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Sample records for genome-wide mammalian consistency-based

  1. Rapid and Pervasive Changes in Genome-Wide Enhancer Usage During Mammalian Development

    PubMed Central

    Nord, Alex S.; Blow, Matthew J.; Attanasio, Catia; Akiyama, Jennifer A.; Holt, Amy; Hosseini, Roya; Phouanenavong, Sengthavy; Plajzer-Frick, Ingrid; Shoukry, Malak; Afzal, Veena; Rubenstein, John L. R.; Rubin, Edward M.; Pennacchio, Len A.; Visel, Axel

    2014-01-01

    Summary Enhancers are distal regulatory elements that can activate tissue-specific gene expression and are abundant throughout mammalian genomes. While substantial progress has been made towards genome-wide annotation of mammalian enhancers, their temporal activity patterns and global contributions in the context of developmental in vivo processes remain poorly explored. Here we used epigenomic profiling for H3K27ac, a mark of active enhancers, coupled to transgenic mouse assays to examine the genome-wide utilization of enhancers in three different mouse tissues across seven developmental stages. The majority of the ~90,000 enhancers identified exhibited tightly temporally restricted predicted activity windows and were associated with stage-specific biological functions and regulatory pathways in individual tissues. Comparative genomic analysis revealed that evolutionary conservation of enhancers decreases following mid-gestation across all tissues examined. The dynamic enhancer activities uncovered in this study illuminate rapid and pervasive temporal in vivo changes in enhancer usage underlying processes central to development and disease. PMID:24360275

  2. Genome-Wide Detection of Gene Extinction in Early Mammalian Evolution

    PubMed Central

    Kuraku, Shigehiro; Kuratani, Shigeru

    2011-01-01

    Detecting gene losses is a novel aspect of evolutionary genomics that has been made feasible by whole-genome sequencing. However, research to date has concentrated on elucidating evolutionary patterns of genomic components shared between species, rather than identifying disparities between genomes. In this study, we searched for gene losses in the lineage leading to eutherian mammals. First, as a pilot analysis, we selected five gene families (Wnt, Fgf, Tbx, TGFβ, and Frizzled) for molecular phylogenetic analyses, and identified mammalian lineage-specific losses of Wnt11b, Tbx6L/VegT/tbx16, Nodal-related, ADMP1, ADMP2, Sizzled, and Crescent. Second, automated genome-wide phylogenetic screening was implemented based on this pilot analysis. As a result, we detected 147 chicken genes without eutherian orthologs, which resulted from 141 gene loss events. Our inventory contained a group of regulatory genes governing early embryonic axis formation, such as Noggins, and multiple members of the opsin and prolactin-releasing hormone receptor (“PRLHR”) gene families. Our findings highlight the potential of genome-wide gene phylogeny (“phylome”) analysis in detecting possible rearrangement of gene networks and the importance of identifying losses of ancestral genomic components in analyzing the molecular basis underlying phenotypic evolution. PMID:22094861

  3. Genome-wide detection of gene extinction in early mammalian evolution.

    PubMed

    Kuraku, Shigehiro; Kuratani, Shigeru

    2011-01-01

    Detecting gene losses is a novel aspect of evolutionary genomics that has been made feasible by whole-genome sequencing. However, research to date has concentrated on elucidating evolutionary patterns of genomic components shared between species, rather than identifying disparities between genomes. In this study, we searched for gene losses in the lineage leading to eutherian mammals. First, as a pilot analysis, we selected five gene families (Wnt, Fgf, Tbx, TGFβ, and Frizzled) for molecular phylogenetic analyses, and identified mammalian lineage-specific losses of Wnt11b, Tbx6L/VegT/tbx16, Nodal-related, ADMP1, ADMP2, Sizzled, and Crescent. Second, automated genome-wide phylogenetic screening was implemented based on this pilot analysis. As a result, we detected 147 chicken genes without eutherian orthologs, which resulted from 141 gene loss events. Our inventory contained a group of regulatory genes governing early embryonic axis formation, such as Noggins, and multiple members of the opsin and prolactin-releasing hormone receptor ("PRLHR") gene families. Our findings highlight the potential of genome-wide gene phylogeny ("phylome") analysis in detecting possible rearrangement of gene networks and the importance of identifying losses of ancestral genomic components in analyzing the molecular basis underlying phenotypic evolution. PMID:22094861

  4. Polysome fractionation and analysis of mammalian translatomes on a genome-wide scale.

    PubMed

    Gandin, Valentina; Sikström, Kristina; Alain, Tommy; Morita, Masahiro; McLaughlan, Shannon; Larsson, Ola; Topisirovic, Ivan

    2014-01-01

    mRNA translation plays a central role in the regulation of gene expression and represents the most energy consuming process in mammalian cells. Accordingly, dysregulation of mRNA translation is considered to play a major role in a variety of pathological states including cancer. Ribosomes also host chaperones, which facilitate folding of nascent polypeptides, thereby modulating function and stability of newly synthesized polypeptides. In addition, emerging data indicate that ribosomes serve as a platform for a repertoire of signaling molecules, which are implicated in a variety of post-translational modifications of newly synthesized polypeptides as they emerge from the ribosome, and/or components of translational machinery. Herein, a well-established method of ribosome fractionation using sucrose density gradient centrifugation is described. In conjunction with the in-house developed "anota" algorithm this method allows direct determination of differential translation of individual mRNAs on a genome-wide scale. Moreover, this versatile protocol can be used for a variety of biochemical studies aiming to dissect the function of ribosome-associated protein complexes, including those that play a central role in folding and degradation of newly synthesized polypeptides.

  5. Mammalian NET-seq analysis defines nascent RNA profiles and associated RNA processing genome-wide.

    PubMed

    Nojima, Takayuki; Gomes, Tomás; Carmo-Fonseca, Maria; Proudfoot, Nicholas J

    2016-03-01

    The transcription cycle of RNA polymerase II (Pol II) correlates with changes to the phosphorylation state of its large subunit C-terminal domain (CTD). We recently developed Native Elongation Transcript sequencing using mammalian cells (mNET-seq), which generates single-nucleotide-resolution genome-wide profiles of nascent RNA and co-transcriptional RNA processing that are associated with different CTD phosphorylation states. Here we provide a detailed protocol for mNET-seq. First, Pol II elongation complexes are isolated with specific phospho-CTD antibodies from chromatin solubilized by micrococcal nuclease digestion. Next, RNA derived from within the Pol II complex is size fractionated and Illumina sequenced. Using mNET-seq, we have previously shown that Pol II pauses at both ends of protein-coding genes but with different CTD phosphorylation patterns, and we have also detected phosphorylation at serine 5 (Ser5-P) CTD-specific splicing intermediates and Pol II accumulation over co-transcriptionally spliced exons. With moderate biochemical and bioinformatic skills, mNET-seq can be completed in ∼6 d, not including sequencing and data analysis. PMID:26844429

  6. Effects of genome-wide copy number variation on expression in mammalian cells

    PubMed Central

    2011-01-01

    Background There is only a limited understanding of the relation between copy number and expression for mammalian genes. We fine mapped cis and trans regulatory loci due to copy number change for essentially all genes using a human-hamster radiation hybrid (RH) panel. These loci are called copy number expression quantitative trait loci (ceQTLs). Results Unexpected findings from a previous study of a mouse-hamster RH panel were replicated. These findings included decreased expression as a result of increased copy number for 30% of genes and an attenuated relationship between expression and copy number on the X chromosome suggesting an Xist independent form of dosage compensation. In a separate glioblastoma dataset, we found conservation of genes in which dosage was negatively correlated with gene expression. These genes were enriched in signaling and receptor activities. The observation of attenuated X-linked gene expression in response to increased gene number was also replicated in the glioblastoma dataset. Of 523 gene deserts of size > 600 kb in the human RH panel, 325 contained trans ceQTLs with -log10 P > 4.1. Recently discovered genes, ultra conserved regions, noncoding RNAs and microRNAs explained only a small fraction of the results, suggesting a substantial portion of gene deserts harbor as yet unidentified functional elements. Conclusion Radiation hybrids are a useful tool for high resolution mapping of cis and trans loci capable of affecting gene expression due to copy number change. Analysis of two independent radiation hybrid panels show agreement in their findings and may serve as a discovery source for novel regulatory loci in noncoding regions of the genome. PMID:22085887

  7. Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library.

    PubMed

    Koike-Yusa, Hiroko; Li, Yilong; Tan, E-Pien; Velasco-Herrera, Martin Del Castillo; Yusa, Kosuke

    2014-03-01

    Identification of genes influencing a phenotype of interest is frequently achieved through genetic screening by RNA interference (RNAi) or knockouts. However, RNAi may only achieve partial depletion of gene activity, and knockout-based screens are difficult in diploid mammalian cells. Here we took advantage of the efficiency and high throughput of genome editing based on type II, clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems to introduce genome-wide targeted mutations in mouse embryonic stem cells (ESCs). We designed 87,897 guide RNAs (gRNAs) targeting 19,150 mouse protein-coding genes and used a lentiviral vector to express these gRNAs in ESCs that constitutively express Cas9. Screening the resulting ESC mutant libraries for resistance to either Clostridium septicum alpha-toxin or 6-thioguanine identified 27 known and 4 previously unknown genes implicated in these phenotypes. Our results demonstrate the potential for efficient loss-of-function screening using the CRISPR-Cas9 system.

  8. Detecting DNA Double-Stranded Breaks in Mammalian Genomes by Linear Amplification-mediated High-Throughput Genome-wide Translocation Sequencing (LAM-HTGTS)

    PubMed Central

    Hu, Jiazhi; Meyers, Robin M.; Dong, Junchao; Panchakshari, Rohit A.; Alt, Frederick W.; Frock, Richard L.

    2016-01-01

    Unbiased, high-throughput assays to detect and quantify DNA double-stranded breaks (DSBs) genome-wide in mammalian cells will facilitate basic studies of mechanisms that generate and repair endogenous DSBs. They will also enable more applied studies, such as evaluating on- and off-target activities of engineered nucleases. Here we describe a linear amplification-mediated high-throughput genome-wide sequencing (LAM-HTGTS) method for detecting genome-wide “prey” DSBs via their translocation in cultured mammalian cells to a fixed “bait” DSB. Bait-prey junctions are cloned directly from isolated genomic DNA using LAM-PCR and unidirectionally ligated to bridge adapters; subsequent PCR steps amplify the single-stranded DNA junction library in preparation for Illumina paired-end Miseq sequencing. A custom bioinformatic pipeline identifies prey sequences that contribute to junctions and maps them across the genome. LAM-HTGTS differs from related approaches because it detects a wide range of broken end structures with nucleotide level resolution. Familiarity with nucleic acid methods and next-generation sequencing analysis are necessary for library generation and data interpretation. LAM-HTGTS assays are sensitive, reproducible, relatively inexpensive, scalable, and straightforward to implement with a turnaround time of less than one week. PMID:27031497

  9. A Genome-Wide siRNA Screen in Mammalian Cells for Regulators of S6 Phosphorylation

    PubMed Central

    Papageorgiou, Angela; Rapley, Joseph; Mesirov, Jill P.; Tamayo, Pablo; Avruch, Joseph

    2015-01-01

    mTOR complex1, the major regulator of mRNA translation in all eukaryotic cells, is strongly activated in most cancers. We performed a genome-wide RNAi screen in a human cancer cell line, seeking genes that regulate S6 phosphorylation, readout of mTORC1 activity. Applying a stringent selection, we retrieved nearly 600 genes wherein at least two RNAis gave significant reduction in S6-P. This cohort contains known regulators of mTOR complex 1 and is significantly enriched in genes whose depletion affects the proliferation/viability of the large set of cancer cell lines in the Achilles database in a manner paralleling that caused by mTOR depletion. We next examined the effect of RNAi pools directed at 534 of these gene products on S6-P in TSC1 null mouse embryo fibroblasts. 76 RNAis reduced S6 phosphorylation significantly in 2 or 3 replicates. Surprisingly, among this cohort of genes the only elements previously associated with the maintenance of mTORC1 activity are two subunits of the vacuolar ATPase and the CUL4 subunit DDB1. RNAi against a second set of 84 targets reduced S6-P in only one of three replicates. However, an indication that this group also bears attention is the presence of rpS6KB1 itself, Rac1 and MAP4K3, a protein kinase that supports amino acid signaling to rpS6KB1. The finding that S6 phosphorylation requires a previously unidentified, functionally diverse cohort of genes that participate in fundamental cellular processes such as mRNA translation, RNA processing, DNA repair and metabolism suggests the operation of feedback pathways in the regulation of mTORC1 operating through novel mechanisms. PMID:25790369

  10. A genome-wide screen identifies a single Β-defensin gene cluster in the chicken: implications for the origin and evolution of mammalian defensins

    SciTech Connect

    Xiao, Yanjing; Hughes, Austin L.; Ando, Junko; Matsuda, Yoichi; Cheng, Jan-Fang; Skinner-Noble, Donald; Zhang, Guolong

    2004-08-13

    Defensins comprise a large family of cationic antimicrobial peptides that are characterized by the presence of a conserved cysteine-rich defensin motif. Based on the spacing pattern of cysteines, these defensins are broadly divided into five groups, namely plant, invertebrate, {alpha}-, {beta}-, and {theta}-defensins, with the last three groups being mostly found in mammalian species. However, the evolutionary relationships among these five groups of defensins remain controversial.

  11. Genome-wide association studies in neurology

    PubMed Central

    Tan, Meng-Shan; Jiang, Teng

    2014-01-01

    Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWAS in common neurological diseases, including Stroke, Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis, migraine, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, restless legs syndrome, intracranial aneurysm, human prion diseases and moyamoya disease. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of potential therapeutic agents. PMID:25568877

  12. Genome-wide identification of enhancer elements.

    PubMed

    Tulin, Sarah; Barsi, Julius C; Bocconcelli, Carlo; Smith, Joel

    2016-01-01

    We present a prospective genome-wide regulatory element database for the sea urchin embryo and the modified chromosome capture-related methodology used to create it. The method we developed is termed GRIP-seq for genome-wide regulatory element immunoprecipitation and combines features of chromosome conformation capture, chromatin immunoprecipitation, and paired-end next-generation sequencing with molecular steps that enrich for active cis-regulatory elements associated with basal transcriptional machinery. The first GRIP-seq database, available to the community, comes from S. purpuratus 24 hpf embryos and takes advantage of the extremely well-characterized cis-regulatory elements in this system for validation. In addition, using the GRIP-seq database, we identify and experimentally validate a novel, intronic cis-regulatory element at the onecut locus. We find GRIP-seq signal sensitively identifies active cis-regulatory elements with a high signal-to-noise ratio for both distal and intronic elements. This promising GRIP-seq protocol has the potential to address a rate-limiting step in resolving comprehensive, predictive network models in all systems.

  13. Genome-wide identification of enhancer elements.

    PubMed

    Tulin, Sarah; Barsi, Julius C; Bocconcelli, Carlo; Smith, Joel

    2016-01-01

    We present a prospective genome-wide regulatory element database for the sea urchin embryo and the modified chromosome capture-related methodology used to create it. The method we developed is termed GRIP-seq for genome-wide regulatory element immunoprecipitation and combines features of chromosome conformation capture, chromatin immunoprecipitation, and paired-end next-generation sequencing with molecular steps that enrich for active cis-regulatory elements associated with basal transcriptional machinery. The first GRIP-seq database, available to the community, comes from S. purpuratus 24 hpf embryos and takes advantage of the extremely well-characterized cis-regulatory elements in this system for validation. In addition, using the GRIP-seq database, we identify and experimentally validate a novel, intronic cis-regulatory element at the onecut locus. We find GRIP-seq signal sensitively identifies active cis-regulatory elements with a high signal-to-noise ratio for both distal and intronic elements. This promising GRIP-seq protocol has the potential to address a rate-limiting step in resolving comprehensive, predictive network models in all systems. PMID:27389984

  14. Genome-wide approaches to schizophrenia.

    PubMed

    Duan, Jubao; Sanders, Alan R; Gejman, Pablo V

    2010-09-30

    Schizophrenia (SZ) is a common and severe psychiatric disorder with both environmental and genetic risk factors, and a high heritability. After over 20 years of molecular genetics research, new molecular strategies, primarily genome-wide association studies (GWAS), have generated major tangible progress. This new data provides evidence for: (1) a number of chromosomal regions with common polymorphisms showing genome-wide association with SZ (the major histocompatibility complex, MHC, region at 6p22-p21; 18q21.2; and 2q32.1). The associated alleles present small odds ratios (the odds of a risk variant being present in cases vs. controls) and suggest causative involvement of gene regulatory mechanisms in SZ. (2) Polygenic inheritance. (3) Involvement of rare (<1%) and large (>100kb) copy number variants (CNVs). (4) A genetic overlap of SZ with autism and with bipolar disorder (BP) challenging the classical clinical classifications. Most new SZ findings (chromosomal regions and genes) have generated new biological leads. These new findings, however, still need to be translated into a better understanding of the underlying biology and into causal mechanisms. Furthermore, a considerable amount of heritability still remains unexplained (missing heritability). Deep resequencing for rare variants and system biology approaches (e.g., integrating DNA sequence and functional data) are expected to further improve our understanding of the genetic architecture of SZ and its underlying biology. PMID:20433910

  15. Genome-Wide Association Studies of Cancer

    PubMed Central

    Stadler, Zsofia K.; Thom, Peter; Robson, Mark E.; Weitzel, Jeffrey N.; Kauff, Noah D.; Hurley, Karen E.; Devlin, Vincent; Gold, Bert; Klein, Robert J.; Offit, Kenneth

    2010-01-01

    Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited. PMID:20585100

  16. Genome-wide Membrane Protein Structure Prediction

    PubMed Central

    Piccoli, Stefano; Suku, Eda; Garonzi, Marianna; Giorgetti, Alejandro

    2013-01-01

    Transmembrane proteins allow cells to extensively communicate with the external world in a very accurate and specific way. They form principal nodes in several signaling pathways and attract large interest in therapeutic intervention, as the majority pharmaceutical compounds target membrane proteins. Thus, according to the current genome annotation methods, a detailed structural/functional characterization at the protein level of each of the elements codified in the genome is also required. The extreme difficulty in obtaining high-resolution three-dimensional structures, calls for computational approaches. Here we review to which extent the efforts made in the last few years, combining the structural characterization of membrane proteins with protein bioinformatics techniques, could help describing membrane proteins at a genome-wide scale. In particular we analyze the use of comparative modeling techniques as a way of overcoming the lack of high-resolution three-dimensional structures in the human membrane proteome. PMID:24403851

  17. Genome-wide analysis correlates Ayurveda Prakriti

    PubMed Central

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K.; Prasanna, B. V.; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S.; Dedge, Amrish P.; Bharadwaj, Ramachandra; Gangadharan, G. G.; Nair, Sreekumaran; Gopinath, Puthiya M.; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-01-01

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as “Prakriti”. To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10−5) were significantly different between Prakritis, without any confounding effect of stratification, after 106 permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India’s traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine. PMID:26511157

  18. Genome-wide analysis correlates Ayurveda Prakriti.

    PubMed

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K; Prasanna, B V; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S; Dedge, Amrish P; Bharadwaj, Ramachandra; Gangadharan, G G; Nair, Sreekumaran; Gopinath, Puthiya M; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-10-29

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti". To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine.

  19. Genome-wide epigenetic modifications in cancer.

    PubMed

    Park, Yoon Jung; Claus, Rainer; Weichenhan, Dieter; Plass, Christoph

    2011-01-01

    Epigenetic alterations in cancer include changes in DNA methylation and associated histone modifications that influence the chromatin states and impact gene expression patterns. Due to recent technological advantages, the scientific community is now obtaining a better picture of the genome-wide epigenetic changes that occur in a cancer genome. These epigenetic alterations are associated with chromosomal instability and changes in transcriptional control which influence the overall gene expression differences seen in many human malignancies. In this review, we will briefly summarize our current knowledge of the epigenetic patterns and mechanisms of gene regulation in healthy tissues and relate this to what is known for cancer genomes. Our focus will be on DNA methylation. We will review the current standing of technologies that have been developed over recent years. This field is experiencing a revolution in the strategies used to measure epigenetic alterations, which includes the incorporation of next generation sequencing tools. We also will review strategies that utilize epigenetic information for translational purposes, with a special emphasis on the potential use of DNA methylation marks for early disease detection and prognosis. The review will close with an outlook on challenges that this field is facing.

  20. Genome Wide Methylome Alterations in Lung Cancer.

    PubMed

    Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  1. Genome Wide Methylome Alterations in Lung Cancer

    PubMed Central

    Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K.; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D.; Spivack, Simon D.

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)–non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  2. Genome-Wide Methylation Profiling of Schizophrenia

    PubMed Central

    Rukova, B; Staneva, R; Hadjidekova, S; Stamenov, G; Milanova; Toncheva, D

    2014-01-01

    Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia and control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 and GIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis. PMID:25937794

  3. Genome-wide transcriptome analysis of 150 cell samples.

    PubMed

    Irimia, Daniel; Mindrinos, Michael; Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G; Davis, Ronald W; Toner, Mehmet

    2009-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples.

