

    2016-01-01

    What’s the neurocognitive deficit as an endophenotype to familial schizophrenia? Here, we investigate the neurocognitive endophenotype in first-episode patients with familial schizophrenia (FS) and sporadic schizophrenia (SS), and their parents. 98 FS patients and their 105 parents; 190 SS patients and their 207 parents; 195 controls matched with patients, and 190 controls matched with the patients’ parents, were assessed with the short version of the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), the immediate and delayed logical memory tests from the Wechsler Memory Scale-Revised in China (WMS-RC), the Verbal Fluency Test (VFT), the Trail Making Test Parts A and B-Modified (TMA, TMB-M), and the Modified Wisconsin Card Sorting Test (WCST-M). The results showed that with age, gender, and education as covariates, after controlling for false discovery rates, the FS group and their parent group performed worse than the SS group and their parent group on VFT. No significant differences were found for other neurocognitive tests between the FS and SS patient groups, and their respective parent groups. Our findings suggest the patients with familial and sporadic schizophrenia and their respective parent groups may have a different genetic predisposition in relation to a cognitive endophenotype. PMID:27581658

  1. Performance of Verbal Fluency as an Endophenotype in Patients with Familial versus Sporadic Schizophrenia and Their Parents.

    PubMed

    Liang, Sugai; Deng, Wei; Wang, Qiang; Ma, Xiaohong; Li, Mingli; Brown, Matthew R G; Hu, Xun; Li, Xinmin; Greenshaw, Andrew J; Li, Tao

    2016-01-01

    What's the neurocognitive deficit as an endophenotype to familial schizophrenia? Here, we investigate the neurocognitive endophenotype in first-episode patients with familial schizophrenia (FS) and sporadic schizophrenia (SS), and their parents. 98 FS patients and their 105 parents; 190 SS patients and their 207 parents; 195 controls matched with patients, and 190 controls matched with the patients' parents, were assessed with the short version of the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC), the immediate and delayed logical memory tests from the Wechsler Memory Scale-Revised in China (WMS-RC), the Verbal Fluency Test (VFT), the Trail Making Test Parts A and B-Modified (TMA, TMB-M), and the Modified Wisconsin Card Sorting Test (WCST-M). The results showed that with age, gender, and education as covariates, after controlling for false discovery rates, the FS group and their parent group performed worse than the SS group and their parent group on VFT. No significant differences were found for other neurocognitive tests between the FS and SS patient groups, and their respective parent groups. Our findings suggest the patients with familial and sporadic schizophrenia and their respective parent groups may have a different genetic predisposition in relation to a cognitive endophenotype. PMID:27581658

  2. Shared Intentionality

    ERIC Educational Resources Information Center

    Tomasello, Michael; Carpenter, Malinda

    2007-01-01

    We argue for the importance of processes of shared intentionality in children's early cognitive development. We look briefly at four important social-cognitive skills and how they are transformed by shared intentionality. In each case, we look first at a kind of individualistic version of the skill--as exemplified most clearly in the behavior of…

  3. The Broad Autism (Endo)Phenotype: Neurostructural and Neurofunctional Correlates in Parents of Individuals with Autism Spectrum Disorders.

    PubMed

    Billeci, Lucia; Calderoni, Sara; Conti, Eugenia; Gesi, Camilla; Carmassi, Claudia; Dell'Osso, Liliana; Cioni, Giovanni; Muratori, Filippo; Guzzetta, Andrea

    2016-01-01

    Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with an early-onset and a strong genetic component in their pathogenesis. According to genetic and epidemiological data, ASD relatives present personality traits similar to, but not as severe as the defining features of ASD, which have been indicated as the "Broader Autism Phenotype" (BAP). BAP features seem to be more prevalent in first-degree relatives of individuals with ASD than in the general population. Characterizing brain profiles of relatives of autistic probands may help to understand ASD endophenotype. The aim of this review was to provide an up-to-date overview of research findings on the neurostructural and neurofunctional substrates in parents of individuals with ASD (pASD). The primary hypothesis was that, like for the behavioral profile, the pASD express an intermediate neurobiological pattern between ASD individuals and healthy controls. The 13 reviewed studies evaluated structural magnetic resonance imaging (MRI) brain volumes, chemical signals using magnetic resonance spectroscopy (MRS), task-related functional activation by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or magnetoencephalography (MEG) in pASD.The studies showed that pASD are generally different from healthy controls at a structural and functional level despite often not behaviorally impaired. More atypicalities in neural patterns of pASD seem to be associated with higher scores at BAP assessment. Some of the observed atypicalities are the same of the ASD probands. In addition, the pattern of neural correlates in pASD resembles that of adult individuals with ASD, or it is specific, possibly due to a compensatory mechanism. Future studies should ideally include a group of pASD and HC with their ASD and non-ASD probands respectively. They should subgrouping the pASD according to the BAP scores, considering gender as a possible confounding factor, and correlating these scores to

  4. Executive Cognitive Dysfunction and ADHD in Cocaine Dependence: Searching for a Common Cognitive Endophenotype for Addictive Disorders

    PubMed Central

    Cunha, Paulo Jannuzzi; Gonçalves, Priscila Dib; Ometto, Mariella; dos Santos, Bernardo; Nicastri, Sergio; Busatto, Geraldo F.; de Andrade, Arthur Guerra

    2013-01-01

    Background: Cocaine-dependent individuals (CDI) present executive cognitive function (ECF) deficits, but the impact of psychiatric comorbidities such as Attention-Deficit Hyperactivity Disorder (ADHD) on neuropsychological functioning is still poorly understood. The aim of this study was to investigate if CDI with ADHD (CDI + ADHD) would have a distinct pattern of executive functioning when compared with CDI without ADHD (CDI). Methods: We evaluated 101 adults, including 69 cocaine-dependent subjects (divided in CDI and CDI + ADHD) and 32 controls. ECF domains were assessed with Digits Forward (DF), Digits Backward (DB), Stroop Color Word Test (SCWT), the Wisconsin Card Sorting Test (WCST), and the Frontal Assessment Battery (FAB). DSM-IV criteria for ADHD were used for diagnosis and previous ADHD symptoms (in the childhood) were retrospectively assessed by the Wender-Utah Rating Scale (WURS). Results: There were no significant differences between CDI + ADHD, CDI, and controls in estimated intellectual quotient (IQ), socioeconomic background, education (in years), and pre-morbid IQ (p > 0.05). SCWT and WCST scores did not differ across groups (p > 0.05). Nevertheless, CDI and CDI + ADHD performed more poorly than controls in total score of the FAB (p < 0.05). Also, CDI + ADHD did worse than CDI on DF (F = 4.756, p = 0.011), DB (F = 8.037, p = 0.001), Conceptualization/FAB (F = 4.635, p = 0.012), and Mental flexibility/FAB (F = 3.678, p = 0.029). We did not find correlations between cocaine-use variables and neuropsychological functioning, but previous ADHD symptoms assessed by WURS were negatively associated with DF (p = 0.016) and with the total score of the FAB (p = 0.017). Conclusion: CDI + ADHD presented more pronounced executive alterations than CDI and CDI exhibited poorer cognitive functioning than controls. Pre-existing ADHD symptoms may have a significant negative impact on

  5. The Broad Autism (Endo)Phenotype: Neurostructural and Neurofunctional Correlates in Parents of Individuals with Autism Spectrum Disorders

    PubMed Central

    Billeci, Lucia; Calderoni, Sara; Conti, Eugenia; Gesi, Camilla; Carmassi, Claudia; Dell'Osso, Liliana; Cioni, Giovanni; Muratori, Filippo; Guzzetta, Andrea

    2016-01-01

    Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with an early-onset and a strong genetic component in their pathogenesis. According to genetic and epidemiological data, ASD relatives present personality traits similar to, but not as severe as the defining features of ASD, which have been indicated as the “Broader Autism Phenotype” (BAP). BAP features seem to be more prevalent in first-degree relatives of individuals with ASD than in the general population. Characterizing brain profiles of relatives of autistic probands may help to understand ASD endophenotype. The aim of this review was to provide an up-to-date overview of research findings on the neurostructural and neurofunctional substrates in parents of individuals with ASD (pASD). The primary hypothesis was that, like for the behavioral profile, the pASD express an intermediate neurobiological pattern between ASD individuals and healthy controls. The 13 reviewed studies evaluated structural magnetic resonance imaging (MRI) brain volumes, chemical signals using magnetic resonance spectroscopy (MRS), task-related functional activation by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or magnetoencephalography (MEG) in pASD.The studies showed that pASD are generally different from healthy controls at a structural and functional level despite often not behaviorally impaired. More atypicalities in neural patterns of pASD seem to be associated with higher scores at BAP assessment. Some of the observed atypicalities are the same of the ASD probands. In addition, the pattern of neural correlates in pASD resembles that of adult individuals with ASD, or it is specific, possibly due to a compensatory mechanism. Future studies should ideally include a group of pASD and HC with their ASD and non-ASD probands respectively. They should subgrouping the pASD according to the BAP scores, considering gender as a possible confounding factor, and correlating these scores

  6. Facial Characteristics and Olfactory Dysfunction: Two Endophenotypes Related to Nonsyndromic Cleft Lip and/or Palate

    PubMed Central

    Roosenboom, J.; Saey, I.; Peeters, H.; Devriendt, K.; Claes, P.; Hens, G.