  4. Genome-wide transcriptome analysis of 150 cell samples†

    PubMed Central

    Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G.; Davis, Ronald W.; Toner, Mehmet

    2013-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples. PMID:20023796

  5. Genome wide functional genetics in haploid cells.

    PubMed

    Elling, Ulrich; Penninger, Josef M

    2014-08-01

    Some organisms such as yeast or males of social insects are haploid, i.e. they carry a single set of chromosomes, while haploidy in mammals is exclusively restricted to mature germ cells. A single copy of the genome provides the basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Most prominently, haploidy in yeast has been utilized for recessive genetic screens that have markedly contributed to our understanding of development, basic physiology, and disease. Somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure genetic analysis. Near haploid human leukemic cells however have been developed as a high throughput screening tool. Although deemed impossible, we and others have generated mammalian haploid embryonic stem cells from parthenogenetic mouse embryos. Haploid stem cells open the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. Haploid genetics has thus become a powerful alternative to RNAi or CRISPR based screens. PMID:24950427

  6. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    MedlinePlus

    ... 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A ... out to see if a technology called whole genome sequencing would help them find other genetic risk ...

  7. Genome-wide mapping of DNase I hypersensitive sites in plants.

    PubMed

    Zhang, Wenli; Jiang, Jiming

    2015-01-01

    Genomic regions associated with regulatory proteins are known to be highly sensitive to DNase I digestion and are termed DNase I hypersensitive sites (DHSs). DHSs can be identified by DNase I digestion followed by high-throughput DNA sequencing (DNase-seq). DNase-seq has become a powerful technique for genome-wide mapping of chromatin accessibility in eukaryotes with a sequenced genome. We have developed a DNase-seq procedure in plants. This procedure was adapted from the protocol originally developed for mammalian cell lines. It includes plant nuclei isolation, digestion of purified nuclei with DNase I, recovery of DNase-trimmed DNA fragments, DNase-seq library development, Illumina sequencing and data analysis. We also introduce a barcoding system for library preparation. We have conducted DNase-seq in both Arabidopsis thaliana and rice, and developed genome-wide open chromatin maps in both species. These DHS datasets have been used to detect footprints from regulatory protein binding and to reveal genome-wide nucleosome positioning patterns.

  8. A novel statistic for genome-wide interaction analysis.

    PubMed

    Wu, Xuesen; Dong, Hua; Luo, Li; Zhu, Yun; Peng, Gang; Reveille, John D; Xiong, Momiao

    2010-09-23

    Although great progress in genome-wide association studies (GWAS) has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked). The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  9. A genome-wide CRISPR screen in primary immune cells to dissect regulatory networks

    PubMed Central

    Parnas, Oren; Jovanovic, Marko; Eisenhaure, Thomas M.; Herbst, Rebecca H.; Dixit, Atray; Ye, Chun Jimmie; Przybylski, Dariusz; Platt, Randall J.; Tirosh, Itay; Sanjana, Neville E.; Shalem, Ophir; Satija, Rahul; Raychowdhury, Raktima; Mertins, Philipp; Carr, Steven A.; Zhang, Feng; Hacohen, Nir; Regev, Aviv

    2015-01-01

    Finding the components of cellular circuits and determining their functions systematically remains a major challenge in mammalian cells. Here, we introduced genome-wide pooled CRISPR-Cas9 libraries into dendritic cells (DCs) to identify genes that control the induction of tumor necrosis factor (Tnf) by bacterial lipopolysaccharide (LPS), a key process in the host response to pathogens, mediated by the Tlr4 pathway. We found many of the known regulators of Tlr4 signaling, as well as dozens of previously unknown candidates that we validated. By measuring protein markers and mRNA profiles in DCs that are deficient in the known or candidate genes, we classified the genes into three functional modules with distinct effects on the canonical responses to LPS, and highlighted functions for the PAF complex and oligosaccharyltransferase (OST) complex. Our findings uncover new facets of innate immune circuits in primary cells, and provide a genetic approach for dissection of mammalian cell circuits. PMID:26189680

  10. Design and bioinformatics analysis of genome-wide CLIP experiments

    PubMed Central

    Wang, Tao; Xiao, Guanghua; Chu, Yongjun; Zhang, Michael Q.; Corey, David R.; Xie, Yang

    2015-01-01

    The past decades have witnessed a surge of discoveries revealing RNA regulation as a central player in cellular processes. RNAs are regulated by RNA-binding proteins (RBPs) at all post-transcriptional stages, including splicing, transportation, stabilization and translation. Defects in the functions of these RBPs underlie a broad spectrum of human pathologies. Systematic identification of RBP functional targets is among the key biomedical research questions and provides a new direction for drug discovery. The advent of cross-linking immunoprecipitation coupled with high-throughput sequencing (genome-wide CLIP) technology has recently enabled the investigation of genome-wide RBP–RNA binding at single base-pair resolution. This technology has evolved through the development of three distinct versions: HITS-CLIP, PAR-CLIP and iCLIP. Meanwhile, numerous bioinformatics pipelines for handling the genome-wide CLIP data have also been developed. In this review, we discuss the genome-wide CLIP technology and focus on bioinformatics analysis. Specifically, we compare the strengths and weaknesses, as well as the scopes, of various bioinformatics tools. To assist readers in choosing optimal procedures for their analysis, we also review experimental design and procedures that affect bioinformatics analyses. PMID:25958398

  11. Genome-wide association mapping of soybean aphid resistance traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean aphid is the most damaging insect pest of soybean in the Upper Midwest and is primarily controlled by insecticides. Soybean aphid resistance (i.e., Rag genes) has been documented in some soybean lines at chromosomes 6, 7, 13, and 16, but more sources of resistance are needed. Genome-wide ass...

  12. A super powerful method for genome wide association study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome-Wide Association Studies shed light on the identification of genes underlying human diseases and agriculturally important traits. This potential has been shadowed by false positive findings. The Mixed Linear Model (MLM) method is flexible enough to simultaneously incorporate population struct...

  13. Massively expedited genome-wide heritability analysis (MEGHA).

    PubMed

    Ge, Tian; Nichols, Thomas E; Lee, Phil H; Holmes, Avram J; Roffman, Joshua L; Buckner, Randy L; Sabuncu, Mert R; Smoller, Jordan W

    2015-02-24

    The discovery and prioritization of heritable phenotypes is a computational challenge in a variety of settings, including neuroimaging genetics and analyses of the vast phenotypic repositories in electronic health record systems and population-based biobanks. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Genome-wide complex trait analysis is an alternative tool to compute heritability estimates from unrelated individuals, using genome-wide data that are increasingly ubiquitous, but is computationally demanding and becomes difficult to apply in evaluating very large numbers of phenotypes. Here we present a fast and accurate statistical method for high-dimensional heritability analysis using genome-wide SNP data from unrelated individuals, termed massively expedited genome-wide heritability analysis (MEGHA) and accompanying nonparametric sampling techniques that enable flexible inferences for arbitrary statistics of interest. MEGHA produces estimates and significance measures of heritability with several orders of magnitude less computational time than existing methods, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. As a demonstration of application, we conducted heritability analyses on global and local morphometric measurements derived from brain structural MRI scans, using genome-wide SNP data from 1,320 unrelated young healthy adults of non-Hispanic European ancestry. We also computed surface maps of heritability for cortical thickness measures and empirically localized cortical regions where thickness measures were significantly heritable. Our analyses demonstrate the unique capability of MEGHA for large-scale heritability-based screening and high-dimensional heritability profile construction.

  14. Genome-wide patterns of selection in 230 ancient Eurasians.

    PubMed

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R; Llamas, Bastien; Dryomov, Stanislav; Pickrell, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vyacheslav; Guerra, Manuel A Rojo; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2015-12-24

    Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  15. Genome wide copy number analysis of single cells

    PubMed Central

    Baslan, Timour; Kendall, Jude; Rodgers, Linda; Cox, Hilary; Riggs, Mike; Stepansky, Asya; Troge, Jennifer; Ravi, Kandasamy; Esposito, Diane; Lakshmi, B.; Wigler, Michael; Navin, Nicholas; Hicks, James

    2016-01-01

    Summary Copy number variation (CNV) is increasingly recognized as an important contributor to phenotypic variation in health and disease. Most methods for determining CNV rely on admixtures of cells, where information regarding genetic heterogeneity is lost. Here, we present a protocol that allows for the genome wide copy number analysis of single nuclei isolated from mixed populations of cells. Single nucleus sequencing (SNS), combines flow sorting of single nuclei based on DNA content, whole genome amplification (WGA), followed by next generation sequencing to quantize genomic intervals in a genome wide manner. Multiplexing of single cells is discussed. Additionally, we outline informatic approaches that correct for biases inherent in the WGA procedure and allow for accurate determination of copy number profiles. All together, the protocol takes ~3 days from flow cytometry to sequence-ready DNA libraries. PMID:22555242

  16. Genome-wide association studies in Alzheimer's disease: a review.

    PubMed

    Tosto, Giuseppe; Reitz, Christiane

    2013-10-01

    Over the past decade, research aiming to disentangle the genetic underpinnings of late-onset Alzheimer's disease has mostly focused on the identification of common variants through genome-wide association studies. The identification of several new susceptibility genes through these efforts has reinforced the importance of amyloid precursor protein and tau metabolism in the cause of the disease and has implicated immune response, inflammation, lipid metabolism, endocytosis/intracellular trafficking, and cell migration in the cause of the disease. Ongoing and future large-scale genome-wide association studies, translational studies, and next-generation whole genome or whole exome sequencing efforts, hold the promise to map the specific causative variants in these genes, to identify several additional risk variants, including rare and structural variants, and to identify novel targets for genetic testing, prevention, and treatment.

  17. Genome-wide patterns of selection in 230 ancient Eurasians

    PubMed Central

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R.; Llamas, Bastien; Dryomov, Stanislav; Pickrel, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vayacheslav; Rojo Guerra, Manuel A.; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W.; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2016-01-01

    Ancient DNA makes it possible to directly witness natural selection by analyzing samples from populations before, during and after adaptation events. Here we report the first scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture whose genetic material we extracted from the DNA-rich petrous bone and who we show were members of the population that was the source of Europe’s first farmers. We also report a complete transect of the steppe region in Samara between 5500 and 1200 BCE that allows us to recognize admixture from at least two external sources into steppe populations during this period. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  18. Genome-Wide Significant Loci: How Important Are They?

    PubMed Central

    Björkegren, Johan L.M.; Kovacic, Jason C.; Dudley, Joel T.; Schadt, Eric E.

    2015-01-01

    Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key “drivers” of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities. PMID:25720628

  19. Genome-wide patterns of selection in 230 ancient Eurasians.

    PubMed

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R; Llamas, Bastien; Dryomov, Stanislav; Pickrell, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vyacheslav; Guerra, Manuel A Rojo; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2015-12-24

    Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height.

  20. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep

    PubMed Central

    Mousel, Michelle R.; Reynolds, James O.; White, Stephen N.

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10-5) were identified including markers in or near PIK3CB (P = 2.22x10-6; additive model), KCNB1 (P = 2.93x10-6; dominance model), ZC3H12C (P = 3.25x10-6; genotypic model), JPH1 (P = 4.68x20-6; genotypic model), and MYO3B (P = 5.74x10-6; recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID:26098909

  1. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.

    PubMed

    Mousel, Michelle R; Reynolds, James O; White, Stephen N

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection.

  2. Genome-wide association studies in pediatric endocrinology.

    PubMed

    Dauber, Andrew; Hirschhorn, Joel N

    2011-01-01

    Genome-wide association (GWA) studies are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWA studies in type 1 diabetes, stature, pubertal timing, obesity, and vitamin D deficiency. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of novel therapeutic agents.

  3. Genome-wide association study of relative telomere length.

    PubMed

    Prescott, Jennifer; Kraft, Peter; Chasman, Daniel I; Savage, Sharon A; Mirabello, Lisa; Berndt, Sonja I; Weissfeld, Joel L; Han, Jiali; Hayes, Richard B; Chanock, Stephen J; Hunter, David J; De Vivo, Immaculata

    2011-05-10

    Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

  4. Genome-wide association study of schizophrenia in Ashkenazi Jews.

    PubMed

    Goes, Fernando S; McGrath, John; Avramopoulos, Dimitrios; Wolyniec, Paula; Pirooznia, Mehdi; Ruczinski, Ingo; Nestadt, Gerald; Kenny, Eimear E; Vacic, Vladimir; Peters, Inga; Lencz, Todd; Darvasi, Ariel; Mulle, Jennifer G; Warren, Stephen T; Pulver, Ann E

    2015-12-01

    Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P < 1 × 10(-4) ) was also found for several previously identified genome-wide significant findings, including the HLA region, CNTN4, IMMP2L, and GRIN2A. The meta-analysis of the U.S. sample with the PGC2 results provided initial genome-wide significant evidence for six new loci. Among the novel potential susceptibility genes is PEPD, a gene involved in proline metabolism, which is associated with a Mendelian disorder characterized by developmental delay and cognitive deficits. PMID:26198764

  5. Integrative genome-wide approaches in embryonic stem cell research.

    PubMed

    Zhang, Xinyue; Huang, Jing

    2010-10-01

    Embryonic stem (ES) cells are derived from blastocysts. They can differentiate into the three embryonic germ layers and essentially any type of somatic cells. They therefore hold great potential in tissue regeneration therapy. The ethical issues associated with the use of human embryonic stem cells are resolved by the technical break-through of generating induced pluripotent stem (iPS) cells from various types of somatic cells. However, how ES and iPS cells self-renew and maintain their pluripotency is still largely unknown in spite of the great progress that has been made in the last two decades. Integrative genome-wide approaches, such as the gene expression microarray, chromatin immunoprecipitation based microarray (ChIP-chip) and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) offer unprecedented opportunities to elucidate the mechanism of the pluripotency, reprogramming and DNA damage response of ES and iPS cells. This frontier article summarizes the fundamental biological questions about ES and iPS cells and reviews the recent advances in ES and iPS cell research using genome-wide technologies. To this end, we offer our perspectives on the future of genome-wide studies on stem cells.

  6. Genome-wide polymorphisms show unexpected targets of natural selection

    PubMed Central

    Pespeni, Melissa H.; Garfield, David A.; Manier, Mollie K.; Palumbi, Stephen R.

    2012-01-01

    Natural selection can act on all the expressed genes of an individual, leaving signatures of genetic differentiation or diversity at many loci across the genome. New power to assay these genome-wide effects of selection comes from associating multi-locus patterns of polymorphism with gene expression and function. Here, we performed one of the first genome-wide surveys in a marine species, comparing purple sea urchins, Strongylocentrotus purpuratus, from two distant locations along the species' wide latitudinal range. We examined 9112 polymorphic loci from upstream non-coding and coding regions of genes for signatures of selection with respect to gene function and tissue- and ontogenetic gene expression. We found that genetic differentiation (FST) varied significantly across functional gene classes. The strongest enrichment occurred in the upstream regions of E3 ligase genes, enzymes known to regulate protein abundance during development and environmental stress. We found enrichment for high heterozygosity in genes directly involved in immune response, particularly NALP genes, which mediate pro-inflammatory signals during bacterial infection. We also found higher heterozygosity in immune genes in the southern population, where disease incidence and pathogen diversity are greater. Similar to the major histocompatibility complex in mammals, balancing selection may enhance genetic diversity in the innate immune system genes of this invertebrate. Overall, our results show that how genome-wide polymorphism data coupled with growing databases on gene function and expression can combine to detect otherwise hidden signals of selection in natural populations. PMID:21993504

  7. Significance of genome-wide association studies in molecular anthropology.

    PubMed

    Gupta, Vipin; Khadgawat, Rajesh; Sachdeva, Mohinder Pal

    2009-12-01

    The successful advent of a genome-wide approach in association studies raises the hopes of human geneticists for solving a genetic maze of complex traits especially the disorders. This approach, which is replete with the application of cutting-edge technology and supported by big science projects (like Human Genome Project; and even more importantly the International HapMap Project) and various important databases (SNP database, CNV database, etc.), has had unprecedented success in rapidly uncovering many of the genetic determinants of complex disorders. The magnitude of this approach in the genetics of classical anthropological variables like height, skin color, eye color, and other genome diversity projects has certainly expanded the horizons of molecular anthropology. Therefore, in this article we have proposed a genome-wide association approach in molecular anthropological studies by providing lessons from the exemplary study of the Wellcome Trust Case Control Consortium. We have also highlighted the importance and uniqueness of Indian population groups in facilitating the design and finding optimum solutions for other genome-wide association-related challenges.

  8. Voxelwise genome-wide association study (vGWAS).

    PubMed

    Stein, Jason L; Hua, Xue; Lee, Suh; Ho, April J; Leow, Alex D; Toga, Arthur W; Saykin, Andrew J; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J; Craig, David W; Gerber, Jill D; Allen, April N; Corneveaux, Jason J; Dechairo, Bryan M; Potkin, Steven G; Weiner, Michael W; Thompson, Paul

    2010-11-15

    The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age+/-s.d.: 75.52+/-6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.

  9. Genome-Wide Analysis of a Wnt1-Regulated Transcriptional Network Implicates Neurodegenerative Pathways

    PubMed Central

    Wexler, Eric M.; Rosen, Ezra; Lu, Daning; Osborn, Gregory E.; Martin, Elizabeth; Raybould, Helen; Geschwind, Daniel H.

    2013-01-01

    Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information–based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer’s disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes. PMID:21971039

  10. Genome-wide mapping of DNA methylation in the human malaria parasite Plasmodium falciparum

    PubMed Central

    Ponts, Nadia; Fu, Lijuan; Harris, Elena Y.; Zhang, Jing; Chung, Duk-Won D.; Cervantes, Michael C.; Prudhomme, Jacques; Atanasova-Penichon, Vessela; Zehraoui, Enric; Bunnik, Evelien; Rodrigues, Elisandra M.; Lonardi, Stefano; Hicks, Glenn R.; Wang, Yinsheng; Le Roch, Karine G.

    2014-01-01

    SUMMARY Cytosine DNA methylation is an epigenetic mark in most eukaryotic cells that regulates numerous processes, including gene expression and stress responses. We performed a genome-wide analysis of DNA methylation in the human malaria parasite Plasmodium falciparum. We mapped the positions of methylated cytosines and identified a single functional DNA methyltransferase, PfDNMT, that may mediate these genomic modifications. These analyses revealed that the malaria genome is asymmetrically methylated, in which only one DNA strand is methylated, and shares common features with undifferentiated plant and mammalian cells. Notably, core promoters are hypomethylated and transcript levels correlate with intra-exonic methylation. Additionally, there are sharp methylation transitions at nucleosome and exon-intron boundaries. These data suggest that DNA methylation could regulate virulence gene expression and transcription elongation. Furthermore, the broad range of action of DNA methylation and uniqueness of PfDNMT suggest that the methylation pathway is a potential target for anti-malarial strategies. PMID:24331467

  11. Genome-wide non-CpG methylation of the host genome during M. tuberculosis infection

    PubMed Central

    Sharma, Garima; Sowpati, Divya Tej; Singh, Prakruti; Khan, Mehak Zahoor; Ganji, Rakesh; Upadhyay, Sandeep; Banerjee, Sharmistha; Nandicoori, Vinay Kumar; Khosla, Sanjeev

    2016-01-01

    A mammalian cell utilizes DNA methylation to modulate gene expression in response to environmental changes during development and differentiation. Aberrant DNA methylation changes as a correlate to diseased states like cancer, neurodegenerative conditions and cardiovascular diseases have been documented. Here we show genome-wide DNA methylation changes in macrophages infected with the pathogen M. tuberculosis. Majority of the affected genomic loci were hypermethylated in M. tuberculosis infected THP1 macrophages. Hotspots of differential DNA methylation were enriched in genes involved in immune response and chromatin reorganization. Importantly, DNA methylation changes were observed predominantly for cytosines present in non-CpG dinucleotide context. This observation was consistent with our previous finding that the mycobacterial DNA methyltransferase, Rv2966c, targets non-CpG dinucleotides in the host DNA during M. tuberculosis infection and reiterates the hypothesis that pathogenic bacteria use non-canonical epigenetic strategies during infection. PMID:27112593

  12. Genome-wide non-CpG methylation of the host genome during M. tuberculosis infection.

    PubMed

    Sharma, Garima; Sowpati, Divya Tej; Singh, Prakruti; Khan, Mehak Zahoor; Ganji, Rakesh; Upadhyay, Sandeep; Banerjee, Sharmistha; Nandicoori, Vinay Kumar; Khosla, Sanjeev

    2016-01-01

    A mammalian cell utilizes DNA methylation to modulate gene expression in response to environmental changes during development and differentiation. Aberrant DNA methylation changes as a correlate to diseased states like cancer, neurodegenerative conditions and cardiovascular diseases have been documented. Here we show genome-wide DNA methylation changes in macrophages infected with the pathogen M. tuberculosis. Majority of the affected genomic loci were hypermethylated in M. tuberculosis infected THP1 macrophages. Hotspots of differential DNA methylation were enriched in genes involved in immune response and chromatin reorganization. Importantly, DNA methylation changes were observed predominantly for cytosines present in non-CpG dinucleotide context. This observation was consistent with our previous finding that the mycobacterial DNA methyltransferase, Rv2966c, targets non-CpG dinucleotides in the host DNA during M. tuberculosis infection and reiterates the hypothesis that pathogenic bacteria use non-canonical epigenetic strategies during infection. PMID:27112593

  13. Genome-Wide Assessment of AU-Rich Elements by the AREScore Algorithm

    PubMed Central

    Spasic, Milan; Friedel, Caroline C.; Schott, Johanna; Kreth, Jochen; Leppek, Kathrin; Hofmann, Sarah; Ozgur, Sevim; Stoecklin, Georg

    2012-01-01

    In mammalian cells, AU-rich elements (AREs) are well known regulatory sequences located in the 3′ untranslated region (UTR) of many short-lived mRNAs. AREs cause mRNAs to be degraded rapidly and thereby suppress gene expression at the posttranscriptional level. Based on the number of AUUUA pentamers, their proximity, and surrounding AU-rich regions, we generated an algorithm termed AREScore that identifies AREs and provides a numerical assessment of their strength. By analyzing the AREScore distribution in the transcriptomes of 14 metazoan species, we provide evidence that AREs were selected for in several vertebrates and Drosophila melanogaster. We then measured mRNA expression levels genome-wide to address the importance of AREs in SL2 cells derived from D. melanogaster hemocytes. Tis11, a zinc finger RNA–binding protein homologous to mammalian tristetraprolin, was found to target ARE–containing reporter mRNAs for rapid degradation in SL2 cells. Drosophila mRNAs whose expression is elevated upon knock down of Tis11 were found to have higher AREScores. Moreover high AREScores correlate with reduced mRNA expression levels on a genome-wide scale. The precise measurement of degradation rates for 26 Drosophila mRNAs revealed that the AREScore is a very good predictor of short-lived mRNAs. Taken together, this study introduces AREScore as a simple tool to identify ARE–containing mRNAs and provides compelling evidence that AREs are widespread regulatory elements in Drosophila. PMID:22242014

  14. Genome-Wide Association Study of Metabolic Syndrome in Koreans

    PubMed Central

    Jeong, Seok Won; Chung, Myungguen; Park, Soo-Jung; Cho, Seong Beom

    2014-01-01

    Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 × 10-8), 8 SNPs with genome-wide suggestive p-values (5 × 10-8 ≤ p < 1 × 10-5), and 2 SNPs of more functional variants with borderline p-values (5 × 10-5 ≤ p < 1 × 10-4). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies. PMID:25705157

  15. Genome-wide association study of antisocial personality disorder.

    PubMed

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.

  16. Voxelwise genome-wide association study (vGWAS)

    PubMed Central

    Stein, Jason L.; Hua, Xue; Lee, Suh; Ho, April J.; Leow, Alex D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J.; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.; DeChairo, Bryan M.; Potkin, Steven G.; Weiner, Michael W.; Thompson, Paul M.

    2010-01-01

    The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age±s.d.: 75.52±6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure. PMID:20171287

  17. Genome-Wide Approaches to Drosophila Heart Development

    PubMed Central

    Frasch, Manfred

    2016-01-01

    The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs into studies of cardiogenesis in vertebrates. Many of the major components that control Drosophila cardiogenesis were discovered based on candidate gene approaches and their functions were defined by employing the outstanding genetic tools and molecular techniques available in this system. More recently, approaches have been taken that aim to interrogate the entire genome in order to identify novel components and describe genomic features that are pertinent to the regulation of heart development. Apart from classical forward genetic screens, the availability of the thoroughly annotated Drosophila genome sequence made new genome-wide approaches possible, which include the generation of massive numbers of RNA interference (RNAi) reagents that were used in forward genetic screens, as well as studies of the transcriptomes and proteomes of the developing heart under normal and experimentally manipulated conditions. Moreover, genome-wide chromatin immunoprecipitation experiments have been performed with the aim to define the full set of genomic binding sites of the major cardiogenic transcription factors, their relevant target genes, and a more complete picture of the regulatory network that drives cardiogenesis. This review will give an overview on these genome-wide approaches to Drosophila heart development and on computational analyses of the obtained information that ultimately aim to provide a description of this process at the systems level. PMID:27294102

  18. Genetics, Genome-Wide Association Studies, and Menarche.

    PubMed

    Witchel, Selma Feldman

    2016-07-01

    Puberty is characterized by maturation of the hypothalamic-pituitary-gonadal axis, development of secondary sexual features, increased linear growth velocity, maturation of the epiphyses limiting additional growth, and achievement of menarche. The age at menarche appears to have a significant genetic component. With the advent of genome-wide association studies (GWASs), the genome has been interrogated to find associations between specific loci and age at menarche. It is apparent that multiple genetic loci, epigenetic mechanisms, and environmental factors modulate this biological event crucial for reproductive competence.

  19. Methodological challenges of genome-wide association analysis in Africa

    PubMed Central

    Teo, Yik-Ying; Small, Kerrin S.; Kwiatkowski, Dominic P.

    2013-01-01

    Medical research in Africa has yet to benefit from the advent of genome-wide association (GWA) analysis, partly because the genotyping tools and statistical methods that have been developed for European and Asian populations struggle to deal with the high levels of genome diversity and population structure in Africa. However, the haplotypic diversity of African populations might help to overcome one of the major roadblocks in GWA research, the fine mapping of causal variants. We review the methodological challenges and consider how GWA studies in Africa will be transformed by new approaches in statistical imputation and large-scale genome sequencing. PMID:20084087

  20. [Genome-wide association study for adolescent idiopathic scoliosis].

    PubMed

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS. PMID:27013625

  1. Genome-wide profiling of alternative splicing in Alzheimer's disease

    PubMed Central

    Lai, Mitchell K.P.; Esiri, Margaret M.; Tan, Michelle G.K.

    2014-01-01

    Alternative splicing is a highly regulated process which generates transcriptome and proteome diversity through the skipping or inclusion of exons within gene loci. Identification of aberrant alternative splicing associated with human diseases has become feasible with the development of new genomic technologies and powerful bioinformatics. We have previously reported genome-wide gene alterations in the neocortex of a well-characterized cohort of Alzheimer's disease (AD) patients and matched elderly controls using a commercial exon microarray platform [1]. Here, we provide detailed description of analyses aimed at identifying differential alternative splicing events associated with AD. PMID:26484111

  2. Genetics, Genome-Wide Association Studies, and Menarche.

    PubMed

    Witchel, Selma Feldman

    2016-07-01

    Puberty is characterized by maturation of the hypothalamic-pituitary-gonadal axis, development of secondary sexual features, increased linear growth velocity, maturation of the epiphyses limiting additional growth, and achievement of menarche. The age at menarche appears to have a significant genetic component. With the advent of genome-wide association studies (GWASs), the genome has been interrogated to find associations between specific loci and age at menarche. It is apparent that multiple genetic loci, epigenetic mechanisms, and environmental factors modulate this biological event crucial for reproductive competence. PMID:27513021

  3. Genome-Wide Association Studies for Polycystic Ovary Syndrome.

    PubMed

    Liu, Hongbin; Zhao, Han; Chen, Zi-Jiang

    2016-07-01

    Over the past several years, the field of reproductive medicine has witnessed great advances in genome-wide association studies (GWASs) of polycystic ovary syndrome (PCOS), leading to identification of several promising genes involved in hormone action, type 2 diabetes, and cell proliferation. This review summarizes the key findings and discusses their potential implications with regard to genetic mechanisms of PCOS. Limitations of GWAS are evaluated, emphasizing the understanding of the reasons for variability in results between individual studies. Root causes of misinterpretations of GWASs are also addressed. Finally, the impact of GWAS on future directions of multi- and interdisciplinary studies is discussed. PMID:27513023

  4. [Genome-wide association study for adolescent idiopathic scoliosis].

    PubMed

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS.

  5. Genome-wide association studies and contribution to cardiovascular physiology

    PubMed Central

    Munroe, Patricia B.

    2015-01-01

    The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology. PMID:26106147

  6. Genome-wide association studies and contribution to cardiovascular physiology.

    PubMed

    Munroe, Patricia B; Tinker, Andrew

    2015-09-01

    The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology.

  7. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    PubMed

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Peltonen, Leena; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  8. Genome-wide analysis of DNA methylation in hepatoblastoma tissues

    PubMed Central

    Cui, Ximao; Liu, Baihui; Zheng, Shan; Dong, Kuiran; Dong, Rui

    2016-01-01

    DNA methylation has a crucial role in cancer biology. In the present study, a genome-wide analysis of DNA methylation in hepatoblastoma (HB) tissues was performed to verify differential methylation levels between HB and normal tissues. As alpha-fetoprotein (AFP) has a critical role in HB, AFP methylation levels were also detected using pyrosequencing. Normal and HB liver tissue samples (frozen tissue) were obtained from patients with HB. Genome-wide analysis of DNA methylation in these tissues was performed using an Infinium HumanMethylation450 BeadChip, and the results were confirmed with reverse transcription-quantitative polymerase chain reaction. The Infinium HumanMethylation450 BeadChip demonstrated distinctively less methylation in HB tissues than in non-tumor tissues. In addition, methylation enrichment was observed in positions near the transcription start site of AFP, which exhibited lower methylation levels in HB tissues than in non-tumor liver tissues. Lastly, a significant negative correlation was observed between AFP messenger RNA expression and DNA methylation percentage, using linear Pearson's R correlation coefficients. The present results demonstrate differential methylation levels between HB and normal tissues, and imply that aberrant methylation of AFP in HB could reflect HB development. Expansion of these findings could provide useful insight into HB biology. PMID:27446465

  9. Genome-wide association study of blood pressure and hypertension

    PubMed Central

    Levy, Daniel; Ehret, Georg B.; Rice, Kenneth; Verwoert, Germaine C.; Launer, Lenore J.; Dehghan, Abbas; Glazer, Nicole L.; Morrison, Alanna C.; Johnson, Andrew D.; Aspelund, Thor; Aulchenko, Yurii; Lumley, Thomas; Köttgen, Anna; Vasan, Ramachandran S.; Rivadeneira, Fernando; Eiriksdottir, Gudny; Guo, Xiuqing; Arking, Dan E.; Mitchell, Gary F.; Mattace-Raso, Francesco U.S.; Smith, Albert V; Taylor, Kent; Scharpf, Robert B.; Hwang, Shih-Jen; Sijbrands, Eric J.G.; Bis, Joshua; Harris, Tamara B.; Ganesh, Santhi K.; O’Donnell, Christopher J.; Hofman, Albert; Rotter, Jerome I.; Coresh, Josef; Benjamin, Emelia J.; Uitterlinden, André G.; Heiss, Gerardo; Fox, Caroline S.; Witteman, Jacqueline C.M.; Boerwinkle, Eric; Wang, Thomas J.; Gudnason, Vilmundur; Larson, Martin G.; Chakravarti, Aravinda; Psaty, Bruce M.; van Duijn, Cornelia M.

    2010-01-01

    Blood pressure (BP) is a major cardiovascular disease risk factor. To date, few variants associated with inter-individual BP variation have been identified. A genome-wide association study of systolic (SBP), diastolic BP (DBP), and hypertension in the CHARGE Consortium (n=29,136) identified 13 SNPs for SBP, 20 for DBP, and 10 for hypertension at p <4×10-7. The top 10 loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to number of risk alleles carried. When 10 CHARGE SNPs for each trait were meta-analyzed jointly with the Global BPgen Consortium (n=34,433), four CHARGE loci attained genome-wide significance (p<5×10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK/ULK3, SH2B3, TBX3/TBX5, ULK4), and one for hypertension (ATP2B1). Identifying novel BP genes advances our understanding of BP regulation and highlights potential drug targets for the prevention or treatment of hypertension. PMID:19430479

  10. Phenome-wide analysis of genome-wide polygenic scores

    PubMed Central

    Krapohl, E; Euesden, J; Zabaneh, D; Pingault, J-B; Rimfeld, K; von Stumm, S; Dale, P S; Breen, G; O'Reilly, P F; Plomin, R

    2016-01-01

    Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents' behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development. PMID:26303664

  11. Genome-wide scans for footprints of natural selection

    PubMed Central

    Oleksyk, Taras K.; Smith, Michael W.; O'Brien, Stephen J.

    2010-01-01

    Detecting recent selected ‘genomic footprints’ applies directly to the discovery of disease genes and in the imputation of the formative events that molded modern population genetic structure. The imprints of historic selection/adaptation episodes left in human and animal genomes allow one to interpret modern and ancestral gene origins and modifications. Current approaches to reveal selected regions applied in genome-wide selection scans (GWSSs) fall into eight principal categories: (I) phylogenetic footprinting, (II) detecting increased rates of functional mutations, (III) evaluating divergence versus polymorphism, (IV) detecting extended segments of linkage disequilibrium, (V) evaluating local reduction in genetic variation, (VI) detecting changes in the shape of the frequency distribution (spectrum) of genetic variation, (VII) assessing differentiating between populations (FST), and (VIII) detecting excess or decrease in admixture contribution from one population. Here, we review and compare these approaches using available human genome-wide datasets to provide independent verification (or not) of regions found by different methods and using different populations. The lessons learned from GWSSs will be applied to identify genome signatures of historic selective pressures on genes and gene regions in other species with emerging genome sequences. This would offer considerable potential for genome annotation in functional, developmental and evolutionary contexts. PMID:20008396

  12. Genome-Wide Patterns of Nucleotide Polymorphism in Domesticated Rice

    PubMed Central

    Hernandez, Ryan D; Boyko, Adam; Fledel-Alon, Adi; York, Thomas L; Polato, Nicholas R; Olsen, Kenneth M; Nielsen, Rasmus; McCouch, Susan R; Bustamante, Carlos D; Purugganan, Michael D

    2007-01-01

    Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i) selectively neutral population bottleneck model, (ii) bottleneck plus migration model, (iii) multiple selective sweeps model, and (iv) bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation. PMID:17907810

  13. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    PubMed

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Peltonen, Leena; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision. PMID:26176695

  14. A Pooled Genome-Wide Association Study of Asperger Syndrome

    PubMed Central

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E.; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision. PMID:26176695

  15. Genome-wide identification of hypoxia-induced enhancer regions

    PubMed Central

    Preston, Jessica L.; Randel, Melissa A.; Johnson, Eric A.

    2015-01-01

    Here we present a genome-wide method for de novo identification of enhancer regions. This approach enables massively parallel empirical investigation of DNA sequences that mediate transcriptional activation and provides a platform for discovery of regulatory modules capable of driving context-specific gene expression. The method links fragmented genomic DNA to the transcription of randomer molecule identifiers and measures the functional enhancer activity of the library by massively parallel sequencing. We transfected a Drosophila melanogaster library into S2 cells in normoxia and hypoxia, and assayed 4,599,881 genomic DNA fragments in parallel. The locations of the enhancer regions strongly correlate with genes up-regulated after hypoxia and previously described enhancers. Novel enhancer regions were identified and integrated with RNAseq data and transcription factor motifs to describe the hypoxic response on a genome-wide basis as a complex regulatory network involving multiple stress-response pathways. This work provides a novel method for high-throughput assay of enhancer activity and the genome-scale identification of 31 hypoxia-activated enhancers in Drosophila. PMID:26713262

  16. Genome-wide association study of Tourette Syndrome

    PubMed Central

    Scharf, Jeremiah M.; Yu, Dongmei; Mathews, Carol A.; Neale, Benjamin M.; Stewart, S. Evelyn; Fagerness, Jesen A; Evans, Patrick; Gamazon, Eric; Edlund, Christopher K.; Service, Susan; Tikhomirov, Anna; Osiecki, Lisa; Illmann, Cornelia; Pluzhnikov, Anna; Konkashbaev, Anuar; Davis, Lea K; Han, Buhm; Crane, Jacquelyn; Moorjani, Priya; Crenshaw, Andrew T.; Parkin, Melissa A.; Reus, Victor I.; Lowe, Thomas L.; Rangel-Lugo, Martha; Chouinard, Sylvain; Dion, Yves; Girard, Simon; Cath, Danielle C; Smit, Jan H; King, Robert A.; Fernandez, Thomas; Leckman, James F.; Kidd, Kenneth K.; Kidd, Judith R.; Pakstis, Andrew J.; State, Matthew; Herrera, Luis Diego; Romero, Roxana; Fournier, Eduardo; Sandor, Paul; Barr, Cathy L; Phan, Nam; Gross-Tsur, Varda; Benarroch, Fortu; Pollak, Yehuda; Budman, Cathy L.; Bruun, Ruth D.; Erenberg, Gerald; Naarden, Allan L; Lee, Paul C; Weiss, Nicholas; Kremeyer, Barbara; Berrío, Gabriel Bedoya; Campbell, Desmond; Silgado, Julio C. Cardona; Ochoa, William Cornejo; Restrepo, Sandra C. Mesa; Muller, Heike; Duarte, Ana V. Valencia; Lyon, Gholson J; Leppert, Mark; Morgan, Jubel; Weiss, Robert; Grados, Marco A.; Anderson, Kelley; Davarya, Sarah; Singer, Harvey; Walkup, John; Jankovic, Joseph; Tischfield, Jay A.; Heiman, Gary A.; Gilbert, Donald L.; Hoekstra, Pieter J.; Robertson, Mary M.; Kurlan, Roger; Liu, Chunyu; Gibbs, J. Raphael; Singleton, Andrew; Hardy, John; Strengman, Eric; Ophoff, Roel; Wagner, Michael; Moessner, Rainald; Mirel, Daniel B.; Posthuma, Danielle; Sabatti, Chiara; Eskin, Eleazar; Conti, David V.; Knowles, James A.; Ruiz-Linares, Andres; Rouleau, Guy A.; Purcell, Shaun; Heutink, Peter; Oostra, Ben A.; McMahon, William; Freimer, Nelson; Cox, Nancy J.; Pauls, David L.

    2012-01-01

    Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder. PMID:22889924

  17. A genome-wide association study of aging.

    PubMed

    Walter, Stefan; Atzmon, Gil; Demerath, Ellen W; Garcia, Melissa E; Kaplan, Robert C; Kumari, Meena; Lunetta, Kathryn L; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J; Völker, Uwe; Yu, Lei; Arnold, Alice; Benjamin, Emelia J; Biffar, Reiner; Buchman, Aron S; Boerwinkle, Eric; Couper, David; De Jager, Philip L; Evans, Denis A; Harris, Tamara B; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J; Lohman, Kurt K; Lutsey, Pamela L; Mackenbach, Johan; Marciante, Kristin; Psaty, Bruce M; Reiman, Eric M; Rotter, Jerome I; Seshadri, Sudha; Shardell, Michelle D; Smith, Albert V; van Duijn, Cornelia; Walston, Jeremy; Zillikens, M Carola; Bandinelli, Stefania; Baumeister, Sebastian E; Bennett, David A; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimaki, Mika; Liu, Yongmei; Murabito, Joanne M; Newman, Anne B; Tiemeier, Henning; Franceschini, Nora

    2011-11-01

    Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.

  18. Genome-wide association interaction analysis for Alzheimer's disease.

    PubMed

    Gusareva, Elena S; Carrasquillo, Minerva M; Bellenguez, Céline; Cuyvers, Elise; Colon, Samuel; Graff-Radford, Neill R; Petersen, Ronald C; Dickson, Dennis W; Mahachie John, Jestinah M; Bessonov, Kyrylo; Van Broeckhoven, Christine; Harold, Denise; Williams, Julie; Amouyel, Philippe; Sleegers, Kristel; Ertekin-Taner, Nilüfer; Lambert, Jean-Charles; Van Steen, Kristel; Ramirez, Alfredo

    2014-11-01

    We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = -0.19, p = 0.0006) and cerebellum (β = -0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach.