    2015-01-01

    Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first-degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways. PMID:26064961

  7. Developmental white matter microstructure in autism phenotype and corresponding endophenotype during adolescence

    PubMed Central

    Lisiecka, D M; Holt, R; Tait, R; Ford, M; Lai, M-C; Chura, L R; Baron-Cohen, S; Spencer, M D; Suckling, J

    2015-01-01

    During adolescence, white matter microstructure undergoes an important stage of development. It is hypothesized that the alterations of brain connectivity that have a key role in autism spectrum conditions (ASCs) may interact with the development of white matter microstructure. This interaction may be present beyond the phenotype of autism in siblings of individuals with ASC, who are 10 to 20 times more likely to develop certain forms of ASC. We use diffusion tensor imaging to examine how white matter microstructure measurements correlate with age in typically developing individuals, and how this correlation differs in n=43 adolescents with ASC and their n=38 siblings. Correlations observed in n=40 typically developing individuals match developmental changes noted in previous longitudinal studies. In comparison, individuals with ASC display weaker negative correlation between age and mean diffusivity in a broad area centred in the right superior longitudinal fasciculus. These differences may be caused either by increased heterogeneity in ASC or by temporal alterations in the group's developmental pattern. Siblings of individuals with ASC also show diminished negative correlation between age and one component of mean diffusivity—second diffusion eigenvalue—in the right superior longitudinal fasciculus. As the observed differences match for location and correlation directionality in our comparison of typically developing individuals to those with ASC and their siblings, we propose that these alterations constitute a part of the endophenotype of autism. PMID:25781228

  8. 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

  9. 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

  10. Animal Models of Maladaptive Traits: Disorders in Sensorimotor Gating and Attentional Quantifiable Responses as Possible Endophenotypes.

    PubMed

    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

  11. Shared Attention.

    PubMed

    Shteynberg, Garriy

    2015-09-01

    Shared attention is extremely common. In stadiums, public squares, and private living rooms, people attend to the world with others. Humans do so across all sensory modalities-sharing the sights, sounds, tastes, smells, and textures of everyday life with one another. The potential for attending with others has grown considerably with the emergence of mass media technologies, which allow for the sharing of attention in the absence of physical co-presence. In the last several years, studies have begun to outline the conditions under which attending together is consequential for human memory, motivation, judgment, emotion, and behavior. Here, I advance a psychological theory of shared attention, defining its properties as a mental state and outlining its cognitive, affective, and behavioral consequences. I review empirical findings that are uniquely predicted by shared-attention theory and discuss the possibility of integrating shared-attention, social-facilitation, and social-loafing perspectives. Finally, I reflect on what shared-attention theory implies for living in the digital world. PMID:26385997

  12. Simultaneous profiling of seed-associated bacteria and fungi reveals antagonistic interactions between microorganisms within a shared epiphytic microbiome on Triticum and Brassica seeds.

    PubMed

    Links, Matthew G; Demeke, Tigst; Gräfenhan, Tom; Hill, Janet E; Hemmingsen, Sean M; Dumonceaux, Tim J

    2014-04-01

    In order to address the hypothesis that seeds from ecologically and geographically diverse plants harbor characteristic epiphytic microbiota, we characterized the bacterial and fungal microbiota associated with Triticum and Brassica seed surfaces. The total microbial complement was determined by amplification and sequencing of a fragment of chaperonin 60 (cpn60). Specific microorganisms were quantified by qPCR. Bacteria and fungi corresponding to operational taxonomic units (OTU) that were identified in the sequencing study were isolated and their interactions examined. A total of 5477 OTU were observed from seed washes. Neither total epiphytic bacterial load nor community richness/evenness was significantly different between the seed types; 578 OTU were shared among all samples at a variety of abundances. Hierarchical clustering revealed that 203 were significantly different in abundance on Triticum seeds compared with Brassica. Microorganisms isolated from seeds showed 99-100% identity between the cpn60 sequences of the isolates and the OTU sequences from this shared microbiome. Bacterial strains identified as Pantoea agglomerans had antagonistic properties toward one of the fungal isolates (Alternaria sp.), providing a possible explanation for their reciprocal abundances on both Triticum and Brassica seeds. cpn60 enabled the simultaneous profiling of bacterial and fungal microbiota and revealed a core seed-associated microbiota shared between diverse plant genera. PMID:24444052

  13. Simultaneous profiling of seed-associated bacteria and fungi reveals antagonistic interactions between microorganisms within a shared epiphytic microbiome on Triticum and Brassica seeds

    PubMed Central

    Links, Matthew G; Demeke, Tigst; Gräfenhan, Tom; Hill, Janet E; Hemmingsen, Sean M; Dumonceaux, Tim J

    2014-01-01

    In order to address the hypothesis that seeds from ecologically and geographically diverse plants harbor characteristic epiphytic microbiota, we characterized the bacterial and fungal microbiota associated with Triticum and Brassica seed surfaces. The total microbial complement was determined by amplification and sequencing of a fragment of chaperonin 60 (cpn60). Specific microorganisms were quantified by qPCR. Bacteria and fungi corresponding to operational taxonomic units (OTU) that were identified in the sequencing study were isolated and their interactions examined. A total of 5477 OTU were observed from seed washes. Neither total epiphytic bacterial load nor community richness/evenness was significantly different between the seed types; 578 OTU were shared among all samples at a variety of abundances. Hierarchical clustering revealed that 203 were significantly different in abundance on Triticum seeds compared with Brassica. Microorganisms isolated from seeds showed 99–100% identity between the cpn60 sequences of the isolates and the OTU sequences from this shared microbiome. Bacterial strains identified as Pantoea agglomerans had antagonistic properties toward one of the fungal isolates (Alternaria sp.), providing a possible explanation for their reciprocal abundances on both Triticum and Brassica seeds. cpn60 enabled the simultaneous profiling of bacterial and fungal microbiota and revealed a core seed-associated microbiota shared between diverse plant genera. PMID:24444052

  14. Socialization of Early Prosocial Behavior: Parents’ Talk about Emotions is Associated with Sharing and Helping in Toddlers

    PubMed Central

    Brownell, Celia A.; Svetlova, Margarita; Anderson, Ranita; Nichols, Sara R.; Drummond, Jesse

    2012-01-01

    What role does socialization play in the origins of prosocial behavior? We examined one potential socialization mechanism, parents’ discourse about others’ emotions with very young children in whom prosocial behavior is still nascent. Two studies are reported, one of sharing in 18- and 24-month-olds (n = 29), and one of instrumental and empathy-based helping in 18- and 30-month-olds (n = 62). In both studies, parents read age-appropriate picture books to their children and the content and structure of their emotion-related and internal state discourse were coded. Results showed that children who helped and shared more quickly and more often, especially in tasks that required more complex emotion understanding, had parents who more often asked them to label and explain the emotions depicted in the books. Moreover, it was parents’ elicitation of children’s talk about emotions rather than parents’ own production of emotion labels and explanations that explained children’s prosocial behavior, even after controlling for age. Thus, it is the quality, not the quantity, of parents’ talk about emotions with their toddlers that matters for early prosocial behavior. PMID:23264753

  15. A Pleiotropy-Informed Bayesian False Discovery Rate Adapted to a Shared Control Design Finds New Disease Associations From GWAS Summary Statistics

    PubMed Central

    Liley, James; Wallace, Chris

    2015-01-01

    Genome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with many traits and diseases. However, at existing sample sizes, these variants explain only part of the estimated heritability. Leverage of GWAS results from related phenotypes may improve detection without the need for larger datasets. The Bayesian conditional false discovery rate (cFDR) constitutes an upper bound on the expected false discovery rate (FDR) across a set of SNPs whose p values for two diseases are both less than two disease-specific thresholds. Calculation of the cFDR requires only summary statistics and have several advantages over traditional GWAS analysis. However, existing methods require distinct control samples between studies. Here, we extend the technique to allow for some or all controls to be shared, increasing applicability. Several different SNP sets can be defined with the same cFDR value, and we show that the expected FDR across the union of these sets may exceed expected FDR in any single set. We describe a procedure to establish an upper bound for the expected FDR among the union of such sets of SNPs. We apply our technique to pairwise analysis of p values from ten autoimmune diseases with variable sharing of controls, enabling discovery of 59 SNP-disease associations which do not reach GWAS significance after genomic control in individual datasets. Most of the SNPs we highlight have previously been confirmed using replication studies or larger GWAS, a useful validation of our technique; we report eight SNP-disease associations across five diseases not previously declared. Our technique extends and strengthens the previous algorithm, and establishes robust limits on the expected FDR. This approach can improve SNP detection in GWAS, and give insight into shared aetiology between phenotypically related conditions. PMID:25658688

  16. 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

    2015-12-01

    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

  17. 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

  18. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.