  19. Genome-wide epigenetic alterations in cloned bovine fetuses.

    PubMed

    Cezar, Gabriela Gebrin; Bartolomei, Marisa S; Forsberg, Erik J; First, Neal L; Bishop, Michael D; Eilertsen, Kenneth J

    2003-03-01

    To gain a better understanding of global methylation differences associated with development of nuclear transfer (NT)-generated cattle, we analyzed the genome-wide methylation status of spontaneously aborted cloned fetuses, cloned fetuses, and adult clones that were derived from transgenic and nontransgenic cumulus, genital ridge, and body cell lines. Cloned fetuses were recovered from ongoing normal pregnancies and were morphologically normal. Fetuses generated by artificial insemination (AI) were used as controls. In vitro fertilization (IVF) fetuses were compared with AI controls to assess effects of in vitro culture on the 5-methylcytosine content of fetal genomes. All of the fetuses were female. Skin biopsies were obtained from cloned and AI-generated adult cows. All of the adult clones were phenotypically normal and lactating and had no history of health or reproductive disorders. Genome-wide cytosine methylation levels were monitored by reverse-phase HPLC, and results indicated reduced levels of methylated cytosine in NT-generated fetuses. In contrast, no differences were observed between adult, lactating clones and similarly aged lactating cows produced by AI. These data imply that survivability of cloned cattle may be closely related to the global DNA methylation status. This is the first report to indicate that global methylation losses may contribute to the developmental failure of cloned bovine fetuses. PMID:12604655

  20. A Genome-Wide Association Study of Aging

    PubMed Central

    Walter, Stefan; Atzmon, Gil; Demerath, Ellen W.; Garcia, Melissa E.; Kaplan, Robert C.; Kumari, Meena; Lunetta, Kathryn L.; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J.; Völker, Uwe; Yu, Lei; Arnold, Alice; Benjamin, Emelia J.; Biffar, Reiner; Buchman, Aron S.; Boerwinkle, Eric; Couper, David; De Jager, Philip L.; Evans, Denis A.; Harris, Tamara B.; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P.; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J.; Lohman, Kurt K.; Lutsey, Pamela L.; Mackenbach, Johan; Marciante, Kristin; Psaty, Bruce M.; Reiman, Eric M.; Rotter, Jerome I.; Seshadri, Sudha; Shardell, Michelle D.; Smith, Albert V.; van Duijn, Cornelia; Walston, Jeremy; Zillikens, M. Carola; Bandinelli, Stefania; Baumeister, Sebastian E.; Bennett, David A.; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimaki, Mika; Liu, Yongmei; Murabito, Joanne M.; Newman, Anne B.; Tiemeier, Henning; Franceschini, Nora

    2011-01-01

    Human longevity and healthy aging show moderate heritability (20–50%). We conducted a meta-analysis of genome-wide association studies from nine studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for two outcomes: a) all-cause mortality and b) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10−8). We found fourteen independent SNPs that predicted risk of death, and eight SNPs that predicted event-free survival (p < 10−5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer’s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity. PMID:21782286

  1. Genome-wide association study of Tourette's syndrome.

    PubMed

    Scharf, J M; Yu, D; Mathews, C A; Neale, B M; Stewart, S E; Fagerness, J A; Evans, P; Gamazon, E; Edlund, C K; Service, S K; Tikhomirov, A; Osiecki, L; Illmann, C; Pluzhnikov, A; Konkashbaev, A; Davis, L K; Han, B; Crane, J; Moorjani, P; Crenshaw, A T; Parkin, M A; Reus, V I; Lowe, T L; Rangel-Lugo, M; Chouinard, S; Dion, Y; Girard, S; Cath, D C; Smit, J H; King, R A; Fernandez, T V; Leckman, J F; Kidd, K K; Kidd, J R; Pakstis, A J; State, M W; Herrera, L D; Romero, R; Fournier, E; Sandor, P; Barr, C L; Phan, N; Gross-Tsur, V; Benarroch, F; Pollak, Y; Budman, C L; Bruun, R D; Erenberg, G; Naarden, A L; Lee, P C; Weiss, N; Kremeyer, B; Berrío, G B; Campbell, D D; Cardona Silgado, J C; Ochoa, W C; Mesa Restrepo, S C; Muller, H; Valencia Duarte, A V; Lyon, G J; Leppert, M; Morgan, J; Weiss, R; Grados, M A; Anderson, K; Davarya, S; Singer, H; Walkup, J; Jankovic, J; Tischfield, J A; Heiman, G A; Gilbert, D L; Hoekstra, P J; Robertson, M M; Kurlan, R; Liu, C; Gibbs, J R; Singleton, A; Hardy, J; Strengman, E; Ophoff, R A; Wagner, M; Moessner, R; Mirel, D B; Posthuma, D; Sabatti, C; Eskin, E; Conti, D V; Knowles, J A; Ruiz-Linares, A; Rouleau, G A; Purcell, S; Heutink, P; Oostra, B A; McMahon, W M; Freimer, N B; Cox, N J; Pauls, D L

    2013-06-01

    Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

  2. Genome-wide association studies of suicidal behaviors: a review.

    PubMed

    Sokolowski, Marcus; Wasserman, Jerzy; Wasserman, Danuta

    2014-10-01

    Suicidal behaviors represent a fatal dimension of mental ill-health, involving both environmental and heritable (genetic) influences. The putative genetic components of suicidal behaviors have until recent years been mainly investigated by hypothesis-driven research (of "candidate genes"). But technological progress in genotyping has opened the possibilities towards (hypothesis-generating) genomic screens and novel opportunities to explore polygenetic perspectives, now spanning a wide array of possible analyses falling under the term Genome-Wide Association Study (GWAS). Here we introduce and discuss broadly some apparent limitations but also certain developing opportunities of GWAS. We summarize the results from all the eight GWAS conducted up to date focused on suicidality outcomes; treatment emergent suicidal ideation (3 studies), suicide attempts (4 studies) and completed suicides (1 study). Clearly, there are few (if any) genome-wide significant and reproducible findings yet to be demonstrated. We then discuss and pinpoint certain future considerations in relation to sample sizes, the units of genetic associations used, study designs and outcome definitions, psychiatric diagnoses or biological measures, as well as the use of genomic sequencing. We conclude that GWAS should have a lot more potential to show in the case of suicidal outcomes, than what has yet been realized. PMID:25219938

  3. Genome-wide signals of positive selection in human evolution

    PubMed Central

    Enard, David; Messer, Philipp W.; Petrov, Dmitri A.

    2014-01-01

    The role of positive selection in human evolution remains controversial. On the one hand, scans for positive selection have identified hundreds of candidate loci, and the genome-wide patterns of polymorphism show signatures consistent with frequent positive selection. On the other hand, recent studies have argued that many of the candidate loci are false positives and that most genome-wide signatures of adaptation are in fact due to reduction of neutral diversity by linked deleterious mutations, known as background selection. Here we analyze human polymorphism data from the 1000 Genomes Project and detect signatures of positive selection once we correct for the effects of background selection. We show that levels of neutral polymorphism are lower near amino acid substitutions, with the strongest reduction observed specifically near functionally consequential amino acid substitutions. Furthermore, amino acid substitutions are associated with signatures of recent adaptation that should not be generated by background selection, such as unusually long and frequent haplotypes and specific distortions in the site frequency spectrum. We use forward simulations to argue that the observed signatures require a high rate of strongly adaptive substitutions near amino acid changes. We further demonstrate that the observed signatures of positive selection correlate better with the presence of regulatory sequences, as predicted by the ENCODE Project Consortium, than with the positions of amino acid substitutions. Our results suggest that adaptation was frequent in human evolution and provide support for the hypothesis of King and Wilson that adaptive divergence is primarily driven by regulatory changes. PMID:24619126

  4. Layers of epistasis: genome-wide regulatory networks and network approaches to genome-wide association studies

    PubMed Central

    Cowper-Sal·lari, Richard; Cole, Michael D.; Karagas, Margaret R.; Lupien, Mathieu; Moore, Jason H.

    2010-01-01

    The conceptual foundation of the genome-wide association study (GWAS) has advanced unchecked since its conception. A revision might seem premature as the potential of GWAS has not been fully realized. Multiple technical and practical limitations need to be overcome before GWAS can be fairly criticized. But with the completion of hundreds of studies and a deeper understanding of the genetic architecture of disease, warnings are being raised. The results compiled to date indicate that risk-associated variants lie predominantly in non-coding regions of the genome. Additionally, alternative methodologies are uncovering large and heterogeneous sets of rare variants underlying disease. The fear is that, even in its fulfilment, the current GWAS paradigm might be incapable of dissecting all kinds of phenotypes. In the following text we review several initiatives that aim to overcome these limitations. The overarching theme of these studies is the inclusion of biological knowledge to both the analysis and interpretation of genotyping data. GWAS is uninformed of biology by design and although there is some virtue in its simplicity it is also its most conspicuous deficiency. We propose a framework in which to integrate these novel approaches, both empirical and theoretical, in the form of a genome-wide regulatory network (GWRN). By processing experimental data into networks, emerging data types based on chromatin-immunoprecipitation are made computationally tractable. This will give GWAS re-analysis efforts the most current and relevant substrates, and root them firmly on our knowledge of human disease. PMID:21197657

  5. Genome-wide association study of antisocial personality disorder

    PubMed Central

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53–3.14), P=1.9 × 10-5). Two polymorphisms at 6p21.2 LINC00951–LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37–1.85), P=1.6 × 10−9) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  6. Genome-wide association study of antisocial personality disorder.

    PubMed

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  7. Genome-wide association studies in pediatric chronic kidney disease.

    PubMed

    Gupta, Jayanta; Kanetsky, Peter A; Wuttke, Matthias; Köttgen, Anna; Schaefer, Franz; Wong, Craig S

    2016-08-01

    The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression.

  8. Biostatistical aspects of genome-wide association studies.

    PubMed

    Ziegler, Andreas; König, Inke R; Thompson, John R

    2008-02-01

    To search the entire human genome for association is a novel and promising approach to unravelling the genetic basis of complex genetic diseases. In these genome-wide association studies (GWAs), several hundreds of thousands of single nucleotide polymorphisms (SNPs) are analyzed at the same time, posing substantial biostatistical and computational challenges. In this paper, we discuss a number of biostatistical aspects of GWAs in detail. We specifically consider quality control issues and show that signal intensity plots are a sine qua condition non in today's GWAs. Approaches to detect and adjust for population stratification are briefly examined. We discuss different strategies aimed at tackling the problem of multiple testing, including adjustment of p -values, the false positive report probability and the false discovery rate. Another aspect of GWAs requiring special attention is the search for gene-gene and gene-environment interactions. We finally describe multistage approaches to GWAs.

  9. Genome-wide transcription factor binding: beyond direct target regulation.

    PubMed

    MacQuarrie, Kyle L; Fong, Abraham P; Morse, Randall H; Tapscott, Stephen J

    2011-04-01

    The binding of transcription factors to specific DNA target sequences is the fundamental basis of gene regulatory networks. Chromatin immunoprecipitation combined with DNA tiling arrays or high-throughput sequencing (ChIP-chip and ChIP-seq, respectively) has been used in many recent studies that detail the binding sites of various transcription factors. Surprisingly, data from a variety of model organisms and tissues have demonstrated that transcription factors vary greatly in their number of genomic binding sites, and that binding events can significantly exceed the number of known or possible direct gene targets. Thus, current understanding of transcription factor function must expand to encompass what role, if any, binding might have outside of direct transcriptional target regulation. In this review, we discuss the biological significance of genome-wide binding of transcription factors and present models that can account for this phenomenon.

  10. Implications of genome-wide association studies in cancer therapeutics.

    PubMed

    Patel, Jai N; McLeod, Howard L; Innocenti, Federico

    2013-09-01

    Genome wide association studies (GWAS) provide an agnostic approach to identifying potential genetic variants associated with disease susceptibility, prognosis of survival and/or predictive of drug response. Although these techniques are costly and interpretation of study results is challenging, they do allow for a more unbiased interrogation of the entire genome, resulting in the discovery of novel genes and understanding of novel biological associations. This review will focus on the implications of GWAS in cancer therapy, in particular germ-line mutations, including findings from major GWAS which have identified predictive genetic loci for clinical outcome and/or toxicity. Lessons and challenges in cancer GWAS are also discussed, including the need for functional analysis and replication, as well as future perspectives for biological and clinical utility. Given the large heterogeneity in response to cancer therapeutics, novel methods of identifying mechanisms and biology of variable drug response and ultimately treatment individualization will be indispensable.

  11. [Peach genomics and genome-wide association study: a review].

    PubMed

    Li, Xiong-Wei; Jia, Hui-Juan; Gao, Zhong-Shan

    2013-10-01

    Peach (Prunus persica (L.) Batsch) is one of the most predominant stone fruits in Rosaceae family. The broad climate adaption, diverse cultivation region and good fruit taste make it one of the favorate fruits by consumers. Improving fruit quality and enhancing disease/pest resistance are always a focus for peach genetists and breeders to follow with interests. This paper reviews the main achievements on linkage map and physical map construction, development of various molecular markers, whole genome sequencing and transcriptome sequencing for peach in recent years, and also elaborates the applications of genome wide association study (GWAS) with high density SNP markers in peach and other plant crops. This review also provides a theoretical basis for GWAS analysis in the future study to identify high efficient markers of targeted traits for peach.

  12. Ultrafast laser nanosurgery in microfluidics for genome-wide screenings

    PubMed Central

    Ben-Yakar, Adela; Bourgeois, Frederic

    2009-01-01

    Summary The use of ultrafast laser pulses in surgery has allowed for unprecedented precision with minimal collateral damage to surrounding tissues. For these reasons, ultrafast laser nanosurgery, as an injury model, has gained tremendous momentum in experimental biology ranging from in-vitro manipulations of subcellular structures to in-vivo studies in whole living organisms. For example, femtosecond laser nanosurgery on such model organism as the nematode Caenorhabditis elegans (C. elegans) has opened new opportunities for in-vivo nerve regeneration studies. Meanwhile, the development of novel microfluidic devices has brought the control in experimental environment to the level required for precise nanosurgery in various animal models. Merging microfluidics and laser nanosurgery has recently improved the specificities and increased the speed of laser surgeries enabling fast genome-wide screenings that can more readily decode the genetic map of various biological processes. PMID:19278850

  13. Genome-wide nucleosome positioning during embryonic stem cell development.

    PubMed

    Teif, Vladimir B; Vainshtein, Yevhen; Caudron-Herger, Maïwen; Mallm, Jan-Philipp; Marth, Caroline; Höfer, Thomas; Rippe, Karsten

    2012-11-01

    We determined genome-wide nucleosome occupancies in mouse embryonic stem cells and their neural progenitor and embryonic fibroblast counterparts to assess features associated with nucleosome positioning during lineage commitment. Cell-type- and protein-specific binding preferences of transcription factors to sites with either low (Myc, Klf4 and Zfx) or high (Nanog, Oct4 and Sox2) nucleosome occupancy as well as complex patterns for CTCF were identified. Nucleosome-depleted regions around transcription start and transcription termination sites were broad and more pronounced for active genes, with distinct patterns for promoters classified according to CpG content or histone methylation marks. Throughout the genome, nucleosome occupancy was correlated with certain histone methylation or acetylation modifications. In addition, the average nucleosome repeat length increased during differentiation by 5-7 base pairs, with local variations for specific regions. Our results reveal regulatory mechanisms of cell differentiation that involve nucleosome repositioning. PMID:23085715

  14. Genome-wide association studies in pharmacogenomics of antidepressants.

    PubMed

    Lin, Eugene; Lane, Hsien-Yuan

    2015-01-01

    Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Doctors must prescribe antidepressants based on educated guesses due to the fact that it is unmanageable to predict the effectiveness of any particular antidepressant in an individual patient. With the recent advent of scientific research, the genome-wide association study (GWAS) is extensively employed to analyze hundreds of thousands of single nucleotide polymorphisms by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been utilized to investigate the determinants of antidepressant response to therapy. In this study, we reviewed GWAS studies, their limitations and future directions with respect to the pharmacogenomics of antidepressants in MDD.

  15. Progress of genome wide association study in domestic animals

    PubMed Central

    2012-01-01

    Domestic animals are invaluable resources for study of the molecular architecture of complex traits. Although the mapping of quantitative trait loci (QTL) responsible for economically important traits in domestic animals has achieved remarkable results in recent decades, not all of the genetic variation in the complex traits has been captured because of the low density of markers used in QTL mapping studies. The genome wide association study (GWAS), which utilizes high-density single-nucleotide polymorphism (SNP), provides a new way to tackle this issue. Encouraging achievements in dissection of the genetic mechanisms of complex diseases in humans have resulted from the use of GWAS. At present, GWAS has been applied to the field of domestic animal breeding and genetics, and some advances have been made. Many genes or markers that affect economic traits of interest in domestic animals have been identified. In this review, advances in the use of GWAS in domestic animals are described. PMID:22958308

  16. Quantitative prediction of genome-wide resource allocation in bacteria.

    PubMed

    Goelzer, Anne; Muntel, Jan; Chubukov, Victor; Jules, Matthieu; Prestel, Eric; Nölker, Rolf; Mariadassou, Mahendra; Aymerich, Stéphane; Hecker, Michael; Noirot, Philippe; Becher, Dörte; Fromion, Vincent

    2015-11-01

    Predicting resource allocation between cell processes is the primary step towards decoding the evolutionary constraints governing bacterial growth under various conditions. Quantitative prediction at genome-scale remains a computational challenge as current methods are limited by the tractability of the problem or by simplifying hypotheses. Here, we show that the constraint-based modeling method Resource Balance Analysis (RBA), calibrated using genome-wide absolute protein quantification data, accurately predicts resource allocation in the model bacterium Bacillus subtilis for a wide range of growth conditions. The regulation of most cellular processes is consistent with the objective of growth rate maximization except for a few suboptimal processes which likely integrate more complex objectives such as coping with stressful conditions and survival. As a proof of principle by using simulations, we illustrated how calibrated RBA could aid rational design of strains for maximizing protein production, offering new opportunities to investigate design principles in prokaryotes and to exploit them for biotechnological applications.

  17. Quality control for genome-wide association studies.

    PubMed

    Gondro, Cedric; Lee, Seung Hwan; Lee, Hak Kyo; Porto-Neto, Laercio R

    2013-01-01

    This chapter overviews the quality control (QC) issues for SNP-based genotyping methods used in genome-wide association studies. The main metrics for evaluating the quality of the genotypes are discussed followed by a worked out example of QC pipeline starting with raw data and finishing with a fully filtered dataset ready for downstream analysis. The emphasis is on automation of data storage, filtering, and manipulation to ensure data integrity throughput the process and on how to extract a global summary from these high dimensional datasets to allow better-informed downstream analytical decisions. All examples will be run using the R statistical programming language followed by a practical example using a fully automated QC pipeline for the Illumina platform.

  18. Genome-wide genetic changes during modern breeding of maize.

    PubMed

    Jiao, Yinping; Zhao, Hainan; Ren, Longhui; Song, Weibin; Zeng, Biao; Guo, Jinjie; Wang, Baobao; Liu, Zhipeng; Chen, Jing; Li, Wei; Zhang, Mei; Xie, Shaojun; Lai, Jinsheng

    2012-06-03

    The success of modern maize breeding has been demonstrated by remarkable increases in productivity over the last four decades. However, the underlying genetic changes correlated with these gains remain largely unknown. We report here the sequencing of 278 temperate maize inbred lines from different stages of breeding history, including deep resequencing of 4 lines with known pedigree information. The results show that modern breeding has introduced highly dynamic genetic changes into the maize genome. Artificial selection has affected thousands of targets, including genes and non-genic regions, leading to a reduction in nucleotide diversity and an increase in the proportion of rare alleles. Genetic changes during breeding happen rapidly, with extensive variation (SNPs, indels and copy-number variants (CNVs)) occurring, even within identity-by-descent regions. Our genome-wide assessment of genetic changes during modern maize breeding provides new strategies as well as practical targets for future crop breeding and biotechnology.

  19. Genome-wide screening using RNAi (RNA interference) to study host factors in viral replication and pathogenesis

    PubMed Central

    Houzet, Laurent; Jeang, Kuan-Teh

    2012-01-01

    With the recent development of siRNA and shRNA expression libraries, RNAi technology has been extensively employed to identify genes involved in diverse cellular processes, such as signal transduction, cell cycle, cancer biology and host-pathogen interactions. In the field of viral infection, this approach has already identified hundreds of new genes not previously known to be important for various virus lifecycles. In this brief review, we focus on recent studies performed using genome-wide RNAi-based screens in mammalian cells for the identification of essential host factors for viral infection and pathogenesis. PMID:21727185

  20. Species Delimitation using Genome-Wide SNP Data

    PubMed Central

    Leaché, Adam D.; Fujita, Matthew K.; Minin, Vladimir N.; Bouckaert, Remco R.

    2014-01-01

    The multispecies coalescent has provided important progress for evolutionary inferences, including increasing the statistical rigor and objectivity of comparisons among competing species delimitation models. However, Bayesian species delimitation methods typically require brute force integration over gene trees via Markov chain Monte Carlo (MCMC), which introduces a large computation burden and precludes their application to genomic-scale data. Here we combine a recently introduced dynamic programming algorithm for estimating species trees that bypasses MCMC integration over gene trees with sophisticated methods for estimating marginal likelihoods, needed for Bayesian model selection, to provide a rigorous and computationally tractable technique for genome-wide species delimitation. We provide a critical yet simple correction that brings the likelihoods of different species trees, and more importantly their corresponding marginal likelihoods, to the same common denominator, which enables direct and accurate comparisons of competing species delimitation models using Bayes factors. We test this approach, which we call Bayes factor delimitation (*with genomic data; BFD*), using common species delimitation scenarios with computer simulations. Varying the numbers of loci and the number of samples suggest that the approach can distinguish the true model even with few loci and limited samples per species. Misspecification of the prior for population size θ has little impact on support for the true model. We apply the approach to West African forest geckos (Hemidactylus fasciatus complex) using genome-wide SNP data. This new Bayesian method for species delimitation builds on a growing trend for objective species delimitation methods with explicit model assumptions that are easily tested. [Bayes factor; model testing; phylogeography; RADseq; simulation; speciation.] PMID:24627183

  1. Genome-Wide Binding Patterns of Thyroid Hormone Receptor Beta

    PubMed Central

    Ayers, Stephen; Switnicki, Michal Piotr; Angajala, Anusha; Lammel, Jan; Arumanayagam, Anithachristy S.; Webb, Paul

    2014-01-01

    Thyroid hormone (TH) receptors (TRs) play central roles in metabolism and are major targets for pharmaceutical intervention. Presently, however, there is limited information about genome wide localizations of TR binding sites. Thus, complexities of TR genomic distribution and links between TRβ binding events and gene regulation are not fully appreciated. Here, we employ a BioChIP approach to capture TR genome-wide binding events in a liver cell line (HepG2). Like other NRs, TRβ appears widely distributed throughout the genome. Nevertheless, there is striking enrichment of TRβ binding sites immediately 5′ and 3′ of transcribed genes and TRβ can be detected near 50% of T3 induced genes. In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system. Canonical TRE half-sites are present in more than 90% of TRβ peaks and classical TREs are also greatly enriched, but individual TRE organization appears highly variable with diverse half-site orientation and spacing. There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks. We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions. Better understanding of genomic context of TR binding sites will help us determine why TR regulates genes in different ways and determine possibilities for selective modulation of TR action. PMID:24558356

  2. Genome-Wide Association Studies for Comb Traits in Chickens

    PubMed Central

    Ma, Meng; Dou, Taocun; Lu, Jian; Guo, Jun; Hu, Yuping; Yi, Guoqiang; Yuan, Jingwei; Sun, Congjiao; Wang, Kehua; Yang, Ning

    2016-01-01

    The comb, as a secondary sexual character, is an important trait in chicken. Indicators of comb length (CL), comb height (CH), and comb weight (CW) are often selected in production. DNA-based marker-assisted selection could help chicken breeders to accelerate genetic improvement for comb or related economic characters by early selection. Although a number of quantitative trait loci (QTL) and candidate genes have been identified with advances in molecular genetics, candidate genes underlying comb traits are limited. The aim of the study was to use genome-wide association (GWA) studies by 600 K Affymetrix chicken SNP arrays to detect genes that are related to comb, using an F2 resource population. For all comb characters, comb exhibited high SNP-based heritability estimates (0.61–0.69). Chromosome 1 explained 20.80% genetic variance, while chromosome 4 explained 6.89%. Independent univariate genome-wide screens for each character identified 127, 197, and 268 novel significant SNPs with CL, CH, and CW, respectively. Three candidate genes, VPS36, AR, and WNT11B, were determined to have a plausible function in all comb characters. These genes are important to the initiation of follicle development, gonadal growth, and dermal development, respectively. The current study provides the first GWA analysis for comb traits. Identification of the genetic basis as well as promising candidate genes will help us understand the underlying genetic architecture of comb development and has practical significance in breeding programs for the selection of comb as an index for sexual maturity or reproduction. PMID:27427764

  3. A genome-wide association study of anorexia nervosa

    PubMed Central

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Landt, Margarita CT Slof-Op t; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2015-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  4. A genome-wide association study of anorexia nervosa

    PubMed Central

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Slof-Op t Landt, Margarita CT; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O’Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2013-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:21079607

  5. Genome-wide association and genomic selection in animal breeding.

    PubMed

    Hayes, Ben; Goddard, Mike

    2010-11-01

    Results from genome-wide association studies in livestock, and humans, has lead to the conclusion that the effect of individual quantitative trait loci (QTL) on complex traits, such as yield, are likely to be small; therefore, a large number of QTL are necessary to explain genetic variation in these traits. Given this genetic architecture, gains from marker-assisted selection (MAS) programs using only a small number of DNA markers to trace a limited number of QTL is likely to be small. This has lead to the development of alternative technology for using the available dense single nucleotide polymorphism (SNP) information, called genomic selection. Genomic selection uses a genome-wide panel of dense markers so that all QTL are likely to be in linkage disequilibrium with at least one SNP. The genomic breeding values are predicted to be the sum of the effect of these SNPs across the entire genome. In dairy cattle breeding, the accuracy of genomic estimated breeding values (GEBV) that can be achieved and the fact that these are available early in life have lead to rapid adoption of the technology. Here, we discuss the design of experiments necessary to achieve accurate prediction of GEBV in future generations in terms of the number of markers necessary and the size of the reference population where marker effects are estimated. We also present a simple method for implementing genomic selection using a genomic relationship matrix. Future challenges discussed include using whole genome sequence data to improve the accuracy of genomic selection and management of inbreeding through genomic relationships.