    PubMed

    Ellinghaus, David; Jostins, Luke; Spain, Sarah L; Cortes, Adrian; Bethune, Jörn; Han, Buhm; Park, Yu Rang; Raychaudhuri, Soumya; Pouget, Jennie G; Hübenthal, Matthias; Folseraas, Trine; Wang, Yunpeng; Esko, Tonu; Metspalu, Andres; Westra, Harm-Jan; Franke, Lude; Pers, Tune H; Weersma, Rinse K; Collij, Valerie; D'Amato, Mauro; Halfvarson, Jonas; Jensen, Anders Boeck; Lieb, Wolfgang; Degenhardt, Franziska; Forstner, Andreas J; Hofmann, Andrea; Schreiber, Stefan; Mrowietz, Ulrich; Juran, Brian D; Lazaridis, Konstantinos N; Brunak, Søren; Dale, Anders M; Trembath, Richard C; Weidinger, Stephan; Weichenthal, Michael; Ellinghaus, Eva; Elder, James T; Barker, Jonathan N W N; Andreassen, Ole A; McGovern, Dermot P; Karlsen, Tom H; Barrett, Jeffrey C; Parkes, Miles; Brown, Matthew A; Franke, Andre

    2016-05-01

    We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes. PMID:26974007

  19. A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12

    PubMed Central

    Massey, Jonathan; Dietschi, Elisabeth; Kierczak, Marcin; Lund-Ziener, Martine; Sundberg, Katarina; Thoresen, Stein Istre; Kämpe, Olle; Andersson, Göran; Ollier, William E. R.; Hedhammar, Åke; Leeb, Tosso; Lindblad-Toh, Kerstin; Kennedy, Lorna J.; Lingaas, Frode; Rosengren Pielberg, Gerli

    2015-01-01

    Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds—the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10-11). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018–5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans. PMID:26261983

  20. UK community prevalence of knee chondrocalcinosis: evidence that correlation with osteoarthritis is through a shared association with osteophyte

    PubMed Central

    Neame, R; Carr, A; Muir, K; Doherty, M

    2003-01-01

    Objectives: (1) To estimate the prevalence of chondrocalcinosis (CC) in the community and to characterise its compartmental distribution within the knee. (2) To investigate the associations between CC and individual radiographic features of osteoarthritis (OA) at the tibiofemoral joint (TFJ) and patellofemoral joint (PFJ). Methods: From three community questionnaire studies investigating the prevalence of knee pain, standing anteroposterior and skyline radiographs were obtained on 1727 subjects (1084 women, 643 men; mean age 63.7; 999 (58%) with knee pain). A single observer recorded the presence and site of CC and graded osteophyte and joint space narrowing (JSN) using a line atlas. "OA" was globally defined as the presence of definite osteophyte and definite JSN. Minimum joint space width (JSW) was measured to 0.1 mm with a metred dial caliper Results: (1) The crude prevalence of CC was 7.0% (95% confidence interval (CI) 5.8 to 8.2). This showed a strong association with age. The age adjusted odds ratio (aOR) for CC in women v men was 0.79 (95% CI 0.52 to 1.12). The age, sex, and knee pain standardised estimate for those aged >40 in Nottingham, UK was 4.5%. Patellofemoral CC was seen in only nine cases, all with tibiofemoral CC. (2) The age-sex aOR for the association between CC and OA was 2.08 at the PFJ (1.38 to 3.12) and 2.00 (1.11 to 3.60) at the TFJ. There was no association between measured JSW and CC at either the PFJ or TFJ. Both total osteophyte score and total number of sites with osteophyte were positively associated with CC; aOR for the upper quartile was 2.40 (1.48 to 3.90) and 1.94 (1.15 to 3.26), respectively. An association between CC and diuretic use was also demonstrated (aOR=2.07, 1.02 to 4.19). Conclusions: In this large UK community study the age, sex, and knee pain adjusted prevalence of CC was 4.5%. There was a strong age association, but no sex predisposition. Patellofemoral CC was uncommon. An association between OA and CC was confirmed

  1. Metabolomics of trauma-associated death: shared and fluid-specific features of human plasma vs lymph

    PubMed Central

    D’Alessandro, Angelo; Nemkov, Travis; Moore, Hunter B.; Moore, Ernest E.; Wither, Matthew; Nydam, Trevor; Slaughter, Annie; Silliman, Christopher C.; Banerjee, Anirban; Hansen, Kirk C.

    2016-01-01

    Background Water-soluble components in mesenteric lymph have been implicated in the pathophysiology of acute lung injury and distal organ failure following trauma and haemorrhagic shock. Proteomics analyses have recently shown similarities and specificities of post-trauma/haemorrhagic shock lymph and plasma. We hypothesise that the metabolic phenotype of post-trauma/haemorrhagic shock mesenteric lymph and plasma share common metabolites, but are also characterised by unique features that differentiate these two fluids. Materials and methods Matched samples were collected from 5 brain-dead organ donors who had suffered extreme trauma/haemorrhagic shock. Metabolomics analyses were performed through ultra-high performance liquid chromatography mass spectrometry. Results Overall, 269 metabolites were identified in either fluid. Despite significant overlapping, metabolic phenotypes of matched lymph or plasma from the same patients could be used to discriminate sample fluid or biological patient/traumatic-injury origin. Metabolites showing relatively high levels in both fluids included markers of haemolysis and cell lysis secondary to tissue injury. Discussion High positive correlations were observed between the quantitative levels of markers of systemic metabolic derangement following traumatic/haemorrhagic hypoxaemia, such as succinate, oxoproline, urate and fatty acids. These metabolites might contribute to coagulopathies of trauma and neutrophil priming driving acute lung injury. Future studies will investigate whether the observed compositional specificities mirror functional or pathological adaptations after trauma and haemorrhage. PMID:27177401

  2. Striatal shape abnormalities as novel neurodevelopmental endophenotypes in schizophrenia: a longitudinal study.

    PubMed

    Chakravarty, M Mallar; Rapoport, Judith L; Giedd, Jay N; Raznahan, Armin; Shaw, Philip; Collins, D Louis; Lerch, Jason P; Gogtay, Nitin

    2015-04-01

    There are varying, often conflicting, reports with respect to altered striatal volume and morphometry in the major psychoses due to the influences of antipsychotic medications on striatal volume. Thus, disassociating disease effects from those of medication become exceedingly difficult. For the first time, using a longitudinally studied sample of structural magnetic resonance images from patients with childhood onset schizophrenia (COS; neurobiologically contiguous with the adult onset form of schizophrenia), their nonpsychotic siblings (COSSIBs), and novel shape mapping algorithms that are volume independent, we report the familial contribution of striatal morphology in schizophrenia. The results of our volumetric analyses demonstrate age-related increases in overall striatal volumes specific only to COS. However, both COS and COSSIBs showed overlapping shape differences in the striatal head, which normalized in COSSIBs by late adolescence. These results mirror previous studies from our group, demonstrating cortical thickness deficits in COS and COSSIBs as these deficits normalize in COSSIBs in the same age range as our striatal findings. Finally, there is a single region of nonoverlapping outward displacement in the dorsal aspect of the caudate body, potentially indicative of a response to medication. Striatal shape may be considered complimentary to volume as an endophenotype, and, in some cases may provide information that is not detectable using standard volumetric techniques. Our striatal shape findings demonstrate the striking localization of abnormalities in striatal the head. The neuroanatomical localization of these findings suggest the presence of abnormalities in the striatal-prefrontal circuits in schizophrenia and resilience mechanisms in COSSIBs with age dependent normalization. PMID:25504933

  3. Magnetic resonance imaging of the endophenotype of a novel familial Möbius-like syndrome

    PubMed Central

    Dumars, Sean; Andrews, Caroline; Chan, Wai-Man; Engle, Elizabeth C.; Demer, Joseph L.

    2008-01-01

    Introduction Möbius’ syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius’ syndrome. Methods We examined three related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes 2 mm thick. Subarachnoid cranial nerves were imaged in planes 1 mm thick. Linkage and mutation analysis were performed to determine if the pedigree harbored mutations in four candidate genes. Results In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals. Conclusions Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius’ syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit, but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius’ syndrome and other congenital cranial dysinnervation disorders (CCDDs). Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the CCDDs defined thus far, rather than a global brainstem insult. PMID:18455936

  4. 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

  5. Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers.

    PubMed

    Shah, Tina; Zabaneh, Delilah; Gaunt, Tom; Swerdlow, Daniel I; Shah, Sonia; Talmud, Philippa J; Day, Ian N; Whittaker, John; Holmes, Michael V; Sofat, Reecha; Humphries, Steve E; Kivimaki, Mika; Kumari, Meena; Hingorani, Aroon D; Casas, Juan P

    2013-04-01

    BACKGROUND- Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. METHODS AND RESULTS- We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women's Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10(-5)), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r(2)>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10(-5)). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410(-22)) in Whitehall II and 1% (P=1.910(-8)) in British Women's Heart and Health Studies. CONCLUSIONS- Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases. PMID:23505291

  6. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects

    PubMed Central

    Peyrot, WJ; Lee, SH; Milaneschi, Y; Abdellaoui, A; Byrne, EM; Esko, T; de Geus, EJC; Hemani, G; Hottenga, JJ; Kloiber, S; Levinson, DF; Lucae, S; Martin, NG; Medland, SE; Metspalu, A; Milani, L; Noethen, MM; Potash, JB; Rietschel, M; Rietveld, CA; Ripke, S; Shi, J; Willemsen, G; Zhu, Z; Boomsma, DI; Wray, NR; Penninx, BWJH

    2015-01-01

    An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9,662 Major Depressive Disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 [0.75–0.82] per standard deviation increase in EA. With data of 884,105 autosomal common SNPs, three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on 120,000 subjects) and MDD (using a ten-fold leave-one-out procedure in the current sample) (ii) bivariate Genomic-Relationship-Matrix Restricted Maximum Likelihood (GREML), and (iii) SNP effect concordance analysis (SECA). With these methods we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not due to measurable pleiotropic genetic effects, which suggests that environmental factors could be involved such as, for example, socioeconomic status. PMID:25917368

  7. The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.

    PubMed

    Peyrot, W J; Lee, S H; Milaneschi, Y; Abdellaoui, A; Byrne, E M; Esko, T; de Geus, E J C; Hemani, G; Hottenga, J J; Kloiber, S; Levinson, D F; Lucae, S; Martin, N G; Medland, S E; Metspalu, A; Milani, L; Noethen, M M; Potash, J B; Rietschel, M; Rietveld, C A; Ripke, S; Shi, J; Willemsen, G; Zhu, Z; Boomsma, D I; Wray, N R; Penninx, B W J H

    2015-06-01

    An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. PMID:25917368

  8. Shared genes related to aggression, rather than chemical communication, are associated with reproductive dominance in paper wasps (Polistes metricus)

    PubMed Central

    2014-01-01

    Background In social groups, dominant individuals may socially inhibit reproduction of subordinates using aggressive interactions or, in the case of highly eusocial insects, pheromonal communication. It has been hypothesized these two modes of reproductive inhibition utilize conserved pathways. Here, we use a comparative framework to investigate the chemical and genomic underpinnings of reproductive dominance in the primitively eusocial wasp Polistes metricus. Our goals were to first characterize transcriptomic and chemical correlates of reproductive dominance and second, to test whether dominance-associated mechanisms in paper wasps overlapped with aggression or pheromone-related gene expression patterns in other species. To explore whether conserved molecular pathways relate to dominance, we compared wasp transcriptomic data to previous studies of gene expression associated with pheromonal communication and queen-worker differences in honey bees, and aggressive behavior in bees, Drosophila, and mice. Results By examining dominant and subordinate females from queen and worker castes in early and late season colonies, we found that cuticular hydrocarbon profiles and genome-wide patterns of brain gene expression were primarily associated with season/social environment rather than dominance status. In contrast, gene expression patterns in the ovaries were associated primarily with caste and ovary activation. Comparative analyses suggest genes identified as differentially expressed in wasp brains are not related to queen pheromonal communication or caste in bees, but were significantly more likely to be associated with aggression in other insects (bees, flies), and even a mammal (mice). Conclusions This study provides the first comprehensive chemical and molecular analysis of reproductive dominance in paper wasps. We found little evidence for a chemical basis for reproductive dominance in P. metricus, and our transcriptomic analyses suggest that different pathways

  9. Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and the rhinoviruses.

    PubMed

    Oberste, M Steven; Maher, Kaija; Schnurr, David; Flemister, Mary R; Lovchik, Judith C; Peters, Heather; Sessions, Wendy; Kirk, Carol; Chatterjee, Nando; Fuller, Susan; Hanauer, J Michael; Pallansch, Mark A

    2004-09-01

    Enterovirus (EV) 68 was originally isolated in California in 1962 from four children with respiratory illness. Since that time, reports of EV68 isolation have been very uncommon. Between 1989 and 2003, 12 additional EV68 clinical isolates were identified and characterized, all of which were obtained from respiratory specimens of patients with respiratory tract illnesses. No EV68 isolates from enteric specimens have been identified from these same laboratories. These recent isolates, as well as the original California strains and human rhinovirus (HRV) 87 (recently shown to be an isolate of EV68 and distinct from the other human rhinoviruses), were compared by partial nucleotide sequencing in three genomic regions (partial sequencing of the 5'-non-translated region and 3D polymerase gene, and complete sequencing of the VP1 capsid gene). The EV68 isolates, including HRV87, were monophyletic in all three regions of the genome. EV68 isolates and HRV87 grew poorly at 37 degrees C relative to growth at 33 degrees C and their titres were reduced by incubation at pH 3.0, whereas the control enterovirus, echovirus 11, grew equally well at 33 and 37 degrees C and its titre was not affected by treatment at pH 3.0. Acid lability and a lower optimum growth temperature are characteristic features of the human rhinoviruses. It is concluded that EV68 is primarily an agent of respiratory disease and that it shares important biological and molecular properties with both the enteroviruses and the rhinoviruses. PMID:15302951

  10. Shared Cataloguing.

    ERIC Educational Resources Information Center

    Westby, Barbara M.

    The National Program for Acquisition and Cataloging (NPAC) authorized under Title IIC of the Higher Education Act of 1965 is called the Shared Cataloging Program. Under this Act the Library of Congress is authorized to: (1) acquire for its own collections all materials currently published throughout the world that are of value to scholarship and…

  11. Sharing the slope: depth partitioning of agariciid corals and associated Symbiodinium across shallow and mesophotic habitats (2-60 m) on a Caribbean reef

    PubMed Central

    2013-01-01

    Background Scleractinian corals and their algal endosymbionts (genus Symbiodinium) exhibit distinct bathymetric distributions on coral reefs. Yet, few studies have assessed the evolutionary context of these ecological distributions by exploring the genetic diversity of closely related coral species and their associated Symbiodinium over large depth ranges. Here we assess the distribution and genetic diversity of five agariciid coral species (Agaricia humilis, A. agaricites, A. lamarcki, A. grahamae, and Helioseris cucullata) and their algal endosymbionts (Symbiodinium) across a large depth gradient (2-60 m) covering shallow to mesophotic depths on a Caribbean reef. Results The five agariciid species exhibited distinct depth distributions, and dominant Symbiodinium associations were found to be species-specific, with each of the agariciid species harbouring a distinct ITS2-DGGE profile (except for a shared profile between A. lamarcki and A. grahamae). Only A. lamarcki harboured different Symbiodinium types across its depth distribution (i.e. exhibited symbiont zonation). Phylogenetic analysis (atp6) of the coral hosts demonstrated a division of the Agaricia genus into two major lineages that correspond to their bathymetric distribution (“shallow”: A. humilis / A. agaricites and “deep”: A. lamarcki / A. grahamae), highlighting the role of depth-related factors in the diversification of these congeneric agariciid species. The divergence between “shallow” and “deep” host species was reflected in the relatedness of the associated Symbiodinium (with A. lamarcki and A. grahamae sharing an identical Symbiodinium profile, and A. humilis and A. agaricites harbouring a related ITS2 sequence in their Symbiodinium profiles), corroborating the notion that brooding corals and their Symbiodinium are engaged in coevolutionary processes. Conclusions Our findings support the hypothesis that the depth-related environmental gradient on reefs has played an important

  12. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.

    PubMed

    Liu, Jimmy Z; van Sommeren, Suzanne; Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Daryani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph J Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Franke, Andre; Alizadeh, Behrooz Z; Parkes, Miles; B K, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2015-09-01

    Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations. PMID:26192919

  13. Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses

    PubMed Central

    Kapeli, Katannya; Pratt, Gabriel A.; Vu, Anthony Q.; Hutt, Kasey R.; Martinez, Fernando J.; Sundararaman, Balaji; Batra, Ranjan; Freese, Peter; Lambert, Nicole J.; Huelga, Stephanie C.; Chun, Seung J.; Liang, Tiffany Y.; Chang, Jeremy; Donohue, John P.; Shiue, Lily; Zhang, Jiayu; Zhu, Haining; Cambi, Franca; Kasarskis, Edward; Hoon, Shawn; Ares Jr., Manuel; Burge, Christopher B.; Ravits, John; Rigo, Frank; Yeo, Gene W.