  6. A genome-wide association study of anorexia nervosa.

    PubMed

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-10-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

  7. A genome-wide association study of anorexia nervosa.

    PubMed

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-10-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  8. Genome-Wide Association Studies for Comb Traits in Chickens.

    PubMed

    Shen, Manman; Qu, Liang; Ma, Meng; Dou, Taocun; Lu, Jian; Guo, Jun; Hu, Yuping; Yi, Guoqiang; Yuan, Jingwei; Sun, Congjiao; Wang, Kehua; Yang, Ning

    2016-01-01

    The comb, as a secondary sexual character, is an important trait in chicken. Indicators of comb length (CL), comb height (CH), and comb weight (CW) are often selected in production. DNA-based marker-assisted selection could help chicken breeders to accelerate genetic improvement for comb or related economic characters by early selection. Although a number of quantitative trait loci (QTL) and candidate genes have been identified with advances in molecular genetics, candidate genes underlying comb traits are limited. The aim of the study was to use genome-wide association (GWA) studies by 600 K Affymetrix chicken SNP arrays to detect genes that are related to comb, using an F2 resource population. For all comb characters, comb exhibited high SNP-based heritability estimates (0.61-0.69). Chromosome 1 explained 20.80% genetic variance, while chromosome 4 explained 6.89%. Independent univariate genome-wide screens for each character identified 127, 197, and 268 novel significant SNPs with CL, CH, and CW, respectively. Three candidate genes, VPS36, AR, and WNT11B, were determined to have a plausible function in all comb characters. These genes are important to the initiation of follicle development, gonadal growth, and dermal development, respectively. The current study provides the first GWA analysis for comb traits. Identification of the genetic basis as well as promising candidate genes will help us understand the underlying genetic architecture of comb development and has practical significance in breeding programs for the selection of comb as an index for sexual maturity or reproduction. PMID:27427764

  9. A genome-wide association study of attempted suicide

    PubMed Central

    Willour, Virginia L.; Seifuddin, Fayaz; Mahon, Pamela B.; Jancic, Dubravka; Pirooznia, Mehdi; Steele, Jo; Schweizer, Barbara; Goes, Fernando S.; Mondimore, Francis M.; MacKinnon, Dean F.; Perlis, Roy H.; Lee, Phil Hyoun; Huang, Jie; Kelsoe, John R.; Shilling, Paul D.; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Purcell, Shaun; Smoller, Jordan W.; Craddock, Nicholas; DePaulo, J. Raymond; Schulze, Thomas G.; McMahon, Francis J.; Zandi, Peter P.; Potash, James B.

    2011-01-01

    The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. While attempted suicide linkage regions have been identified on 2p11–12 and 6q25–26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single nucleotide polymorphism (SNP) genotypes of 1,201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1,497 BP subjects without a history of suicide attempts. 2,507 SNPs with evidence for association at p<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (p= 5.07 × 10−8). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide. PMID:21423239

  10. A genome-wide association study of attempted suicide.

    PubMed

    Willour, V L; Seifuddin, F; Mahon, P B; Jancic, D; Pirooznia, M; Steele, J; Schweizer, B; Goes, F S; Mondimore, F M; Mackinnon, D F; Perlis, R H; Lee, P H; Huang, J; Kelsoe, J R; Shilling, P D; Rietschel, M; Nöthen, M; Cichon, S; Gurling, H; Purcell, S; Smoller, J W; Craddock, N; DePaulo, J R; Schulze, T G; McMahon, F J; Zandi, P P; Potash, J B

    2012-04-01

    The heritable component to attempted and completed suicide is partly related to psychiatric disorders and also partly independent of them. Although attempted suicide linkage regions have been identified on 2p11-12 and 6q25-26, there are likely many more such loci, the discovery of which will require a much higher resolution approach, such as the genome-wide association study (GWAS). With this in mind, we conducted an attempted suicide GWAS that compared the single-nucleotide polymorphism (SNP) genotypes of 1201 bipolar (BP) subjects with a history of suicide attempts to the genotypes of 1497 BP subjects without a history of suicide attempts. In all, 2507 SNPs with evidence for association at P<0.001 were identified. These associated SNPs were subsequently tested for association in a large and independent BP sample set. None of these SNPs were significantly associated in the replication sample after correcting for multiple testing, but the combined analysis of the two sample sets produced an association signal on 2p25 (rs300774) at the threshold of genome-wide significance (P=5.07 × 10(-8)). The associated SNPs on 2p25 fall in a large linkage disequilibrium block containing the ACP1 (acid phosphatase 1) gene, a gene whose expression is significantly elevated in BP subjects who have completed suicide. Furthermore, the ACP1 protein is a tyrosine phosphatase that influences Wnt signaling, a pathway regulated by lithium, making ACP1 a functional candidate for involvement in the phenotype. Larger GWAS sample sets will be required to confirm the signal on 2p25 and to identify additional genetic risk factors increasing susceptibility for attempted suicide. PMID:21423239

  11. The CHR site: definition and genome-wide identification of a cell cycle transcriptional element

    PubMed Central

    Müller, Gerd A.; Wintsche, Axel; Stangner, Konstanze; Prohaska, Sonja J.; Stadler, Peter F.; Engeland, Kurt

    2014-01-01

    The cell cycle genes homology region (CHR) has been identified as a DNA element with an important role in transcriptional regulation of late cell cycle genes. It has been shown that such genes are controlled by DREAM, MMB and FOXM1-MuvB and that these protein complexes can contact DNA via CHR sites. However, it has not been elucidated which sequence variations of the canonical CHR are functional and how frequent CHR-based regulation is utilized in mammalian genomes. Here, we define the spectrum of functional CHR elements. As the basis for a computational meta-analysis, we identify new CHR sequences and compile phylogenetic motif conservation as well as genome-wide protein-DNA binding and gene expression data. We identify CHR elements in most late cell cycle genes binding DREAM, MMB, or FOXM1-MuvB. In contrast, Myb- and forkhead-binding sites are underrepresented in both early and late cell cycle genes. Our findings support a general mechanism: sequential binding of DREAM, MMB and FOXM1-MuvB complexes to late cell cycle genes requires CHR elements. Taken together, we define the group of CHR-regulated genes in mammalian genomes and provide evidence that the CHR is the central promoter element in transcriptional regulation of late cell cycle genes by DREAM, MMB and FOXM1-MuvB. PMID:25106871

  12. Neuroinformatics for genome-wide 3D gene expression mapping in the mouse brain.

    PubMed

    Ng, Lydia; Pathak, Sayan D; Kuan, Chihchau; Lau, Chris; Dong, Hongwei; Sodt, Andrew; Dang, Chinh; Avants, Brian; Yushkevich, Paul; Gee, James C; Haynor, David; Lein, Ed; Jones, Allan; Hawrylycz, Mike

    2007-01-01

    Large scale gene expression studies in the mammalian brain offer the promise of understanding the topology, networks and ultimately the function of its complex anatomy, opening previously unexplored avenues in neuroscience. High-throughput methods permit genome-wide searches to discover genes that are uniquely expressed in brain circuits and regions that control behavior. Previous gene expression mapping studies in model organisms have employed situ hybridization (ISH), a technique that uses labeled nucleic acid probes to bind to specific mRNA transcripts in tissue sections. A key requirement for this effort is the development of fast and robust algorithms for anatomically mapping and quantifying gene expression for ISH. We describe a neuroinformatics pipeline for automatically mapping expression profiles of ISH data and its use to produce the first genomic scale 3-D mapping of gene expression in a mammalian brain. The pipeline is fully automated and adaptable to other organisms and tissues. Our automated study of over 20,000 genes indicates that at least 78.8 percent are expressed at some level in the adult C56BL/6J mouse brain. In addition to providing a platform for genomic scale search, high-resolution images and visualization tools for expression analysis are available at the Allen Brain Atlas web site (http://www.brain-map.org).

  13. H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase

    PubMed Central

    Zhou, Jichun; Yang, Lihua; Zhong, Tianyu; Mueller, Martin; Men, Yi; Zhang, Na; Xie, Juanke; Giang, Karolyn; Chung, Hunter; Sun, Xueguang; Lu, Lingeng; Carmichael, Gordon G; Taylor, Hugh S; Huang, Yingqun

    2015-01-01

    DNA methylation is essential for mammalian development and physiology. Here we report that the developmentally regulated H19 lncRNA binds to and inhibits S-adenosylhomocysteine hydrolase (SAHH), the only mammalian enzyme capable of hydrolysing S-adenosylhomocysteine (SAH). SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases that methylate diverse cellular components, including DNA, RNA, proteins, lipids and neurotransmitters. We show that H19 knockdown activates SAHH, leading to increased DNMT3B-mediated methylation of an lncRNA-encoding gene Nctc1 within the Igf2-H19-Nctc1 locus. Genome-wide methylation profiling reveals methylation changes at numerous gene loci consistent with SAHH modulation by H19. Our results uncover an unanticipated regulatory circuit involving broad epigenetic alterations by a single abundantly expressed lncRNA that may underlie gene methylation dynamics of development and diseases and suggest that this mode of regulation may extend to other cellular components. PMID:26687445

  14. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  15. Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei.

    PubMed

    Mony, Binny M; MacGregor, Paula; Ivens, Alasdair; Rojas, Federico; Cowton, Andrew; Young, Julie; Horn, David; Matthews, Keith

    2014-01-30

    The protozoan parasites Trypanosoma brucei spp. cause important human and livestock diseases in sub-Saharan Africa. In mammalian blood, two developmental forms of the parasite exist: proliferative 'slender' forms and arrested 'stumpy' forms that are responsible for transmission to tsetse flies. The slender to stumpy differentiation is a density-dependent response that resembles quorum sensing in microbial systems and is crucial for the parasite life cycle, ensuring both infection chronicity and disease transmission. This response is triggered by an elusive 'stumpy induction factor' (SIF) whose intracellular signalling pathway is also uncharacterized. Laboratory-adapted (monomorphic) trypanosome strains respond inefficiently to SIF but can generate forms with stumpy characteristics when exposed to cell-permeable cAMP and AMP analogues. Exploiting this, we have used a genome-wide RNA interference library screen to identify the signalling components driving stumpy formation. In separate screens, monomorphic parasites were exposed to 8-(4-chlorophenylthio)-cAMP (pCPT-cAMP) or 8-pCPT-2'-O-methyl-5'-AMP to select cells that were unresponsive to these signals and hence remained proliferative. Genome-wide Ion Torrent based RNAi target sequencing identified cohorts of genes implicated in each step of the signalling pathway, from purine metabolism, through signal transducers (kinases, phosphatases) to gene expression regulators. Genes at each step were independently validated in cells naturally capable of stumpy formation, confirming their role in density sensing in vivo. The putative RNA-binding protein, RBP7, was required for normal quorum sensing and promoted cell-cycle arrest and transmission competence when overexpressed. This study reveals that quorum sensing signalling in trypanosomes shares similarities to fundamental quiescence pathways in eukaryotic cells, its components providing targets for quorum-sensing interference-based therapeutics.

  16. Genome-wide 5-hydroxymethylcytosine modification pattern is a novel epigenetic feature of globozoospermia.

    PubMed

    Wang, Xiu-Xia; Sun, Bao-Fa; Jiao, Jiao; Chong, Ze-Chen; Chen, Yu-Shen; Wang, Xiao-Li; Zhao, Yue; Zhou, Yi-Ming; Li, Da

    2015-03-30

    Discovery of 5-hydroxymethylcytosine (5hmC) in mammalian genomes has excited the field of epigenetics, but information on the genome-wide distribution of 5hmC is limited. Globozoospermia is a rare but severe cause of male infertility. To date, the epigenetic mechanism, especially 5hmC profiles involved in globozoospermia progression, remains largely unknown. Here, utilizing the chemical labeling and biotin-enrichment approach followed by Illumina HiSeq sequencing, we showed that (i) 6664, 9029 and 6318 genes contain 5hmC in normal, abnormal, and globozoospermia sperm, respectively; (ii) some 5hmC-containing genes significantly involves in spermatogenesis, sperm motility and morphology, and gamete generation; (iii) 5hmC is exclusively localized in sperm intron; (iv) approximately 40% imprinted genes have 5hmC modification in sperm genomes, but globozoospermia sperm exhibiting a large portion of imprinted genes lose the 5hmC modification; (v) six imprinted genes showed different 5hmC patterns in abnormal sperm (GDAP1L1, GNAS, KCNK9, LIN28B, RB1, RTL1), and five imprinted genes showed different 5hmC patterns in globozoospermia sperm (KCNK9, LIN28B, RB1, SLC22A18, ZDBF2). These results suggested that differences in genome-wide 5hmC patterns may in part be responsible for the sperm phenotype. All of this may improve our understanding of the basic molecular mechanism underlying sperm biology and the etiology of male infertility.

  17. Genome-wide 5-hydroxymethylcytosine modification pattern is a novel epigenetic feature of globozoospermia.

    PubMed

    Wang, Xiu-Xia; Sun, Bao-Fa; Jiao, Jiao; Chong, Ze-Chen; Chen, Yu-Shen; Wang, Xiao-Li; Zhao, Yue; Zhou, Yi-Ming; Li, Da

    2015-03-30

    Discovery of 5-hydroxymethylcytosine (5hmC) in mammalian genomes has excited the field of epigenetics, but information on the genome-wide distribution of 5hmC is limited. Globozoospermia is a rare but severe cause of male infertility. To date, the epigenetic mechanism, especially 5hmC profiles involved in globozoospermia progression, remains largely unknown. Here, utilizing the chemical labeling and biotin-enrichment approach followed by Illumina HiSeq sequencing, we showed that (i) 6664, 9029 and 6318 genes contain 5hmC in normal, abnormal, and globozoospermia sperm, respectively; (ii) some 5hmC-containing genes significantly involves in spermatogenesis, sperm motility and morphology, and gamete generation; (iii) 5hmC is exclusively localized in sperm intron; (iv) approximately 40% imprinted genes have 5hmC modification in sperm genomes, but globozoospermia sperm exhibiting a large portion of imprinted genes lose the 5hmC modification; (v) six imprinted genes showed different 5hmC patterns in abnormal sperm (GDAP1L1, GNAS, KCNK9, LIN28B, RB1, RTL1), and five imprinted genes showed different 5hmC patterns in globozoospermia sperm (KCNK9, LIN28B, RB1, SLC22A18, ZDBF2). These results suggested that differences in genome-wide 5hmC patterns may in part be responsible for the sperm phenotype. All of this may improve our understanding of the basic molecular mechanism underlying sperm biology and the etiology of male infertility. PMID:25762640

  18. Genome-wide detection of DNase I hypersensitive sites in single cells and FFPE tissue samples.

    PubMed

    Jin, Wenfei; Tang, Qingsong; Wan, Mimi; Cui, Kairong; Zhang, Yi; Ren, Gang; Ni, Bing; Sklar, Jeffrey; Przytycka, Teresa M; Childs, Richard; Levens, David; Zhao, Keji

    2015-12-01

    DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells. Conventional DNase sequencing (DNase-seq) for genome-wide DHSs profiling is limited by the requirement of millions of cells. Here we report an ultrasensitive strategy, called single-cell DNase sequencing (scDNase-seq) for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single-cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and enhancers associated with multiple active histone modifications display constitutive DHS whereas chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply scDNase-seq to pools of tumour cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded tissue slides from patients with thyroid cancer, and detect thousands of tumour-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one mutation (chr18: 52417839G>C) in the tumour cells of a patient with follicular thyroid carcinoma, which affects the binding of the tumour suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, scDNase-seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis both for basic and for translational research, and may provide critical information for personalized medicine. PMID:26605532

  19. Genome-wide Detection of DNase I Hypersensitive Sites in Single Cells and FFPE Samples

    PubMed Central

    Jin, Wenfei; Tang, Qingsong; Wan, Mimi; Cui, Kairong; Zhang, Yi; Ren, Gang; Ni, Bing; Sklar, Jeffrey; Przytycka, Teresa M.; Childs, Richard; Levens, David; Zhao, Keji

    2015-01-01

    DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells1–3. Conventional DNase-Seq for genome-wide DHSs profiling is limited by the requirement of millions of cells4,5. Here we report an ultrasensitive strategy, called Pico-Seq, for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and the enhancers associated with multiple active histone modifications display constitutive DHS while chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply Pico-Seq to pools of tumor cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded (FFPE) tissue slides from thyroid cancer patients, and detect thousands of tumor-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one single-nucleotide variant (chr18:52417839 G>C) in the tumor cells of a follicular thyroid carcinoma patient, which affects the binding of the tumor suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, Pico-Seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis for both basic and translational research and may provide critical information for personalized medicine. PMID:26605532

  20. Comparative analysis of methods for genome-wide nucleosome cartography.

    PubMed

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use. PMID:25296770

  1. Insights into kidney diseases from genome-wide association studies.

    PubMed

    Wuttke, Matthias; Köttgen, Anna

    2016-09-01

    Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin-to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD-defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology.

  2. Genome-wide significant risk associations for mucinous ovarian carcinoma.

    PubMed

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; Lee, Janet M; Seo, Ji-Heui; Phelan, Catherine M; Beesley, Jonathan; Chen, Xiaoqing; Spindler, Tassja J; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia

    2015-08-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  3. Genome-wide discovery of DNA polymorphism in Brassica rapa.

    PubMed

    Park, Soomin; Yu, Hee-Ju; Mun, Jeong-Hwan; Lee, Seung-Chan

    2010-02-01

    Single nucleotide polymorphisms (SNPs) and/or insertion/deletions (InDels) are frequent sequence variations in the plant genome, which can be developed as molecular markers for genetic studies on crop improvement. The ongoing Brassica rapa genome sequencing project has generated vast amounts of sequence data useful in genetic research. Here, we report a genome-wide survey of DNA polymorphisms in the B. rapa genome based on the 557 bacterial artificial clone sequences of B. rapa ssp. pekinensis cv. Chiifu. We identified and characterized 21,311 SNPs and 6,753 InDels in the gene space of the B. rapa genome by re-sequencing 1,398 sequence-tagged sites (STSs) in eight genotypes. Comparison of our findings with a B. rapa genetic linkage map confirmed that STS loci were distributed randomly over the B. rapa whole genome. In the 1.4 Mb of aligned sequences, mean nucleotide polymorphism and diversity were theta = 0.00890 and pi = 0.00917, respectively. Additionally, the nucleotide diversity in introns was almost three times greater than that in exons, and the frequency of observed InDel was almost 17 times higher in introns than in exons. Information regarding SNPs/InDels obtained here will provide an important resource for genetic studies and breeding programs of B. rapa.

  4. Genome-wide association study and premature ovarian failure.

    PubMed

    Christin-Maitre, S; Tachdjian, G

    2010-05-01

    Premature ovarian failure (POF) is defined as an amenorrhea for more than 4months, associated with elevated gonadotropins, usually higher than 20mIU/ml, occurring in a woman before the age of 40. Some candidate genes have been identified in the past 15years, such as FOXL2, FSHR, BMP15, GDF9, Xfra premutation. However, POF etiology remains unknown in more than 90% of cases. The first strategy to identify candidate gene, apart from studying genes involved in ovarian failure in animal models, relies on the study of X chromosome deletions and X;autosome translocations in patients. The second strategy is based on linkage analysis, the third one on Comparative Genomic Hybridization (CGH) array. The latest strategy relies on Genome-Wide Association Studies (GWAS). This technique consists in screening single nucleotide polymorphisms (SNPs) in patients and controls. So far, three studies have been performed and have identified different loci potentially linked to POF, such as PTHB1 and ADAMTS19. However, replications in independent cohorts need to be performed. GWAS studies on large cohorts of women with POF should find new candidate genes in the near future.