    2016-01-01

    The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3′ untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism. PMID:27378374

  14. The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.

    PubMed

    Kottyan, Leah C; Zoller, Erin E; Bene, Jessica; Lu, Xiaoming; Kelly, Jennifer A; Rupert, Andrew M; Lessard, Christopher J; Vaughn, Samuel E; Marion, Miranda; Weirauch, Matthew T; Namjou, Bahram; Adler, Adam; Rasmussen, Astrid; Glenn, Stuart; Montgomery, Courtney G; Hirschfield, Gideon M; Xie, Gang; Coltescu, Catalina; Amos, Chris; Li, He; Ice, John A; Nath, Swapan K; Mariette, Xavier; Bowman, Simon; Rischmueller, Maureen; Lester, Sue; Brun, Johan G; Gøransson, Lasse G; Harboe, Erna; Omdal, Roald; Cunninghame-Graham, Deborah S; Vyse, Tim; Miceli-Richard, Corinne; Brennan, Michael T; Lessard, James A; Wahren-Herlenius, Marie; Kvarnström, Marika; Illei, Gabor G; Witte, Torsten; Jonsson, Roland; Eriksson, Per; Nordmark, Gunnel; Ng, Wan-Fai; Anaya, Juan-Manuel; Rhodus, Nelson L; Segal, Barbara M; Merrill, Joan T; James, Judith A; Guthridge, Joel M; Scofield, R Hal; Alarcon-Riquelme, Marta; Bae, Sang-Cheol; Boackle, Susan A; Criswell, Lindsey A; Gilkeson, Gary; Kamen, Diane L; Jacob, Chaim O; Kimberly, Robert; Brown, Elizabeth; Edberg, Jeffrey; Alarcón, Graciela S; Reveille, John D; Vilá, Luis M; Petri, Michelle; Ramsey-Goldman, Rosalind; Freedman, Barry I; Niewold, Timothy; Stevens, Anne M; Tsao, Betty P; Ying, Jun; Mayes, Maureen D; Gorlova, Olga Y; Wakeland, Ward; Radstake, Timothy; Martin, Ezequiel; Martin, Javier; Siminovitch, Katherine; Moser Sivils, Kathy L; Gaffney, Patrick M; Langefeld, Carl D; Harley, John B; Kaufman, Kenneth M

    2015-01-15

    Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. PMID:25205108

  15. [Are the neuropsychological alterations in eating disorders endophenotypes of the disease? Review and state of the art].

    PubMed

    Idini, E; Marquez-Medina, D; Pifarre, J; Buj-Alvarez, I; Castan-Campanera, E

    2012-12-16

    INTRODUCTION. Recent studies have shown that alterations to the executive cognitive functions may be endophenotypes of eating disorders. AIM. To perform a critical review of the literature on neuropsychological alterations in patients with eating disorders and their first-degree relatives. DEVELOPMENT. We review the papers written in English and in Spanish indexed in Medline and PsycINFO over the last 10 years. We included abstracts of papers that have still not been published and search terms were crossed. Excluding some isolated clinical cases, we obtained 41 studies on patients with anorexia nervosa (n = 17), bulimia nervosa (n = 5), both (n = 13) or a non-specific eating disorder (n = 6). CONCLUSIONS. The studies reviewed display important limitations due to their heterogeneous methodology and small samples, which give rise to contradictory results. Most of them were conducted on anorexia nervosa. Cognitive rigidity seems to be more frequent in patients with anorexia and their relatives, and alterations in decision-making or central coherence is more often found in bulimia nervosa. There is evidence suggesting that the neuropsychological alterations found in eating disorders are endophenotypes of the disease. PMID:23233141

  16. 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

  17. 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. PMID:27143193

  18. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

    PubMed Central

    Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Dayani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; BK, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2016-01-01

    Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations. PMID:26192919

  19. Sharing Physician Notes Through an Electronic Portal is Associated With Improved Medication Adherence: Quasi-Experimental Study

    PubMed Central

    Darer, Jonathan; Tang, Xiaoqin; Thompson, Jason; Tusing, Lorraine; Fossa, Alan; Delbanco, Tom

    2015-01-01

    Background In surveys, interviews, and focus groups, patients taking medications and offered Web portal access to their primary care physicians’ (PCPs) notes report improved adherence to their regimens. However, objective confirmation has yet to be reported. Objective To evaluate the association between patient Internet portal access to primary care physician visit notes and medication adherence. Methods This study is a retrospective comparative analysis at one site of the OpenNotes quasi-experimental trial. The setting includes primary care practices at the Geisinger Health System (GHS) in Danville, Pennsylvania. Participants include patients 18 years of age or older with electronic portal access, GHS primary care physicians, and Geisinger health plan insurance, and taking at least one antihypertensive or antihyperlipidemic agent from March 2009 to June 2011. Starting in March 2010, intervention patients were invited and reminded to read their PCPs' notes. Control patients also had Web portal access throughout, but their PCPs' notes were not available. From prescription claims, adherence was assessed by using the proportion of days covered (PDC). Patients with a PDC ≥.80 were considered adherent and were compared across groups using generalized linear models. Results A total of 2147 patients (756 intervention participants, 35.21%; 1391 controls, 64.79%) were included in the analysis. Compared to those without access, patients invited to review notes were more adherent to antihypertensive medications—adherence rate 79.7% for intervention versus 75.3% for control group; adjusted risk ratio, 1.06 (95% CI 1.00-1.12). Adherence was similar among patient groups taking antihyperlipidemic agents—adherence rate 77.6% for intervention versus 77.3% for control group; adjusted risk ratio, 1.01 (95% CI 0.95-1.07). Conclusions Availability of notes following PCP visits was associated with improved adherence by patients prescribed antihypertensive, but not

  20. The high turnover Drosophila multidrug resistance-associated protein shares the biochemical features of its human orthologues.

    PubMed

    Szeri, Flóra; Iliás, Attila; Pomozi, Viola; Robinow, Steven; Bakos, Eva; Váradi, András

    2009-02-01

    DMRP, an ABC transporter encoded by the dMRP/CG6214 gene, is the Drosophila melanogaster orthologue of the "long" human multidrug resistance-associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP6/ABCC6, and MRP7/ABCC10). In order to provide a detailed biochemical characterisation we expressed DMRP in Sf9 insect cell membranes. We demonstrated DMRP as a functional orthologue of its human counterparts capable of transporting several human MRP substrates like beta-estradiol 17-beta-D-glucuronide, leukotriene C4, calcein, fluo3 and carboxydichlorofluorescein. Unexpectedly, we found DMRP to exhibit an extremely high turnover rate for the substrate transport as compared to its human orthologues. Furthermore, DMRP showed remarkably high basal ATPase activity (68-75 nmol Pi/mg membrane protein/min), which could be further stimulated by probenecid and the glutathione conjugate of N-ethylmaleimide. Surprisingly, this high level basal ATPase activity was inhibited by the transported substrates. We discussed this phenomenon in the light of a potential endogenous substrate (or activator) present in the Sf9 membrane. PMID:19059376

  1. 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.…

  2. Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases.

    PubMed

    Marzano, Angelo V; Ceccherini, Isabella; Gattorno, Marco; Fanoni, Daniele; Caroli, Francesco; Rusmini, Marta; Grossi, Alice; De Simone, Clara; Borghi, Orietta M; Meroni, Pier Luigi; Crosti, Carlo; Cugno, Massimo

    2014-12-01

    The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin. PMID:25501066

  3. Epileptic Electroencephalography Profile Associates with Attention Problems in Children with Fragile X Syndrome: Review and Case Series.

    PubMed

    Cowley, Benjamin; Kirjanen, Svetlana; Partanen, Juhani; Castrén, Maija L

    2016-01-01

    Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and a variant of autism spectrum disorder (ASD). The FXS population is quite heterogeneous with respect to comorbidities, which implies the need for a personalized medicine approach, relying on biomarkers or endophenotypes to guide treatment. There is evidence that quantitative electroencephalography (EEG) endophenotype-guided treatments can support increased clinical benefit by considering the patient's neurophysiological profile. We describe a case series of 11 children diagnosed with FXS, aged one to 14 years, mean 4.6 years. Case data are based on longitudinal clinically-observed reports by attending physicians for comorbid symptoms including awake and asleep EEG profiles. We tabulate the comorbid EEG symptoms in this case series, and relate them to the literature on EEG endophenotypes and associated treatment options. The two most common endophenotypes in the data were diffuse slow oscillations and epileptiform EEG, which have been associated with attention and epilepsy respectively. This observation agrees with reported prevalence of comorbid behavioral symptoms for FXS. In this sample of FXS children, attention problems were found in 37% (4 of 11), and epileptic seizures in 45% (5 of 11). Attention problems were found to associate with the epilepsy endophenotype. From the synthesis of this case series and literature review, we argue that the evidence-based personalized treatment approach, exemplified by neurofeedback, could benefit FXS children by focusing on observable, specific characteristics of comorbid disease symptoms. PMID:27462212

  4. Epileptic Electroencephalography Profile Associates with Attention Problems in Children with Fragile X Syndrome: Review and Case Series

    PubMed Central

    Cowley, Benjamin; Kirjanen, Svetlana; Partanen, Juhani; Castrén, Maija L.

    2016-01-01

    Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and a variant of autism spectrum disorder (ASD). The FXS population is quite heterogeneous with respect to comorbidities, which implies the need for a personalized medicine approach, relying on biomarkers or endophenotypes to guide treatment. There is evidence that quantitative electroencephalography (EEG) endophenotype-guided treatments can support increased clinical benefit by considering the patient's neurophysiological profile. We describe a case series of 11 children diagnosed with FXS, aged one to 14 years, mean 4.6 years. Case data are based on longitudinal clinically-observed reports by attending physicians for comorbid symptoms including awake and asleep EEG profiles. We tabulate the comorbid EEG symptoms in this case series, and relate them to the literature on EEG endophenotypes and associated treatment options. The two most common endophenotypes in the data were diffuse slow oscillations and epileptiform EEG, which have been associated with attention and epilepsy respectively. This observation agrees with reported prevalence of comorbid behavioral symptoms for FXS. In this sample of FXS children, attention problems were found in 37% (4 of 11), and epileptic seizures in 45% (5 of 11). Attention problems were found to associate with the epilepsy endophenotype. From the synthesis of this case series and literature review, we argue that the evidence-based personalized treatment approach, exemplified by neurofeedback, could benefit FXS children by focusing on observable, specific characteristics of comorbid disease symptoms. PMID:27462212

  5. Data Sharing.

    PubMed

    Longo, Dan L; Drazen, Jeffrey M

    2016-01-21

    The aerial view of the concept of data sharing is beautiful. What could be better than having high-quality information carefully reexamined for the possibility that new nuggets of useful data are lying there, previously unseen? The potential for leveraging existing results for even more benefit pays appropriate increased tribute to the patients who put themselves at risk to generate the data. The moral imperative to honor their collective sacrifice is the trump card that takes this trick. However, many of us who have actually conducted clinical research, managed clinical studies and data collection and analysis, and curated data sets have . . . PMID:26789876

  6. Association of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Shares Genetic and Cytokine Profiles With Other Autoinflammatory Diseases

    PubMed Central

    Marzano, Angelo V.; Ceccherini, Isabella; Gattorno, Marco; Fanoni, Daniele; Caroli, Francesco; Rusmini, Marta; Grossi, Alice; De Simone, Clara; Borghi, Orietta M.; Meroni, Pier Luigi; Crosti, Carlo; Cugno, Massimo

    2014-01-01

    Abstract The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1β and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1β, tumor necrosis factor-α, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin. PMID:25501066

  7. Association of AKT1 with verbal learning, verbal memory, and regional cortical gray matter density in twins.

    PubMed

    Pietiläinen, Olli P H; Paunio, Tiina; Loukola, Anu; Tuulio-Henriksson, Annamari; Kieseppä, Tuula; Thompson, Paul; Toga, Arthur W; van Erp, Theo G M; Silventoinen, Karri; Soronen, Pia; Hennah, William; Turunen, Joni A; Wedenoja, Juho; Palo, Outi M; Silander, Kaisa; Lönnqvist, Jouko; Kaprio, Jaakko; Cannon, Tyrone D; Peltonen, Leena

    2009-07-01

    AKT1, encoding the protein kinase B, has been associated with the genetic etiology of schizophrenia and bipolar disorder. However, minuscule data exist on the role of different alleles of AKT1 in measurable quantitative endophenotypes, such as cognitive abilities and neuroanatomical features, showing deviations in schizophrenia and bipolar disorder. We evaluated the contribution of AKT1 to quantitative cognitive traits and 3D high-resolution neuroanatomical images in a Finnish twin sample consisting of 298 twins: 61 pairs with schizophrenia (8 concordant), 31 pairs with bipolar disorder (5 concordant) and 65 control pairs matched for age, sex and demographics. An AKT1 allele defined by the SNP rs1130214 located in the UTR of the gene revealed association with cognitive traits related to verbal learning and memory (P = 0.0005 for a composite index). This association was further fortified by a higher degree of resemblance of verbal memory capacity in pairs sharing the rs1130214 genotype compared to pairs not sharing the genotype. Furthermore, the same allele was also associated with decreased gray matter density in medial and dorsolateral prefrontal cortex (P < 0.05). Our findings support the role of AKT1 in the genetic background of cognitive and anatomical features, known to be affected by psychotic disorders. The established association of the same allelic variant of AKT1 with both cognitive and neuroanatomical aberrations could suggest that AKT1 exerts its effect on verbal learning and memory via neural networks involving prefrontal cortex. PMID:19051289

  8. Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.

    PubMed

    Nebel, Rebecca A; Kirschen, Jill; Cai, Jinlu; Woo, Young Jae; Cherian, Koshi; Abrahams, Brett S

    2015-01-01

    Microcephaly and macrocephaly are overrepresented in individuals with autism and are thought to be disease-related risk factors or endophenotypes. Analysis of DNA microarray results from a family with a low functioning autistic child determined that the proband and two additional unaffected family members who carry a rare inherited 760 kb duplication of unknown clinical significance at 19p13.12 are macrocephalic. Consideration alongside overlapping deletion and duplication events in the literature provides support for a strong relationship between gene dosage at this locus and head size, with losses and gains associated with microcephaly (p=1.11x10(-11)) and macrocephaly (p=2.47x10(-11)), respectively. Data support A kinase anchor protein 8 and 8-like (AKAP8 and AKAP8L) as candidate genes involved in regulation of head growth, an interesting finding given previous work implicating the AKAP gene family in autism. Towards determination of which of AKAP8 and AKAP8L may be involved in the modulation of head size and risk for disease, we analyzed exome sequencing data for 693 autism families (2591 individuals) where head circumference data were available. No predicted loss of function variants were observed, precluding insights into relationship to head size, but highlighting strong evolutionary conservation. Taken together, findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to autism risk. Exome sequencing of the family also identified a rare inherited variant predicted to disrupt splicing of TPTE / PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and autism risk. PMID:26076356

  9. 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

  10. 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

  11. Semantic fluency and executive functions as candidate endophenotypes for the early diagnosis of schizophrenia in Han Chinese.

    PubMed

    Hu, Maorong; Chen, Jindong; Li, Lehua; Zheng, Yingjun; Wang, Juan; Guo, Xiaofeng; Wu, Renrong; Zhao, Jingping

    2011-09-20

    Neurocognitive deficits are recognized as core features of schizophrenia. The aim of this study was to compare the cognitive performance of antipsychotic, drug-naive patients with first-episode schizophrenia (FES patients) to their healthy siblings and to healthy controls from the Han Chinese population for exploring potential endophenotypes for the early detection of schizophrenia. A battery of cognitive assessment tools was used to measure seven cognitive domains in matched groups consisting of 56 subjects each. Cognitive tests included the grooved pegboard test (GPT), the category fluency test (CFT), the trail making test A (TMT-A), the Wechsler memory scale-III spatial span test (WMS-III SST), the Hopkins verbal learning test-revised (HVLT-R), the brief visuospatial memory test-revised (BVMT-R), the paced auditory serial addition test (PASAT), and the Wisconsin card sorting test-64 cards version (WCST-64). The performances of FEP patients were inferior to normal controls on all neuropsychological tests, while siblings were lower than healthy controls in many of the same tasks. Patients' performances were lower than siblings' on all tests except for the CFT, the WMS-III SST backward test, and four subtests of the WCST-64. Our data suggest that FEP patients exhibited pronounced impairment of fine motor skills, speed of processing, attention, verbal memory, visual memory, and executive function, while siblings exhibited deficits intermediate between those of schizophrenic patients and the control group. Semantic fluency function and executive function may be potential endophenotypes for the early diagnosis of schizophrenia. PMID:21827833

  12. Association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope and smoking status in Brazilian patients with rheumatoid arthritis

    PubMed Central

    Yazbek, Michel Alexandre; de Barros-Mazon, Silvia; Rossi, Cláudio Lúcio; Londe, Ana Carolina; Costallat, Lilian Tereza Lavras; Bértolo, Manoel Barros

    2011-01-01

    INTRODUCTION: Epstein-Barr virus exposure appears to be an environmental trigger for rheumatoid arthritis that interacts with other risk factors. Relationships among anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status have been observed in patients with rheumatoid arthritis from different populations. OBJECTIVE: To perform an association analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status in Brazilian patients with rheumatoid arthritis. METHODS: In a case-control study, 140 rheumatoid arthritis patients and 143 healthy volunteers who were matched for age, sex, and ethnicity were recruited. Anti-Epstein-Barr nuclear antigen-1 antibodies and anti-cyclic citrullinated peptide antibodies were examined using an enzyme-linked immunosorbent assay, and shared epitope alleles were identified by genotyping. Smoking information was collected from all subjects. A comparative analysis of anti-Epstein-Barr nuclear antigen-1 antibodies, anti-cyclic citrullinated peptide antibodies, the shared epitope, and smoking status was performed in the patient group. Logistic regression analysis models were used to analyze the risk of rheumatoid arthritis. RESULTS: Anti-Epstein-Barr nuclear antigen-1 antibodies were not associated with anti-cyclic citrullinated peptide antibodies, shared epitope alleles, or smoking status. Anti-cyclic citrullinated peptide antibody positivity was significantly higher in smoking patients with shared epitope alleles (OR = 3.82). In a multivariate logistic regression analysis using stepwise selection, only anti-cyclic citrullinated peptide antibodies were found to be independently associated with rheumatoid arthritis (OR = 247.9). CONCLUSION: Anti-Epstein-Barr nuclear antigen-1 antibodies did not increase the risk of rheumatoid arthritis and were not associated with the rheumatoid arthritis risk factors studied. Smoking and

  13. Sharing values, sharing a vision

    SciTech Connect

    Not Available

    1993-12-31

    Teamwork, partnership and shared values emerged as recurring themes at the Third Technology Transfer/Communications Conference. The program drew about 100 participants who sat through a packed two days to find ways for their laboratories and facilities to better help American business and the economy. Co-hosts were the Lawrence Livermore National Laboratory and the Lawrence Berkeley Laboratory, where most meetings took place. The conference followed traditions established at the First Technology Transfer/Communications Conference, conceived of and hosted by the Pacific Northwest Laboratory in May 1992 in Richmond, Washington, and the second conference, hosted by the National Renewable Energy Laboratory in January 1993 in Golden, Colorado. As at the other conferences, participants at the third session represented the fields of technology transfer, public affairs and communications. They came from Department of Energy headquarters and DOE offices, laboratories and production facilities. Continued in this report are keynote address; panel discussion; workshops; and presentations in technology transfer.