  5. Genome-wide discovery of maternal effect variants

    PubMed Central

    2009-01-01

    Many phenotypes may be influenced by the prenatal environment of the mother and/or maternal care, and these maternal effects may have a heritable component. We have implemented in the computer program SOLAR a variance components-based method for detecting indirect effects of maternal genotype on offspring phenotype. Of six phenotypes measured in three generations of the Framingham Heart Study, height showed the strongest evidence (P = 0.02) of maternal effect. We conducted a genome-wide association analysis for height, testing both the direct effect of the focal individual's genotype and the indirect effect of the maternal genotype. Offspring height showed suggestive evidence of association with maternal genotype for two single-nucleotide polymorphisms in the trafficking protein particle complex 9 gene TRAPPC9 (NIBP), which plays a role in neuronal NF-κB signalling. This work establishes a methodological framework for identifying genetic variants that may influence the contribution of the maternal environment to offspring phenotypes. PMID:20018008

  6. Genome-wide transcriptome analysis of human epidermal melanocytes

    PubMed Central

    Haltaufderhyde, Kirk D.; Oancea, Elena

    2015-01-01

    Because human epidermal melanocytes (HEMs) provide critical protection against skin cancer, sunburn, and photoaging, a genome-wide perspective of gene expression in these cells is vital to understanding human skin physiology. In this study we performed high throughput sequencing of HEMs to obtain a complete data set of transcript sizes, abundances, and splicing. As expected, we found that melanocyte specific genes that function in pigmentation were among the highest expressed genes. We analyzed receptor, ion channel and transcription factor gene families to get a better understanding of the cell signalling pathways used by melanocytes. We also performed a comparative transcriptomic analysis of lightly versus darkly pigmented HEMs and found 16 genes differentially expressed in the two pigmentation phenotypes; of those, only one putative melanosomal transporter (SLC45A2) has known function in pigmentation. In addition, we found 166 genes with splice isoforms expressed exclusively in one pigmentation phenotype, 17 of which are genes involved in signal transduction. Our melanocyte transcriptome study provides a comprehensive view and may help identify novel pigmentation genes and potential pharmacological targets. PMID:25451175

  7. Genome-wide profiling of forum domains in Drosophila melanogaster

    PubMed Central

    Tchurikov, Nickolai A.; Kretova, Olga V.; Sosin, Dmitri V.; Zykov, Ivan A.; Zhimulev, Igor F.; Kravatsky, Yuri V.

    2011-01-01

    Forum domains are stretches of chromosomal DNA that are excised from eukaryotic chromosomes during their spontaneous non-random fragmentation. Most forum domains are 50–200 kb in length. We mapped forum domain termini using FISH on polytene chromosomes and we performed genome-wide mapping using a Drosophila melanogaster genomic tiling microarray consisting of overlapping 3 kb fragments. We found that forum termini very often correspond to regions of intercalary heterochromatin and regions of late replication in polytene chromosomes. We found that forum domains contain clusters of several or many genes. The largest forum domains correspond to the main clusters of homeotic genes inside BX-C and ANTP-C, cluster of histone genes and clusters of piRNAs. PRE/TRE and transcription factor binding sites often reside inside domains and do not overlap with forum domain termini. We also found that about 20% of forum domain termini correspond to small chromosomal regions where Ago1, Ago2, small RNAs and repressive chromatin structures are detected. Our results indicate that forum domains correspond to big multi-gene chromosomal units, some of which could be coordinately expressed. The data on the global mapping of forum domains revealed a strong correlation between fragmentation sites in chromosomes, particular sets of mobile elements and regions of intercalary heterochromatin. PMID:21247882

  8. Genome-wide association study of selenium concentrations

    PubMed Central

    Cornelis, Marilyn C.; Fornage, Myriam; Foy, Millennia; Xun, Pengcheng; Gladyshev, Vadim N.; Morris, Steve; Chasman, Daniel I.; Hu, Frank B.; Rimm, Eric B.; Kraft, Peter; Jordan, Joanne M.; Mozaffarian, Dariush; He, Ka

    2015-01-01

    Selenium (Se) is an essential trace element in human nutrition, but its role in certain health conditions, particularly among Se sufficient populations, is controversial. A genome-wide association study (GWAS) of blood Se concentrations previously identified a locus at 5q14 near BHMT. We performed a GW meta-analysis of toenail Se concentrations, which reflect a longer duration of exposure than blood Se concentrations, including 4162 European descendants from four US cohorts. Toenail Se was measured using neutron activation analysis. We identified a GW-significant locus at 5q14 (P < 1 × 10−16), the same locus identified in the published GWAS of blood Se based on independent cohorts. The lead single-nucleotide polymorphism (SNP) explained ∼1% of the variance in toenail Se concentrations. Using GW-summary statistics from both toenail and blood Se, we observed statistical evidence of polygenic overlap (P < 0.001) and meta-analysis of results from studies of either trait (n = 9639) yielded a second GW-significant locus at 21q22.3, harboring CBS (P < 4 × 10−8). Proteins encoded by genes at 5q14 and 21q22.3 function in homocysteine (Hcy) metabolism, and index SNPs for each have previously been associated with betaine and Hcy levels in GWAS. Our findings show evidence of a genetic link between Se and Hcy pathways, both involved in cardiometabolic disease. PMID:25343990

  9. Genome-wide association studies and infectious disease.

    PubMed

    Bowcock, Anne M

    2010-01-01

    The identification of genetic variants predisposing to complex diseases and phenotypes represent a challenge for geneticists in the early part of the 21st century. These are not simple Mendelian disorders caused by single mutations, such as cystic fibrosis or Huntington's disease, but common diseases that are usually polygenic in origin. The predisposing genes can be susceptibility factors or protective factors. One example of such a complex disease is the inflammatory skin disease psoriasis. However, another example could be protection from an infectious disease. Both of these phenotypes are due in part to the presence of low-risk variants in the host. Moreover, all of these complex phenotypes require environmental triggers as well and, in the case of infectious diseases, these are pathogens. In the case of other common diseases such as cardiovascular disease the triggers are often lifestyle-related issues such as diet or exercise. Genome-wide association studies are now identifying some of these genetic susceptibility factors. PMID:20370638

  10. A genome-wide association study in multiple system atrophy

    PubMed Central

    Sailer, Anna; Nalls, Michael A.; Schulte, Claudia; Federoff, Monica; Price, T. Ryan; Lees, Andrew; Ross, Owen A.; Dickson, Dennis W.; Mok, Kin; Mencacci, Niccolo E.; Schottlaender, Lucia; Chelban, Viorica; Ling, Helen; O'Sullivan, Sean S.; Wood, Nicholas W.; Traynor, Bryan J.; Ferrucci, Luigi; Federoff, Howard J.; Mhyre, Timothy R.; Morris, Huw R.; Deuschl, Günther; Quinn, Niall; Widner, Hakan; Albanese, Alberto; Infante, Jon; Bhatia, Kailash P.; Poewe, Werner; Oertel, Wolfgang; Höglinger, Günter U.; Wüllner, Ullrich; Goldwurm, Stefano; Pellecchia, Maria Teresa; Ferreira, Joaquim; Tolosa, Eduardo; Bloem, Bastiaan R.; Rascol, Olivier; Meissner, Wassilios G.; Hardy, John A.; Revesz, Tamas; Holton, Janice L.; Gasser, Thomas; Wenning, Gregor K.; Singleton, Andrew B.

    2016-01-01

    Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10−6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps. PMID:27629089

  11. Genome-Wide Association Studies of the Human Gut Microbiota.

    PubMed

    Davenport, Emily R; Cusanovich, Darren A; Michelini, Katelyn; Barreiro, Luis B; Ober, Carole; Gilad, Yoav

    2015-01-01

    The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both). These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%). For example, we identified an association between a taxon known to affect obesity (genus Akkermansia) and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL) mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7). Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut. PMID:26528553

  12. Genome-Wide Association Studies of the Human Gut Microbiota

    PubMed Central

    Davenport, Emily R.; Cusanovich, Darren A.; Michelini, Katelyn; Barreiro, Luis B.; Ober, Carole; Gilad, Yoav

    2015-01-01

    The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both). These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%). For example, we identified an association between a taxon known to affect obesity (genus Akkermansia) and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL) mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10−7). Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut. PMID:26528553

  13. Genome-Wide Mapping of Yeast RNA Polymerase II Termination

    PubMed Central

    Schaughency, Paul; Merran, Jonathan; Corden, Jeffry L.

    2014-01-01

    Yeast RNA polymerase II (Pol II) terminates transcription of coding transcripts through the polyadenylation (pA) pathway and non-coding transcripts through the non-polyadenylation (non-pA) pathway. We have used PAR-CLIP to map the position of Pol II genome-wide in living yeast cells after depletion of components of either the pA or non-pA termination complexes. We show here that Ysh1, responsible for cleavage at the pA site, is required for efficient removal of Pol II from the template. Depletion of Ysh1 from the nucleus does not, however, lead to readthrough transcription. In contrast, depletion of the termination factor Nrd1 leads to widespread runaway elongation of non-pA transcripts. Depletion of Sen1 also leads to readthrough at non-pA terminators, but in contrast to Nrd1, this readthrough is less processive, or more susceptible to pausing. The data presented here provide delineation of in vivo Pol II termination regions and highlight differences in the sequences that signal termination of different classes of non-pA transcripts. PMID:25299594

  14. Assessing Predictive Properties of Genome-Wide Selection in Soybeans.

    PubMed

    Xavier, Alencar; Muir, William M; Rainey, Katy Martin

    2016-01-01

    Many economically important traits in plant breeding have low heritability or are difficult to measure. For these traits, genomic selection has attractive features and may boost genetic gains. Our goal was to evaluate alternative scenarios to implement genomic selection for yield components in soybean (Glycine max L. merr). We used a nested association panel with cross validation to evaluate the impacts of training population size, genotyping density, and prediction model on the accuracy of genomic prediction. Our results indicate that training population size was the factor most relevant to improvement in genome-wide prediction, with greatest improvement observed in training sets up to 2000 individuals. We discuss assumptions that influence the choice of the prediction model. Although alternative models had minor impacts on prediction accuracy, the most robust prediction model was the combination of reproducing kernel Hilbert space regression and BayesB. Higher genotyping density marginally improved accuracy. Our study finds that breeding programs seeking efficient genomic selection in soybeans would best allocate resources by investing in a representative training set. PMID:27317786

  15. Comparative analysis of methods for genome-wide nucleosome cartography.

    PubMed

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use.

  16. Evolution of mate choice for genome-wide heterozygosity.

    PubMed

    Fromhage, Lutz; Kokko, Hanna; Reid, Jane M

    2009-03-01

    The extent to which indirect genetic benefits can drive the evolution of directional mating preferences for more ornamented mates, and the mechanisms that maintain such preferences without depleting genetic variance, remain key questions in evolutionary ecology. We used an individual-based genetic model to examine whether a directional preference for mates with higher genome-wide heterozygosity (H), and consequently greater ornamentation, could evolve and be maintained in the absence of direct fitness benefits of mate choice. We specifically considered finite populations of varying size and spatial genetic structure, in which parent-offspring resemblance in heterozygosity could provide an indirect benefit of mate choice. A directional preference for heterozygous mates evolved under broad conditions, even given a substantial direct cost of mate choice, low mutation rate, and stochastic variation in the link between individual heterozygosity and ornamentation. Furthermore, genetic variance was retained under directional sexual selection. Preference evolution was strongest in smaller populations, but weaker in populations with greater internal genetic structure in which restricted dispersal increased local inbreeding among offspring of neighboring females that all preferentially mated with the same male. These results suggest that directional preferences for heterozygous or outbred mates could evolve and be maintained in finite populations in the absence of direct fitness benefits, suggesting a novel resolution to the lek paradox.

  17. Genome-wide significant risk associations for mucinous ovarian carcinoma

    PubMed Central

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  18. Genome-Wide Silencing in Drosophila Captures Conserved Apoptotic Effectors

    PubMed Central

    Chew, Su Kit; Chen, Po; Link, Nichole; Galindo, Kathleen A.; Pogue, Kristi; Abrams, John M.

    2009-01-01

    Summary Apoptosis is a conserved form of programmed cell death (PCD) firmly established in the etiology, pathogenesis and treatment of many human diseases. Central to the core machinery of apoptosis are the caspases and their proximal regulators. Current models for caspase control envision a balance of opposing elements, with variable contributions from positive regulators and negative regulators among different cell types and species1. To advance a comprehensive view of components that support caspase-dependent cell death, we conducted a genome-wide silencing screen in the Drosophila model. Our strategy combined a library of dsRNAs together with a chemical antagonist of Inhibitor of Apoptosis Proteins (IAPs) that simulates the action of native regulators in the Reaper/Smac family2. A highly validated set of targets necessary for death provoked by multiple stimuli was identified. Among these, Tango7 is advanced here as a novel effector. Cells depleted for this gene resisted apoptosis at a step prior to induction of effector caspase activity and directed silencing of Tango7 in the animal prevented caspase-dependent PCD. Unlike known apoptosis regulators in this model3, Tango7 activity did not influence stimulus-dependent loss of Drosophila IAP1 (DIAP1) but, instead, regulated levels of the apical caspase Dronc. Likewise, the human Tango7 counterpart, PCID1, similarly impinged on caspase 9, revealing a novel regulatory axis impacting the apoptosome. PMID:19483676

  19. Genome-Wide Analysis of Human Metapneumovirus Evolution

    PubMed Central

    Kim, Jin Il; Park, Sehee; Lee, Ilseob; Park, Kwang Sook; Kwak, Eun Jung; Moon, Kwang Mee; Lee, Chang Kyu; Bae, Joon-Yong; Park, Man-Seong; Song, Ki-Joon

    2016-01-01

    Human metapneumovirus (HMPV) has been described as an important etiologic agent of upper and lower respiratory tract infections, especially in young children and the elderly. Most of school-aged children might be introduced to HMPVs, and exacerbation with other viral or bacterial super-infection is common. However, our understanding of the molecular evolution of HMPVs remains limited. To address the comprehensive evolutionary dynamics of HMPVs, we report a genome-wide analysis of the eight genes (N, P, M, F, M2, SH, G, and L) using 103 complete genome sequences. Phylogenetic reconstruction revealed that the eight genes from one HMPV strain grouped into the same genetic group among the five distinct lineages (A1, A2a, A2b, B1, and B2). A few exceptions of phylogenetic incongruence might suggest past recombination events, and we detected possible recombination breakpoints in the F, SH, and G coding regions. The five genetic lineages of HMPVs shared quite remote common ancestors ranging more than 220 to 470 years of age with the most recent origins for the A2b sublineage. Purifying selection was common, but most protein genes except the F and M2-2 coding regions also appeared to experience episodic diversifying selection. Taken together, these suggest that the five lineages of HMPVs maintain their individual evolutionary dynamics and that recombination and selection forces might work on shaping the genetic diversity of HMPVs. PMID:27046055

  20. Genome-wide association study of aggressive behaviour in chicken

    PubMed Central

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  1. Genome-wide linkage-disequilibrium profiles from single individuals.

    PubMed

    Lynch, Michael; Xu, Sen; Maruki, Takahiro; Jiang, Xiaoqian; Pfaffelhuber, Peter; Haubold, Bernhard

    2014-09-01

    Although the analysis of linkage disequilibrium (LD) plays a central role in many areas of population genetics, the sampling variance of LD is known to be very large with high sensitivity to numbers of nucleotide sites and individuals sampled. Here we show that a genome-wide analysis of the distribution of heterozygous sites within a single diploid genome can yield highly informative patterns of LD as a function of physical distance. The proposed statistic, the correlation of zygosity, is closely related to the conventional population-level measure of LD, but is agnostic with respect to allele frequencies and hence likely less prone to outlier artifacts. Application of the method to several vertebrate species leads to the conclusion that >80% of recombination events are typically resolved by gene-conversion-like processes unaccompanied by crossovers, with the average lengths of conversion patches being on the order of one to several kilobases in length. Thus, contrary to common assumptions, the recombination rate between sites does not scale linearly with distance, often even up to distances of 100 kb. In addition, the amount of LD between sites separated by <200 bp is uniformly much greater than can be explained by the conventional neutral model, possibly because of the nonindependent origin of mutations within this spatial scale. These results raise questions about the application of conventional population-genetic interpretations to LD on short spatial scales and also about the use of spatial patterns of LD to infer demographic histories.

  2. Genome-wide association study of aggressive behaviour in chicken.

    PubMed

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-08-03

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF.

  3. Genome-wide association studies in pharmacogenetics research debate

    PubMed Central

    Bailey, Kent R; Cheng, Cheng

    2016-01-01

    Will genome-wide association studies (GWAS) ‘work’ for pharmacogenetics research? This question was the topic of a staged debate, with pro and con sides, aimed to bring out the strengths and weaknesses of GWAS for pharmacogenetics studies. After a full day of seminars at the Fifth Statistical Analysis Workshop of the Pharmacogenetics Research Network, the lively debate was held – appropriately – at Goonies Comedy Club in Rochester (MN, USA). The pro side emphasized that the many GWAS successes for identifying genetic variants associated with disease risk show that it works; that the current genotyping platforms are efficient, with good imputation methods to fill in missing data; that its global assessment is always a success even if no significant associations are detected; and that genetic effects are likely to be large because humans have not evolved in a drug-therapy environment. By contrast, the con side emphasized that we have limited knowledge of the complexity of the genome; limited clinical phenotypes compromise studies; the likely multifactorial nature of drug response clouding the small genetic effects; and limitations of sample size and replication studies in pharmacogenetic studies. Lively and insightful discussions emphasized further research efforts that might benefit GWAS in pharmacogenetics. PMID:20235786

  4. Genome-wide association study of aggressive behaviour in chicken.

    PubMed

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  5. Genome-Wide Analysis of Polyadenylation Events in Schmidtea mediterranea

    PubMed Central

    Lakshmanan, Vairavan; Bansal, Dhiru; Kulkarni, Jahnavi; Poduval, Deepak; Krishna, Srikar; Sasidharan, Vidyanand; Anand, Praveen; Seshasayee, Aswin; Palakodeti, Dasaradhi

    2016-01-01

    In eukaryotes, 3′ untranslated regions (UTRs) play important roles in regulating posttranscriptional gene expression. The 3′UTR is defined by regulated cleavage/polyadenylation of the pre-mRNA. The advent of next-generation sequencing technology has now enabled us to identify these events on a genome-wide scale. In this study, we used poly(A)-position profiling by sequencing (3P-Seq) to capture all poly(A) sites across the genome of the freshwater planarian, Schmidtea mediterranea, an ideal model system for exploring the process of regeneration and stem cell function. We identified the 3′UTRs for ∼14,000 transcripts and thus improved the existing gene annotations. We found 97 transcripts, which are polyadenylated within an internal exon, resulting in the shrinking of the ORF and loss of a predicted protein domain. Around 40% of the transcripts in planaria were alternatively polyadenylated (ApA), resulting either in an altered 3′UTR or a change in coding sequence. We identified specific ApA transcript isoforms that were subjected to miRNA mediated gene regulation using degradome sequencing. In this study, we also confirmed a tissue-specific expression pattern for alternate polyadenylated transcripts. The insights from this study highlight the potential role of ApA in regulating the gene expression essential for planarian regeneration. PMID:27489207

  6. Genome-Wide Discriminatory Information Patterns of Cytosine DNA Methylation

    PubMed Central

    Sanchez, Robersy; Mackenzie, Sally A.