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

    PubMed Central

    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

  15. Association between secondhand smoke exposure at home and cigarette gifting and sharing in Zhejiang, China: a repeat cross-sectional study

    PubMed Central

    Xu, Yue; Xu, ShuiYang; Wu, QingQing; Guo, YuJie

    2016-01-01

    Objectives The aims of the current study were to assess the prevalence of household cigarette gifting and sharing, and to evaluate the relationship between secondhand smoke (SHS) exposure, and cigarette gifting and sharing, in Zhejiang, China. Design A repeat cross-sectional design. Setting 10 sites in 5 cities in Zhejiang, China. Participants Two surveys were conducted with adults in Zhejiang, China, in 2010 (N=2112) and 2012 (N=2279), respectively. At both waves, the same questionnaire was used; respondents were asked questions on residence, number of family smokers, indoor smoking rules, household income and cigarette gifting and sharing. Results The findings revealed that more than half of respondents’ families (54.50% in 2010, 52.79% in 2012) reported exposure to SHS. Many families (54.73% in 2010, 47.04% in 2012) shared cigarettes with others, and a minority (14.91% in 2010, 14.17% in 2012) reported their family giving cigarettes as a gift. There was a significant decrease in cigarette sharing from 2010 to 2012, irrespective of household with SHS exposure status; and the cigarette gifting was significantly decreased in household without SHS exposure. Conclusions Compared to households without SHS exposure, the prevalence of cigarette gifting and sharing in households with SHS exposure was more obvious. Encouraging and promoting a smoke-free household environment is necessary to change public smoking customs in Zhejiang, China. PMID:26940109

  16. A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

    PubMed Central

    Boucher, Gabrielle; Beauchamp, Claudine; Trynka, Gosia; Dubois, Patrick C.; Lagacé, Caroline; Stokkers, Pieter C. F.; Hommes, Daan W.; Barisani, Donatella; Palmieri, Orazio; Annese, Vito; van Heel, David A.; Weersma, Rinse K.; Daly, Mark J.; Wijmenga, Cisca; Rioux, John D.

    2011-01-01

    Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. PMID:21298027

  17. Can power be shared?

    PubMed

    Ten Pas, William S

    2013-01-01

    Dental insurance began with a partnership between dental service organizations and state dental associations with a view toward expanding the number of Americans receiving oral health care and as a means for permitting firms and other organizations to offer employee benefits. The goals have been achieved, but the alliance between dentistry and insurance has become strained. A lack of dialogue has fostered mutual misconceptions, some of which are reviewed in this paper. It is possible that the public, the profession, and the dental insurance industry can all be strengthened, but only through power-sharing around the original common objective. PMID:24761578

  18. SHARING EDUCATIONAL SERVICES.

    ERIC Educational Resources Information Center

    Catskill Area Project in Small School Design, Oneonta, NY.

    SHARED SERVICES, A COOPERATIVE SCHOOL RESOURCE PROGRAM, IS DEFINED IN DETAIL. INCLUDED IS A DISCUSSION OF THEIR NEED, ADVANTAGES, GROWTH, DESIGN, AND OPERATION. SPECIFIC PROCEDURES FOR OBTAINING STATE AID IN SHARED SERVICES, EFFECTS OF SHARED SERVICES ON THE SCHOOL, AND HINTS CONCERNING SHARED SERVICES ARE DESCRIBED. CHARACTERISTICS OF THE SMALL…

  19. Shared clinical decision making

    PubMed Central

    AlHaqwi, Ali I.; AlDrees, Turki M.; AlRumayyan, Ahmad; AlFarhan, Ali I.; Alotaibi, Sultan S.; AlKhashan, Hesham I.; Badri, Motasim

    2015-01-01

    Objectives: To determine preferences of patients regarding their involvement in the clinical decision making process and the related factors in Saudi Arabia. Methods: This cross-sectional study was conducted in a major family practice center in King Abdulaziz Medical City, Riyadh, Saudi Arabia, between March and May 2012. Multivariate multinomial regression models were fitted to identify factors associated with patients preferences. Results: The study included 236 participants. The most preferred decision-making style was shared decision-making (57%), followed by paternalistic (28%), and informed consumerism (14%). The preference for shared clinical decision making was significantly higher among male patients and those with higher level of education, whereas paternalism was significantly higher among older patients and those with chronic health conditions, and consumerism was significantly higher in younger age groups. In multivariate multinomial regression analysis, compared with the shared group, the consumerism group were more likely to be female [adjusted odds ratio (AOR) =2.87, 95% confidence interval [CI] 1.31-6.27, p=0.008] and non-dyslipidemic (AOR=2.90, 95% CI: 1.03-8.09, p=0.04), and the paternalism group were more likely to be older (AOR=1.03, 95% CI: 1.01-1.05, p=0.04), and female (AOR=2.47, 95% CI: 1.32-4.06, p=0.008). Conclusion: Preferences of patients for involvement in the clinical decision-making varied considerably. In our setting, underlying factors that influence these preferences identified in this study should be considered and tailored individually to achieve optimal treatment outcomes. PMID:26620990

  20. Investigation of the HLA component involved in rheumatoid arthritis (RA) by using the marker association-segregation [chi][sup 2] (MASC) method: Rejection of the unifying-shared-epitope hypothesis

    SciTech Connect

    Dizier, M.H.; Eliaou, J.F.; Babron, M.C.; Combe, B.; Sany, J.; Clot, J.; Clerget-Darpoux, F.

    1993-09-01

    In order to investigate the HLA component involved in rheumatoid arthritis (RA), the authors tested genetic models by the marker association-segregation [chi][sup 2] (MASC) method, using the HLA genotypic distribution observed in a sample of 97 RA patients. First they tested models assuming the involvement of a susceptibility gene linked to the DR locus. They showed that the present data are compatible with a simple model assuming the effect of a recessive allele of a biallelic locus linked to the DR locus and without any assumption of synergistic effect. Then they considered models assuming the direct involvement of the DR allele products, and tested the unifying-shared-epitope hypothesis, which has been proposed. Under this hypothesis the DR alleles are assumed to be directly involved in the susceptibility to the disease because of the presence of similar or identical amino acid sequences in position 70-74 of the third hypervariable region of the DRBI molecules, shared by the RA-associated DR alleles DR4Dw4, DR4Dw14, and DR1. This hypothesis was strongly rejected with the present data. In the case of the direct involvement of the DR alleles, hypotheses more complex that the unifying-shared-epitope hypothesis would have to be considered. 28 refs., 2 tabs.

  1. Targeting Neural Endophenotypes of Eating Disorders with Non-invasive Brain Stimulation

    PubMed Central

    Dunlop, Katharine A.; Woodside, Blake; Downar, Jonathan

    2016-01-01

    The term “eating disorders” (ED) encompasses a wide variety of disordered eating and compensatory behaviors, and so the term is associated with considerable clinical and phenotypic heterogeneity. This heterogeneity makes optimizing treatment techniques difficult. One class of treatments is non-invasive brain stimulation (NIBS). NIBS, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), are accessible forms of neuromodulation that alter the cortical excitability of a target brain region. It is crucial for NIBS to be successful that the target is well selected for the patient population in question. Targets may best be selected by stepping back from conventional DSM-5 diagnostic criteria to identify neural substrates of more basic phenotypes, including behavior related to rewards and punishment, cognitive control, and social processes. These phenotypic dimensions have been recently laid out by the Research Domain Criteria (RDoC) initiative. Consequently, this review is intended to identify potential dimensions as outlined by the RDoC and the underlying behavioral and neurobiological targets associated with ED. This review will also identify candidate targets for NIBS based on these dimensions and review the available literature on rTMS and tDCS in ED. This review systematically reviews abnormal neural circuitry in ED within the RDoC framework, and also systematically reviews the available literature investigating NIBS as a treatment for ED. PMID:26909013

  2. Share Your Values

    MedlinePlus

    ... Español Text Size Email Print Share Share Your Values Page Content Article Body Today, teenagers are bombarded ... mid-twenties. The Most Effective Way to Instill Values? By Example Your words will carry more weight ...