    2016-01-01

    Cytosine DNA methylation (CDM) is a highly abundant, heritable but reversible chemical modification to the genome. Herein, a machine learning approach was applied to analyze the accumulation of epigenetic marks in methylomes of 152 ecotypes and 85 silencing mutants of Arabidopsis thaliana. In an information-thermodynamics framework, two measurements were used: (1) the amount of information gained/lost with the CDM changes IR and (2) the uncertainty of not observing a SNP LCR. We hypothesize that epigenetic marks are chromosomal footprints accounting for different ontogenetic and phylogenetic histories of individual populations. A machine learning approach is proposed to verify this hypothesis. Results support the hypothesis by the existence of discriminatory information (DI) patterns of CDM able to discriminate between individuals and between individual subpopulations. The statistical analyses revealed a strong association between the topologies of the structured population of Arabidopsis ecotypes based on IR and on LCR, respectively. A statistical-physical relationship between IR and LCR was also found. Results to date imply that the genome-wide distribution of CDM changes is not only part of the biological signal created by the methylation regulatory machinery, but ensures the stability of the DNA molecule, preserving the integrity of the genetic message under continuous stress from thermal fluctuations in the cell environment. PMID:27322251

  7. Genome-Wide Specific Selection in Three Domestic Sheep Breeds

    PubMed Central

    Cao, Jiaxve; Wu, Mingming; Ma, Xiaomeng; Liu, Zhen; Liu, Ruizao; Zhao, Fuping; Wei, Caihong; Du, Lixin

    2015-01-01

    Background Commercial sheep raised for mutton grow faster than traditional Chinese sheep breeds. Here, we aimed to evaluate genetic selection among three different types of sheep breed: two well-known commercial mutton breeds and one indigenous Chinese breed. Results We first combined locus-specific branch lengths and di statistical methods to detect candidate regions targeted by selection in the three different populations. The results showed that the genetic distances reached at least medium divergence for each pairwise combination. We found these two methods were highly correlated, and identified many growth-related candidate genes undergoing artificial selection. For production traits, APOBR and FTO are associated with body mass index. For meat traits, ALDOA, STK32B and FAM190A are related to marbling. For reproduction traits, CCNB2 and SLC8A3 affect oocyte development. We also found two well-known genes, GHR (which affects meat production and quality) and EDAR (associated with hair thickness) were associated with German mutton merino sheep. Furthermore, four genes (POL, RPL7, MSL1 and SHISA9) were associated with pre-weaning gain in our previous genome-wide association study. Conclusions Our results indicated that combine locus-specific branch lengths and di statistical approaches can reduce the searching ranges for specific selection. And we got many credible candidate genes which not only confirm the results of previous reports, but also provide a suite of novel candidate genes in defined breeds to guide hybridization breeding. PMID:26083354

  8. How to interpret a genome-wide association study.

    PubMed

    Pearson, Thomas A; Manolio, Teri A

    2008-03-19

    Genome-wide association (GWA) studies use high-throughput genotyping technologies to assay hundreds of thousands of single-nucleotide polymorphisms (SNPs) and relate them to clinical conditions and measurable traits. Since 2005, nearly 100 loci for as many as 40 common diseases and traits have been identified and replicated in GWA studies, many in genes not previously suspected of having a role in the disease under study, and some in genomic regions containing no known genes. GWA studies are an important advance in discovering genetic variants influencing disease but also have important limitations, including their potential for false-positive and false-negative results and for biases related to selection of study participants and genotyping errors. Although these studies are clearly many steps removed from actual clinical use, and specific applications of GWA findings in prevention and treatment are actively being pursued, at present these studies mainly represent a valuable discovery tool for examining genomic function and clarifying pathophysiologic mechanisms. This article describes the design, interpretation, application, and limitations of GWA studies for clinicians and scientists for whom this evolving science may have great relevance.

  9. Defining the RNA polymerase III transcriptome: Genome-wide localization of the RNA polymerase III transcription machinery in human cells

    PubMed Central

    Canella, Donatella; Praz, Viviane; Reina, Jaime H.; Cousin, Pascal; Hernandez, Nouria

    2010-01-01

    Our view of the RNA polymerase III (Pol III) transcription machinery in mammalian cells arises mostly from studies of the RN5S (5S) gene, the Ad2 VAI gene, and the RNU6 (U6) gene, as paradigms for genes with type 1, 2, and 3 promoters. Recruitment of Pol III onto these genes requires prior binding of well-characterized transcription factors. Technical limitations in dealing with repeated genomic units, typically found at mammalian Pol III genes, have so far hampered genome-wide studies of the Pol III transcription machinery and transcriptome. We have localized, genome-wide, Pol III and some of its transcription factors. Our results reveal broad usage of the known Pol III transcription machinery and define a minimal Pol III transcriptome in dividing IMR90hTert fibroblasts. This transcriptome consists of some 500 actively transcribed genes including a few dozen candidate novel genes, of which we confirmed nine as Pol III transcription units by additional methods. It does not contain any of the microRNA genes previously described as transcribed by Pol III, but reveals two other microRNA genes, MIR886 (hsa-mir-886) and MIR1975 (RNY5, hY5, hsa-mir-1975), which are genuine Pol III transcription units. PMID:20413673

  10. A Genome-wide Association Study of Myasthenia Gravis

    PubMed Central

    Renton, Alan E.; Pliner, Hannah A.; Provenzano, Carlo; Evoli, Amelia; Ricciardi, Roberta; Nalls, Michael A.; Marangi, Giuseppe; Abramzon, Yevgeniya; Arepalli, Sampath; Chong, Sean; Hernandez, Dena G.; Johnson, Janel O.; Bartoccioni, Emanuela; Scuderi, Flavia; Maestri, Michelangelo; Raphael Gibbs, J.; Errichiello, Edoardo; Chiò, Adriano; Restagno, Gabriella; Sabatelli, Mario; Macek, Mark; Scholz, Sonja W.; Corse, Andrea; Chaudhry, Vinay; Benatar, Michael; Barohn, Richard J.; McVey, April; Pasnoor, Mamatha; Dimachkie, Mazen M.; Rowin, Julie; Kissel, John; Freimer, Miriam; Kaminski, Henry J.; Sanders, Donald B.; Lipscomb, Bernadette; Massey, Janice M.; Chopra, Manisha; Howard, James F.; Koopman, Wilma J.; Nicolle, Michael W.; Pascuzzi, Robert M.; Pestronk, Alan; Wulf, Charlie; Florence, Julaine; Blackmore, Derrick; Soloway, Aimee; Siddiqi, Zaeem; Muppidi, Srikanth; Wolfe, Gil; Richman, David; Mezei, Michelle M.; Jiwa, Theresa; Oger, Joel; Drachman, Daniel B.; Traynor, Bryan J.

    2016-01-01

    IMPORTANCE Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES We calculated P values for association between 8114394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10−8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS In the over all case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10−8; odds ratio, 1.37; 95% CI, 1.25–1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10−8; odds ratio, 2.31; 95% CI, 2.02 – 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10−9; odds ratio, 1.41; 95% CI, 1.29–1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10−12; odds ratio, 1.56; 95% CI, 1.44–1.68) and the other was detected

  11. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

    PubMed Central

    Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura e Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22–2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08–2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29–2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  12. Genome-wide analysis of condensin binding in Caenorhabditis elegans

    PubMed Central

    2013-01-01

    Background Condensins are multi-subunit protein complexes that are essential for chromosome condensation during mitosis and meiosis, and play key roles in transcription regulation during interphase. Metazoans contain two condensins, I and II, which perform different functions and localize to different chromosomal regions. Caenorhabditis elegans contains a third condensin, IDC, that is targeted to and represses transcription of the X chromosome for dosage compensation. Results To understand condensin binding and function, we performed ChIP-seq analysis of C. elegans condensins in mixed developmental stage embryos, which contain predominantly interphase nuclei. Condensins bind to a subset of active promoters, tRNA genes and putative enhancers. Expression analysis in kle-2-mutant larvae suggests that the primary effect of condensin II on transcription is repression. A DNA sequence motif, GCGC, is enriched at condensin II binding sites. A sequence extension of this core motif, AGGG, creates the condensin IDC motif. In addition to differences in recruitment that result in X-enrichment of condensin IDC and condensin II binding to all chromosomes, we provide evidence for a shared recruitment mechanism, as condensin IDC recruiter SDC-2 also recruits condensin II to the condensin IDC recruitment sites on the X. In addition, we found that condensin sites overlap extensively with the cohesin loader SCC-2, and that SDC-2 also recruits SCC-2 to the condensin IDC recruitment sites. Conclusions Our results provide the first genome-wide view of metazoan condensin II binding in interphase, define putative recruitment motifs, and illustrate shared loading mechanisms for condensin IDC and condensin II. PMID:24125077

  13. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

    PubMed Central

    Dijkstra, Akkelies E.; Smolonska, Joanna; van den Berge, Maarten; Wijmenga, Ciska; Zanen, Pieter; Luinge, Marjan A.; Platteel, Mathieu; Lammers, Jan-Willem; Dahlback, Magnus; Tosh, Kerrie; Hiemstra, Pieter S.; Sterk, Peter J.; Spira, Avi; Vestbo, Jorgen; Nordestgaard, Borge G.; Benn, Marianne; Nielsen, Sune F.; Dahl, Morten; Verschuren, W. Monique; Picavet, H. Susan J.; Smit, Henriette A.; Owsijewitsch, Michael; Kauczor, Hans U.; de Koning, Harry J.; Nizankowska-Mogilnicka, Eva; Mejza, Filip; Nastalek, Pawel; van Diemen, Cleo C.; Cho, Michael H.; Silverman, Edwin K.; Crapo, James D.; Beaty, Terri H.; Lomas, David A.; Bakke, Per; Gulsvik, Amund; Bossé, Yohan; Obeidat, M. A.; Loth, Daan W.; Lahousse, Lies; Rivadeneira, Fernando; Uitterlinden, Andre G.; Hofman, Andre; Stricker, Bruno H.; Brusselle, Guy G.; van Duijn, Cornelia M.; Brouwer, Uilke; Koppelman, Gerard H.; Vonk, Judith M.; Nawijn, Martijn C.; Groen, Harry J. M.; Timens, Wim; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Background Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH. PMID:24714607

  14. Genome-Wide Approaches for RNA Structure Probing.

    PubMed

    Silverman, Ian M; Berkowitz, Nathan D; Gosai, Sager J; Gregory, Brian D

    2016-01-01

    RNA molecules of all types fold into complex secondary and tertiary structures that are important for their function and regulation. Structural and catalytic RNAs such as ribosomal RNA (rRNA) and transfer RNA (tRNA) are central players in protein synthesis, and only function through their proper folding into intricate three-dimensional structures. Studies of messenger RNA (mRNA) regulation have also revealed that structural elements embedded within these RNA species are important for the proper regulation of their total level in the transcriptome. More recently, the discovery of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) has shed light on the importance of RNA structure to genome, transcriptome, and proteome regulation. Due to the relatively small number, high conservation, and importance of structural and catalytic RNAs to all life, much early work in RNA structure analysis mapped out a detailed view of these molecules. Computational and physical methods were used in concert with enzymatic and chemical structure probing to create high-resolution models of these fundamental biological molecules. However, the recent expansion in our knowledge of the importance of RNA structure to coding and regulatory RNAs has left the field in need of faster and scalable methods for high-throughput structural analysis. To address this, nuclease and chemical RNA structure probing methodologies have been adapted for genome-wide analysis. These methods have been deployed to globally characterize thousands of RNA structures in a single experiment. Here, we review these experimental methodologies for high-throughput RNA structure determination and discuss the insights gained from each approach. PMID:27256381

  15. Genome-wide association study of sleep in Drosophila melanogaster

    PubMed Central

    2013-01-01

    Background Sleep is a highly conserved behavior, yet its duration and pattern vary extensively among species and between individuals within species. The genetic basis of natural variation in sleep remains unknown. Results We used the Drosophila Genetic Reference Panel (DGRP) to perform a genome-wide association (GWA) study of sleep in D. melanogaster. We identified candidate single nucleotide polymorphisms (SNPs) associated with differences in the mean as well as the environmental sensitivity of sleep traits; these SNPs typically had sex-specific or sex-biased effects, and were generally located in non-coding regions. The majority of SNPs (80.3%) affecting sleep were at low frequency and had moderately large effects. Additive models incorporating multiple SNPs explained as much as 55% of the genetic variance for sleep in males and females. Many of these loci are known to interact physically and/or genetically, enabling us to place them in candidate genetic networks. We confirmed the role of seven novel loci on sleep using insertional mutagenesis and RNA interference. Conclusions We identified many SNPs in novel loci that are potentially associated with natural variation in sleep, as well as SNPs within genes previously known to affect Drosophila sleep. Several of the candidate genes have human homologues that were identified in studies of human sleep, suggesting that genes affecting variation in sleep are conserved across species. Our discovery of genetic variants that influence environmental sensitivity to sleep may have a wider application to all GWA studies, because individuals with highly plastic genotypes will not have consistent phenotypes. PMID:23617951

  16. Genome-wide examination of myoblast cell cycle withdrawal duringdifferentiation

    SciTech Connect

    Shen, Xun; Collier, John Michael; Hlaing, Myint; Zhang, Leanne; Delshad, Elizabeth H.; Bristow, James; Bernstein, Harold S.

    2002-12-02

    Skeletal and cardiac myocytes cease division within weeks of birth. Although skeletal muscle retains limited capacity for regeneration through recruitment of satellite cells, resident populations of adult myocardial stem cells have not been identified. Because cell cycle withdrawal accompanies myocyte differentiation, we hypothesized that C2C12 cells, a mouse myoblast cell line previously used to characterize myocyte differentiation, also would provide a model for studying cell cycle withdrawal during differentiation. C2C12 cells were differentiated in culture medium containing horse serum and harvested at various time points to characterize the expression profiles of known cell cycle and myogenic regulatory factors by immunoblot analysis. BrdU incorporation decreased dramatically in confluent cultures 48 hr after addition of horse serum, as cells started to form myotubes. This finding was preceded by up-regulation of MyoD, followed by myogenin, and activation of Bcl-2. Cyclin D1 was expressed in proliferating cultures and became undetectable in cultures containing 40 percent fused myotubes, as levels of p21(WAF1/Cip1) increased and alpha-actin became detectable. Because C2C12 myoblasts withdraw from the cell cycle during myocyte differentiation following a course that recapitulates this process in vivo, we performed a genome-wide screen to identify other gene products involved in this process. Using microarrays containing approximately 10,000 minimally redundant mouse sequences that map to the UniGene database of the National Center for Biotechnology Information, we compared gene expression profiles between proliferating, differentiating, and differentiated C2C12 cells and verified candidate genes demonstrating differential expression by RT-PCR. Cluster analysis of differentially expressed genes revealed groups of gene products involved in cell cycle withdrawal, muscle differentiation, and apoptosis. In addition, we identified several genes, including DDAH2 and Ly

  17. Mosaic paternal genome-wide uniparental isodisomy with down syndrome.

    PubMed

    Darcy, Diana; Atwal, Paldeep Singh; Angell, Cathy; Gadi, Inder; Wallerstein, Robert

    2015-10-01

    We report on a 6-month-old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome-wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith-Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no specific features of AS. Clinical features of this patient include: dysmorphic features consistent with trisomy 21, tetralogy of Fallot, hemihypertrophy, swirled skin hyperpigmentation, hepatoblastoma, and Wilms tumor. Her karyotype is 47,XX,+21[19]/46,XX[4], and microarray results suggest that the cell line with trisomy 21 is biparentally inherited and represents 40-50% of the genomic material in the tested specimen. The difference in the level of cytogenetically detected mosaicism versus the level of mosaicism observed via microarray analysis is likely caused by differences in the test methodologies. While a handful of cases of mosaic paternal GWUPiD have been reported, this patient is the only reported case that also involves trisomy 21. Other GWUPiD patients have presented with features associated with multiple imprinted regions, as does our patient. PMID:26219535

  18. Assessing statistical significance in multivariable genome wide association analysis

    PubMed Central

    Buzdugan, Laura; Kalisch, Markus; Navarro, Arcadi; Schunk, Daniel; Fehr, Ernst; Bühlmann, Peter

    2016-01-01

    Motivation: Although Genome Wide Association Studies (GWAS) genotype a very large number of single nucleotide polymorphisms (SNPs), the data are often analyzed one SNP at a time. The low predictive power of single SNPs, coupled with the high significance threshold needed to correct for multiple testing, greatly decreases the power of GWAS. Results: We propose a procedure in which all the SNPs are analyzed in a multiple generalized linear model, and we show its use for extremely high-dimensional datasets. Our method yields P-values for assessing significance of single SNPs or groups of SNPs while controlling for all other SNPs and the family wise error rate (FWER). Thus, our method tests whether or not a SNP carries any additional information about the phenotype beyond that available by all the other SNPs. This rules out spurious correlations between phenotypes and SNPs that can arise from marginal methods because the ‘spuriously correlated’ SNP merely happens to be correlated with the ‘truly causal’ SNP. In addition, the method offers a data driven approach to identifying and refining groups of SNPs that jointly contain informative signals about the phenotype. We demonstrate the value of our method by applying it to the seven diseases analyzed by the Wellcome Trust Case Control Consortium (WTCCC). We show, in particular, that our method is also capable of finding significant SNPs that were not identified in the original WTCCC study, but were replicated in other independent studies. Availability and implementation: Reproducibility of our research is supported by the open-source Bioconductor package hierGWAS. Contact: peter.buehlmann@stat.math.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153677

  19. Genephony: a knowledge management tool for genome-wide research

    PubMed Central

    Nuzzo, Angelo; Riva, Alberto

    2009-01-01

    Background One of the consequences of the rapid and widespread adoption of high-throughput experimental technologies is an exponential increase of the amount of data produced by genome-wide experiments. Researchers increasingly need to handle very large volumes of heterogeneous data, including both the data generated by their own experiments and the data retrieved from publicly available repositories of genomic knowledge. Integration, exploration, manipulation and interpretation of data and information therefore need to become as automated as possible, since their scale and breadth are, in general, beyond the limits of what individual researchers and the basic data management tools in normal use can handle. This paper describes Genephony, a tool we are developing to address these challenges. Results We describe how Genephony can be used to manage large datesets of genomic information, integrating them with existing knowledge repositories. We illustrate its functionalities with an example of a complex annotation task, in which a set of SNPs coming from a genotyping experiment is annotated with genes known to be associated to a phenotype of interest. We show how, thanks to the modular architecture of Genephony and its user-friendly interface, this task can be performed in a few simple steps. Conclusion Genephony is an online tool for the manipulation of large datasets of genomic information. It can be used as a browser for genomic data, as a high-throughput annotation tool, and as a knowledge discovery tool. It is designed to be easy to use, flexible and extensible. Its knowledge management engine provides fine-grained control over individual data elements, as well as efficient operations on large datasets. PMID:19728881

  20. Improved Statistics for Genome-Wide Interaction Analysis

    PubMed Central

    Ueki, Masao; Cordell, Heather J.

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new “joint effects” statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  1. Genome-wide inference of regulatory networks in Streptomyces coelicolor

    PubMed Central

    2010-01-01

    Background The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. Results In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements. Conclusions Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification. PMID:20955611

  2. Genome-Wide Methylation Analyses in Glioblastoma Multiforme

    PubMed Central

    Lai, Rose K.; Chen, Yanwen; Guan, Xiaowei; Nousome, Darryl; Sharma, Charu; Canoll, Peter; Bruce, Jeffrey; Sloan, Andrew E.; Cortes, Etty; Vonsattel, Jean-Paul; Su, Tao; Delgado-Cruzata, Lissette; Gurvich, Irina; Santella, Regina M.; Ostrom, Quinn; Lee, Annette; Gregersen, Peter; Barnholtz-Sloan, Jill

    2014-01-01

    Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal. PMID:24586730

  3. A Comprehensive, Quantitative, and Genome-Wide Model of Translation

    PubMed Central

    Siwiak, Marlena; Zielenkiewicz, Piotr

    2010-01-01

    Translation is still poorly characterised at the level of individual proteins and its role in regulation of gene expression has been constantly underestimated. To better understand the process of protein synthesis we developed a comprehensive and quantitative model of translation, characterising protein synthesis separately for individual genes. The main advantage of the model is that basing it on only a few datasets and general assumptions allows the calculation of many important translational parameters, which are extremely difficult to measure experimentally. In the model, each gene is attributed with a set of translational parameters, namely the absolute number of transcripts, ribosome density, mean codon translation time, total transcript translation time, total time required for translation initiation and elongation, translation initiation rate, mean mRNA lifetime, and absolute number of proteins produced by gene transcripts. Most parameters were calculated based on only one experimental dataset of genome-wide ribosome profiling. The model was implemented in Saccharomyces cerevisiae, and its results were compared with available data, yielding reasonably good correlations. The calculated coefficients were used to perform a global analysis of translation in yeast, revealing some interesting aspects of the process. We have shown that two commonly used measures of translation efficiency – ribosome density and number of protein molecules produced – are affected by two distinct factors. High values of both measures are caused, i.a., by very short times of translation initiation, however, the origins of initiation time reduction are completely different in both cases. The model is universal and can be applied to any organism, if the necessary input data are available. The model allows us to better integrate transcriptomic and proteomic data. A few other possibilities of the model utilisation are discussed concerning the example of the yeast system. PMID:20686685

  4. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax.

    PubMed

    Sousa, Inês; Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura E Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís; Feijó, Salvato; Oliveira, Sofia A

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  5. Genome-wide profiling of Populus small RNAs

    PubMed Central

    2009-01-01

    Background Short RNAs, and in particular microRNAs, are important regulators of gene expression both within defined regulatory pathways and at the epigenetic scale. We investigated the short RNA (sRNA) population (18-24 nt) of the transcriptome of green leaves from the sequenced Populus trichocarpa using a concatenation strategy in combination with 454 sequencing. Results The most abundant size class of sRNAs were 24 nt. Long Terminal Repeats were particularly associated with 24 nt sRNAs. Additionally, some repetitive elements were associated with 22 nt sRNAs. We identified an sRNA hot-spot on chromosome 19, overlapping a region containing both the proposed sex-determining locus and a major cluster of NBS-LRR genes. A number of phased siRNA loci were identified, a subset of which are predicted to target PPR and NBS-LRR disease resistance genes, classes of genes that have been significantly expanded in Populus. Additional loci enriched for sRNA production were identified and characterised. We identified 15 novel predicted microRNAs (miRNAs), including miRNA*sequences, and identified a novel locus that may encode a dual miRNA or a miRNA and short interfering RNAs (siRNAs). Conclusions The short RNA population of P. trichocarpa is at least as complex as that of Arabidopsis thaliana. We provide a first genome-wide view of short RNA production for P. trichocarpa and identify new, non-conserved miRNAs. PMID:20021695

  6. Genome-wide Association Studies of Maximum Number of Drinks

    PubMed Central

    Pan, Yue; Luo, Xingguang; Liu, Xuefeng; Wu, Long-Yang; Zhang, Qunyuan; Wang, Liang; Wang, Weize; Zuo, Lingjun; Wang, Ke-Sheng

    2014-01-01

    Maximum number of drinks (MaxDrinks) defined as “Maximum number of alcoholic drinks consumed in a 24-hour period” is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction – Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p < 10−4). The most significant association with MaxDrinks was observed with SNP rs11128951 (p = 4.27×10−8) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p < 5×10−7) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p< 5×10−7) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders. PMID:23953852

  7. Genome-wide characteristics of de novo mutations in autism

    PubMed Central

    Yuen, Ryan K C; Merico, Daniele; Cao, Hongzhi; Pellecchia, Giovanna; Alipanahi, Babak; Thiruvahindrapuram, Bhooma; Tong, Xin; Sun, Yuhui; Cao, Dandan; Zhang, Tao; Wu, Xueli; Jin, Xin; Zhou, Ze; Liu, Xiaomin; Nalpathamkalam, Thomas; Walker, Susan; Howe, Jennifer L.; Wang, Zhuozhi; MacDonald, Jeffrey R.; Chan, Ada; D’Abate, Lia; Deneault, Eric; Siu, Michelle T.; Tammimies, Kristiina; Uddin, Mohammed; Zarrei, Mehdi; Wang, Mingbang; Li, Yingrui; Wang, Jun; Wang, Jian; Yang, Huanming; Bookman, Matt; Bingham, Jonathan; Gross, Samuel S.; Loy, Dion; Pletcher, Mathew; Marshall, Christian R.; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Weksberg, Rosanna; Fernandez, Bridget A; Roberts, Wendy; Szatmari, Peter; Glazer, David; Frey, Brendan J.; Ring, Robert H.; Xu, Xun; Scherer, Stephen W.