  3. Generalized quantum secret sharing

    SciTech Connect

    Singh, Sudhir Kumar; Srikanth, R.

    2005-01-01

    We explore a generalization of quantum secret sharing (QSS) in which classical shares play a complementary role to quantum shares, exploring further consequences of an idea first studied by Nascimento, Mueller-Quade, and Imai [Phys. Rev. A 64, 042311 (2001)]. We examine three ways, termed inflation, compression, and twin thresholding, by which the proportion of classical shares can be augmented. This has the important application that it reduces quantum (information processing) players by replacing them with their classical counterparts, thereby making quantum secret sharing considerably easier and less expensive to implement in a practical setting. In compression, a QSS scheme is turned into an equivalent scheme with fewer quantum players, compensated for by suitable classical shares. In inflation, a QSS scheme is enlarged by adding only classical shares and players. In a twin-threshold scheme, we invoke two separate thresholds for classical and quantum shares based on the idea of information dilution.

  4. LACC Shared Governance Model.

    ERIC Educational Resources Information Center

    Spangler, Mary

    This document discusses Los Angeles City College's (LACC) (California) Shared Governance Model. In response to California Assembly Bill 1725, LACC set forth a plan to implement the statutory requirements of shared governance. Shared governance is a concept grounded in the idea that decision-making is a process that affects the entire campus…

  5. Mitochondrial haplotypes associated with biomarkers for Alzheimer's disease.

    PubMed

    Ridge, Perry G; Koop, Andre; Maxwell, Taylor J; Bailey, Matthew H; Swerdlow, Russell H; Kauwe, John S K; Honea, Robyn A

    2013-01-01

    Various studies have suggested that the mitochondrial genome plays a role in late-onset Alzheimer's disease, although results are mixed. We used an endophenotype-based approach to further characterize mitochondrial genetic variation and its relationship to risk markers for Alzheimer's disease. We analyzed longitudinal data from non-demented, mild cognitive impairment, and late-onset Alzheimer's disease participants in the Alzheimer's Disease Neuroimaging Initiative with genetic, brain imaging, and behavioral data. We assessed the relationship of structural MRI and cognitive biomarkers with mitochondrial genome variation using TreeScanning, a haplotype-based approach that concentrates statistical power by analyzing evolutionarily meaningful groups (or clades) of haplotypes together for association with a phenotype. Four clades were associated with three different endophenotypes: whole brain volume, percent change in temporal pole thickness, and left hippocampal atrophy over two years. This is the first study of its kind to identify mitochondrial variation associated with brain imaging endophenotypes of Alzheimer's disease. Our results provide additional evidence that the mitochondrial genome plays a role in risk for Alzheimer's disease. PMID:24040196

  6. Functional Network Endophenotypes Unravel the Effects of Apolipoprotein E Epsilon 4 in Middle-Aged Adults

    PubMed Central

    Chen, Gang; Li, Wenjun; Ward, B. Douglas; Franczak, Malgorzata B.; Jones, Jennifer L.; Antuono, Piero G.; Li, Shi-Jiang

    2013-01-01

    Apolipoprotein E-ε4 (APOE-ε4) accentuates memory decline, structural volume loss and cerebral amyloid deposition in cognitively healthy adults. We investigated whether APOE-ε4 carriers will show disruptions in the intrinsic cognitive networks, including the default mode (DMN), executive control (ECN) and salience (SN) networks, relative to noncarriers in middle-aged healthy adults; and the extent to which episodic-memory performance is related to the altered functional connectivity (Fc) in these networks. Resting-state functional connectivity MRI (R-fMRI) was used to measure the differences in the DMN, ECN and SN Fc between 20 APOE-ε4 carriers and 26 noncarriers. Multiple linear regression analyses were performed to determine the relationship between episodic-memory performance and Fc differences in the three resting-state networks across all subjects. There were no significant differences in the demographic and neuropsychological characteristics and the gray-matter volumes in the carriers and noncarriers. While mostly diminished DMN and ECN functional connectivities were seen, enhanced connections to the DMN structures were found in the SN in ε4 carriers. Altered DMN and ECN were associated with episodic memory performance. Significant Fc differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD, in the absence of cognitive decline and gray-matter atrophy. Prospective studies are essential to elucidate the potential of R-fMRI technique as a biomarker for predicting conversion from normal to early AD in healthy APOE-ε4 carriers. PMID:23424640

  7. In Search of Neural Endophenotypes of Postpartum Psychopathology and Disrupted Maternal Caregiving

    PubMed Central

    Moses-Kolko, E. L.; Horner, M. S.; Phillips, M. L.; Hipwell, A. E.; Swain, J. E.

    2015-01-01

    This is a selective review that provides the context for the study of perinatal affective disorder mechanisms and outlines directions for future research. We integrate existing literature along neural networks of interest for affective disorders and maternal caregiving: (i) the salience/fear network; (ii) the executive network; (iii) the reward/social attachment network; and (iv) the default mode network. Extant salience/fear network research reveals disparate responses and corticolimbic coupling to various stimuli based upon a predominantly depressive versus anxious (post-traumatic stress disorder) clinical phenotype. Executive network and default mode connectivity abnormalities have been described in postpartum depression (PPD), although studies are very limited in these domains. Reward/social attachment studies confirm a robust ventral striatal response to infant stimuli, including cry and happy infant faces, which is diminished in depressed, insecurely attached and substance-using mothers. The adverse parenting experiences received and the attachment insecurity of current mothers are factors that are associated with a diminution in infant stimulus-related neural activity similar to that in PPD, and raise the need for additional studies that integrate mood and attachment concepts in larger study samples. Several studies examining functional connectivity in resting state and emotional activation functional magnetic resonance imaging paradigms have revealed attenuated corticolimbic connectivity, which remains an important outcome that requires dissection with increasing precision to better define neural treatment targets. Methodological progress is expected in the coming years in terms of refining clinical phenotypes of interest and experimental paradigms, as well as enlarging samples to facilitate the examination of multiple constructs. Functional imaging promises to determine neural mechanisms underlying maternal psychopathology and impaired caregiving, such

  8. Root-Associated Ectomycorrhizal Fungi Shared by Various Boreal Forest Seedlings Naturally Regenerating after a Fire in Interior Alaska and Correlation of Different Fungi with Host Growth Responses ▿

    PubMed Central

    Bent, Elizabeth; Kiekel, Preston; Brenton, Rebecca; Taylor, D. Lee

    2011-01-01

    The role of common mycorrhizal networks (CMNs) in postfire boreal forest successional trajectories is unknown. We investigated this issue by sampling a 50-m by 40-m area of naturally regenerating black spruce (Picea mariana), trembling aspen (Populus tremuloides), and paper birch (Betula papyrifera) seedlings at various distances from alder (Alnus viridis subsp. crispa), a nitrogen-fixing shrub, 5 years after wildfire in an Alaskan interior boreal forest. Shoot biomasses and stem diameters of 4-year-old seedlings were recorded, and the fungal community associated with ectomycorrhizal (ECM) root tips from each seedling was profiled using molecular techniques. We found distinct assemblages of fungi associated with alder compared with those associated with the other tree species, making the formation of CMNs between them unlikely. However, among the spruce, aspen, and birch seedlings, there were many shared fungi (including members of the Pezoloma ericae [Hymenoscyphus ericae] species aggregate, Thelephora terrestris, and Russula spp.), raising the possibility that these regenerating seedlings may form interspecies CMNs. Distance between samples did not influence how similar ECM root tip-associated fungal communities were, and of the fungal groups identified, only one of them was more likely to be shared between seedlings that were closer together, suggesting that the majority of fungi surveyed did not have a clumped distribution across the small scale of this study. The presence of some fungal ribotypes was associated with larger or smaller seedlings, suggesting that these fungi may play a role in the promotion or inhibition of seedling growth. The fungal ribotypes associated with larger seedlings were different between spruce, aspen, and birch, suggesting differential impacts of some host-fungus combinations. One may speculate that wildfire-induced shifts in a given soil fungal community could result in variation in the growth response of different plant species

  9. Complying with physician gain-sharing restrictions.

    PubMed

    O'Hare, P K

    1998-05-01

    Many IDSs are considering implementing gain-sharing programs as a way to motivate their physicians to provide high-quality, cost-effective services. Before embarking on such programs, however, IDSs need to understand the legal requirements associated with such programs to ensure that the gain-sharing arrangement is in compliance with Federal law. PMID:10179436

  10. Mother and Adolescent Reports of Associations between Child Behavior Problems and Mother-Child Relationship Qualities: Separating Shared Variance from Individual Variance

    ERIC Educational Resources Information Center

    Burk, William J.; Laursen, Brett

    2010-01-01

    This study contrasts results from different correlational methods for examining links between mother and child (N = 72 dyads) reports of early adolescent (M = 11.5 years) behavior problems and relationship negativity and support. Simple (Pearson) correlations revealed a consistent pattern of statistically significant associations, regardless of…