    2016-01-01

    De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10−10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10−13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10−24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10−9; OR=1.84), of which 15.6% (p=4.3×10−3) and 22.5% (p=7.0×10−5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD. PMID:27525107

  8. Improved statistics for genome-wide interaction analysis.

    PubMed

    Ueki, Masao; Cordell, Heather J

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new "joint effects" statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  9. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells

    PubMed Central

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Dargham, Daria Bou; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P.; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B. Franklin; Gérard, Matthieu

    2015-01-01

    Summary ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers1–3 target specific nucleosomes to regulate transcription is unclear. Here, we present genome-wide remodeller-nucleosome interaction profiles for Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank MNase-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites (TSSs) are nevertheless chromatinized with non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and modifications (H3K4me3 and H3K27ac). RNA polymerase (pol) II therefore navigates hundreds of bp of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3′ end of the NFR. Transcriptome analysis upon remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers play either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs. PMID:26814966

  10. Genome-wide identification of phospho-regulators of Wnt signaling in Drosophila.

    PubMed

    Swarup, Sharan; Pradhan-Sundd, Tirthadipa; Verheyen, Esther M

    2015-04-15

    Evolutionarily conserved intercellular signaling pathways regulate embryonic development and adult tissue homeostasis in metazoans. The precise control of the state and amplitude of signaling pathways is achieved in part through the kinase- and phosphatase-mediated reversible phosphorylation of proteins. In this study, we performed a genome-wide in vivo RNAi screen for kinases and phosphatases that regulate the Wnt pathway under physiological conditions in the Drosophila wing disc. Our analyses have identified 54 high-confidence kinases and phosphatases capable of modulating the Wnt pathway, including 22 novel regulators. These candidates were also assayed for a role in the Notch pathway, and numerous phospho-regulators were identified. Additionally, each regulator of the Wnt pathway was evaluated in the wing disc for its ability to affect the mechanistically similar Hedgehog pathway. We identified 29 dual regulators that have the same effect on the Wnt and Hedgehog pathways. As proof of principle, we established that Cdc37 and Gilgamesh/CK1γ inhibit and promote signaling, respectively, by functioning at analogous levels of these pathways in both Drosophila and mammalian cells. The Wnt and Hedgehog pathways function in tandem in multiple developmental contexts, and the identification of several shared phospho-regulators serve as potential nodes of control under conditions of aberrant signaling and disease. PMID:25852200

  11. Genome-wide RNAi screen for nuclear actin reveals a network of cofilin regulators

    PubMed Central

    Dopie, Joseph; Rajakylä, Eeva K.; Joensuu, Merja S.; Huet, Guillaume; Ferrantelli, Evelina; Xie, Tiao; Jäälinoja, Harri; Jokitalo, Eija; Vartiainen, Maria K.

    2015-01-01

    ABSTRACT Nuclear actin plays an important role in many processes that regulate gene expression. Cytoplasmic actin dynamics are tightly controlled by numerous actin-binding proteins, but regulation of nuclear actin has remained unclear. Here, we performed a genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins that influence either nuclear polymerization or import of actin. We validate 19 factors as specific hits, and show that Chinmo (known as Bach2 in mammals), SNF4Aγ (Prkag1 in mammals) and Rab18 play a role in nuclear localization of actin in both fly and mammalian cells. We identify several new regulators of cofilin activity, and characterize modulators of both cofilin kinases and phosphatase. For example, Chinmo/Bach2, which regulates nuclear actin levels also in vivo, maintains active cofilin by repressing the expression of the kinase Cdi (Tesk in mammals). Finally, we show that Nup98 and lamin are candidates for regulating nuclear actin polymerization. Our screen therefore reveals new aspects of actin regulation and links nuclear actin to many cellular processes. PMID:26021350

  12. Genome-wide association study of behavioral, physiological and gene expression traits in outbred CFW mice.

    PubMed

    Parker, Clarissa C; Gopalakrishnan, Shyam; Carbonetto, Peter; Gonzales, Natalia M; Leung, Emily; Park, Yeonhee J; Aryee, Emmanuel; Davis, Joe; Blizard, David A; Ackert-Bicknell, Cheryl L; Lionikas, Arimantas; Pritchard, Jonathan K; Palmer, Abraham A

    2016-08-01

    Although mice are the most widely used mammalian model organism, genetic studies have suffered from limited mapping resolution due to extensive linkage disequilibrium (LD) that is characteristic of crosses among inbred strains. Carworth Farms White (CFW) mice are a commercially available outbred mouse population that exhibit rapid LD decay in comparison to other available mouse populations. We performed a genome-wide association study (GWAS) of behavioral, physiological and gene expression phenotypes using 1,200 male CFW mice. We used genotyping by sequencing (GBS) to obtain genotypes at 92,734 SNPs. We also measured gene expression using RNA sequencing in three brain regions. Our study identified numerous behavioral, physiological and expression quantitative trait loci (QTLs). We integrated the behavioral QTL and eQTL results to implicate specific genes, including Azi2 in sensitivity to methamphetamine and Zmynd11 in anxiety-like behavior. The combination of CFW mice, GBS and RNA sequencing constitutes a powerful approach to GWAS in mice. PMID:27376237

  13. Novel skin phenotypes revealed by a genome-wide mouse reverse genetic screen

    PubMed Central

    Liakath-Ali, Kifayathullah; Vancollie, Valerie E.; Heath, Emma; Smedley, Damian P.; Estabel, Jeanne; Sunter, David; DiTommaso, Tia; White, Jacqueline K.; Ramirez-Solis, Ramiro; Smyth, Ian; Steel, Karen P.; Watt, Fiona M.

    2014-01-01

    Permanent stop-and-shop large-scale mouse mutant resources provide an excellent platform to decipher tissue phenogenomics. Here we analyse skin from 538 knockout mouse mutants generated by the Sanger Institute Mouse Genetics Project. We optimize immunolabelling of tail epidermal wholemounts to allow systematic annotation of hair follicle, sebaceous gland and interfollicular epidermal abnormalities using ontology terms from the Mammalian Phenotype Ontology. Of the 50 mutants with an epidermal phenotype, 9 map to human genetic conditions with skin abnormalities. Some mutant genes are expressed in the skin, whereas others are not, indicating systemic effects. One phenotype is affected by diet and several are incompletely penetrant. In-depth analysis of three mutants, Krt76, Myo5a (a model of human Griscelli syndrome) and Mysm1, provides validation of the screen. Our study is the first large-scale genome-wide tissue phenotype screen from the International Knockout Mouse Consortium and provides an open access resource for the scientific community. PMID:24721909

  14. Genome-wide nucleosome specificity and function of chromatin remodellers in ES cells.

    PubMed

    de Dieuleveult, Maud; Yen, Kuangyu; Hmitou, Isabelle; Depaux, Arnaud; Boussouar, Fayçal; Bou Dargham, Daria; Jounier, Sylvie; Humbertclaude, Hélène; Ribierre, Florence; Baulard, Céline; Farrell, Nina P; Park, Bongsoo; Keime, Céline; Carrière, Lucie; Berlivet, Soizick; Gut, Marta; Gut, Ivo; Werner, Michel; Deleuze, Jean-François; Olaso, Robert; Aude, Jean-Christophe; Chantalat, Sophie; Pugh, B Franklin; Gérard, Matthieu

    2016-02-01

    ATP-dependent chromatin remodellers allow access to DNA for transcription factors and the general transcription machinery, but whether mammalian chromatin remodellers target specific nucleosomes to regulate transcription is unclear. Here we present genome-wide remodeller-nucleosome interaction profiles for the chromatin remodellers Chd1, Chd2, Chd4, Chd6, Chd8, Chd9, Brg1 and Ep400 in mouse embryonic stem (ES) cells. These remodellers bind one or both full nucleosomes that flank micrococcal nuclease (MNase)-defined nucleosome-free promoter regions (NFRs), where they separate divergent transcription. Surprisingly, large CpG-rich NFRs that extend downstream of annotated transcriptional start sites are nevertheless bound by non-nucleosomal or subnucleosomal histone variants (H3.3 and H2A.Z) and marked by H3K4me3 and H3K27ac modifications. RNA polymerase II therefore navigates hundreds of base pairs of altered chromatin in the sense direction before encountering an MNase-resistant nucleosome at the 3' end of the NFR. Transcriptome analysis after remodeller depletion reveals reciprocal mechanisms of transcriptional regulation by remodellers. Whereas at active genes individual remodellers have either positive or negative roles via altering nucleosome stability, at polycomb-enriched bivalent genes the same remodellers act in an opposite manner. These findings indicate that remodellers target specific nucleosomes at the edge of NFRs, where they regulate ES cell transcriptional programs.

  15. Genome-wide quantitative assessment of variation in DNA methylation patterns

    PubMed Central

    Xie, Hehuang; Wang, Min; de Andrade, Alexandre; de F. Bonaldo, Maria; Galat, Vasil; Arndt, Kelly; Rajaram, Veena; Goldman, Stewart; Tomita, Tadanori; Soares, Marcelo B.

    2011-01-01

    Genomic DNA methylation contributes substantively to transcriptional regulations that underlie mammalian development and cellular differentiation. Much effort has been made to decipher the molecular mechanisms governing the establishment and maintenance of DNA methylation patterns. However, little is known about genome-wide variation of DNA methylation patterns. In this study, we introduced the concept of methylation entropy, a measure of the randomness of DNA methylation patterns in a cell population, and exploited it to assess the variability in DNA methylation patterns of Alu repeats and promoters. A few interesting observations were made: (i) within a cell population, methylation entropy varies among genomic loci; (ii) among cell populations, the methylation entropies of most genomic loci remain constant; (iii) compared to normal tissue controls, some tumors exhibit greater methylation entropies; (iv) Alu elements with high methylation entropy are associated with high GC content but depletion of CpG dinucleotides and (v) Alu elements in the intronic regions or far from CpG islands are associated with low methylation entropy. We further identified 12 putative allelic-specific methylated genomic loci, including four Alu elements and eight promoters. Lastly, using subcloned normal fibroblast cells, we demonstrated the highly variable methylation patterns are resulted from low fidelity of DNA methylation inheritance. PMID:21278160

  16. Genome-wide RNAi screen for nuclear actin reveals a network of cofilin regulators.

    PubMed

    Dopie, Joseph; Rajakylä, Eeva K; Joensuu, Merja S; Huet, Guillaume; Ferrantelli, Evelina; Xie, Tiao; Jäälinoja, Harri; Jokitalo, Eija; Vartiainen, Maria K

    2015-07-01

    Nuclear actin plays an important role in many processes that regulate gene expression. Cytoplasmic actin dynamics are tightly controlled by numerous actin-binding proteins, but regulation of nuclear actin has remained unclear. Here, we performed a genome-wide RNA interference (RNAi) screen in Drosophila cells to identify proteins that influence either nuclear polymerization or import of actin. We validate 19 factors as specific hits, and show that Chinmo (known as Bach2 in mammals), SNF4Aγ (Prkag1 in mammals) and Rab18 play a role in nuclear localization of actin in both fly and mammalian cells. We identify several new regulators of cofilin activity, and characterize modulators of both cofilin kinases and phosphatase. For example, Chinmo/Bach2, which regulates nuclear actin levels also in vivo, maintains active cofilin by repressing the expression of the kinase Cdi (Tesk in mammals). Finally, we show that Nup98 and lamin are candidates for regulating nuclear actin polymerization. Our screen therefore reveals new aspects of actin regulation and links nuclear actin to many cellular processes.

  17. A Genome-Wide Association Study Identifies Multiple Regions Associated with Head Size in Catfish

    PubMed Central

    Geng, Xin; Liu, Shikai; Yao, Jun; Bao, Lisui; Zhang, Jiaren; Li, Chao; Wang, Ruijia; Sha, Jin; Zeng, Peng; Zhi, Degui; Liu, Zhanjiang

    2016-01-01

    Skull morphology is fundamental to evolution and the biological adaptation of species to their environments. With aquaculture fish species, head size is also important for economic reasons because it has a direct impact on fillet yield. However, little is known about the underlying genetic basis of head size. Catfish is the primary aquaculture species in the United States. In this study, we performed a genome-wide association study using the catfish 250K SNP array with backcross hybrid catfish to map the QTL for head size (head length, head width, and head depth). One significantly associated region on linkage group (LG) 7 was identified for head length. In addition, LGs 7, 9, and 16 contain suggestively associated regions for head length. For head width, significantly associated regions were found on LG9, and additional suggestively associated regions were identified on LGs 5 and 7. No region was found associated with head depth. Head size genetic loci were mapped in catfish to genomic regions with candidate genes involved in bone development. Comparative analysis indicated that homologs of several candidate genes are also involved in skull morphology in various other species ranging from amphibian to mammalian species, suggesting possible evolutionary conservation of those genes in the control of skull morphologies. PMID:27558670

  18. A Genome-wide CRISPR Screen in Toxoplasma Identifies Essential Apicomplexan Genes.

    PubMed

    Sidik, Saima M; Huet, Diego; Ganesan, Suresh M; Huynh, My-Hang; Wang, Tim; Nasamu, Armiyaw S; Thiru, Prathapan; Saeij, Jeroen P J; Carruthers, Vern B; Niles, Jacquin C; Lourido, Sebastian

    2016-09-01

    Apicomplexan parasites are leading causes of human and livestock diseases such as malaria and toxoplasmosis, yet most of their genes remain uncharacterized. Here, we present the first genome-wide genetic screen of an apicomplexan. We adapted CRISPR/Cas9 to assess the contribution of each gene from the parasite Toxoplasma gondii during infection of human fibroblasts. Our analysis defines ∼200 previously uncharacterized, fitness-conferring genes unique to the phylum, from which 16 were investigated, revealing essential functions during infection of human cells. Secondary screens identify as an invasion factor the claudin-like apicomplexan microneme protein (CLAMP), which resembles mammalian tight-junction proteins and localizes to secretory organelles, making it critical to the initiation of infection. CLAMP is present throughout sequenced apicomplexan genomes and is essential during the asexual stages of the malaria parasite Plasmodium falciparum. These results provide broad-based functional information on T. gondii genes and will facilitate future approaches to expand the horizon of antiparasitic interventions. PMID:27594426

  19. Genome-wide maps of nuclear lamina interactions in single human cells

    PubMed Central

    Kind, Jop; Pagie, Ludo; de Vries, Sandra S.; Nahidiazar, Leila; Dey, Siddharth S.; Bienko, Magda; Zhan, Ye; Lajoie, Bryan; de Graaf, Carolyn A.; Amendola, Mario; Fudenberg, Geoffrey; Imakaev, Maxim; Mirny, Leonid A.; Jalink, Kees; Dekker, Job; van Oudenaarden, Alexander; van Steensel, Bas

    2015-01-01

    Summary Mammalian interphase chromosomes interact with the nuclear lamina (NL) through hundreds of large Lamina Associated Domains (LADs). We report a method to map NL contacts genome-wide in single human cells. Analysis of nearly 400 maps reveals a core architecture of gene-poor LADs that contact the NL with high cell-to-cell consistency, interspersed by LADs with more variable NL interactions. The variable contacts tend to be cell-type specific and are more sensitive to changes in genome ploidy than the consistent contacts. Single-cell maps indicate that NL contacts involve multivalent interactions over hundreds of kilobases. Moreover, we observe extensive intra-chromosomal coordination of NL contacts, even over tens of megabases. Such coordinated loci exhibit preferential interactions as detected by Hi-C. Finally, consistency of NL contacts is inversely linked to gene activity in single cells, and correlates positively with the heterochromatic histone modification H3K9me3. These results highlight fundamental principles of single cell chromatin organization. PMID:26365489

  20. Genome-wide association study of colorectal cancer in Hispanics

    PubMed Central

    Schmit, Stephanie L.; Schumacher, Fredrick R.; Edlund, Christopher K.; Conti, David V.; Ihenacho, Ugonna; Wan, Peggy; Van Den Berg, David; Casey, Graham; Fortini, Barbara K.; Lenz, Heinz-Josef; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Moreno-Macías, Hortensia; Huerta-Chagoya, Alicia; Ordóñez-Sánchez, María Luisa; Rodríguez-Guillén, Rosario; Cruz-Bautista, Ivette; Rodríguez-Torres, Maribel; Muñóz-Hernández, Linda Liliana; Arellano-Campos, Olimpia; Gómez, Donají; Alvirde, Ulices; González-Villalpando, Clicerio; González-Villalpando, María Elena; Le Marchand, Loic; Haiman, Christopher A.; Figueiredo, Jane C.

    2016-01-01

    Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10−8. Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10−6) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47–2.36); P = 2.5×10−7], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21–1.55); P = 4.0×10−7), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36–2.01); P = 4.1×10−7) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37–2.08); P=7.8×10−7]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10–5) and 11q12.2 (P = 6.8×10−5), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations. PMID:27207650

  1. Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii

    PubMed Central

    2010-01-01

    Background Genome-wide computational analysis of alternative splicing (AS) in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs. Results Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy. Conclusions The extent of AS in Chlamydomonas that we observed is much smaller than observed in

  2. Genome-wide screening and identification of antigens for rickettsial vaccine development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The capacity to identify immunogens for vaccine development by genome-wide screening has been markedly enhanced by the availability of complete microbial genome sequences coupled to rapid proteomic and bioinformatic analysis. Critical to this genome-wide screening is in vivo testing in the context o...

  3. Assessing Genome-Wide Statistical Significance for Large p Small n Problems

    PubMed Central

    Diao, Guoqing; Vidyashankar, Anand N.

    2013-01-01

    Assessing genome-wide statistical significance is an important issue in genetic studies. We describe a new resampling approach for determining the appropriate thresholds for statistical significance. Our simulation results demonstrate that the proposed approach accurately controls the genome-wide type I error rate even under the large p small n situations. PMID:23666935

  4. Assessing genome-wide statistical significance for large p small n problems.

    PubMed

    Diao, Guoqing; Vidyashankar, Anand N

    2013-07-01

    Assessing genome-wide statistical significance is an important issue in genetic studies. We describe a new resampling approach for determining the appropriate thresholds for statistical significance. Our simulation results demonstrate that the proposed approach accurately controls the genome-wide type I error rate even under the large p small n situations.

  5. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2010-01-01

    Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of…

  6. Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J. L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schafer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genome-wide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases…

  7. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  8. More heritability probably captured by psoriasis genome-wide association study in Han Chinese.

    PubMed

    Jiang, Long; Liu, Lu; Cheng, Yuyan; Lin, Yan; Shen, Changbing; Zhu, Caihong; Yang, Sen; Yin, Xianyong; Zhang, Xuejun

    2015-11-15

    Missing heritability is a common problem in genome-wide association studies in complex diseases/traits. To quantify the unbiased heritability estimate, we applied the phenotype correlation-genotype correlation regression in psoriasis genome-wide association data in Han Chinese which comprises 1139 cases and 1132 controls. We estimated that 45.7% heritability of psoriasis in Han Chinese were captured by common variants (s.e.=12.5%), which reinforced that the majority of psoriasis heritability can be covered by common variants in genome-wide association data (68.2%). The results provided evidence that the heritability covered by psoriasis genome-wide genotyping data was probably underestimated in previous restricted maximum likelihood method. Our study highlights the broad role of common variants in the etiology of psoriasis and sheds light on the possibility to identify more common variants of small effect by increasing the sample size in psoriasis genome-wide association studies.

  9. No genome-wide protein sequence convergence for echolocation.

    PubMed

    Zou, Zhengting; Zhang, Jianzhi

    2015-05-01

    Toothed whales and two groups of bats independently acquired echolocation, the ability to locate and identify objects by reflected sound. Echolocation requires physiologically complex and coordinated vocal, auditory, and neural functions, but the molecular basis of the capacity for echolocation is not well understood. A recent study suggested that convergent amino acid substitutions widespread in the proteins of echolocators underlay the convergent origins of mammalian echolocation. Here, we show that genomic signatures of molecular convergence between echolocating lineages are generally no stronger than those between echolocating and comparable nonecholocating lineages. The same is true for the group of 29 hearing-related proteins claimed to be enriched with molecular convergence. Reexamining the previous selection test reveals several flaws and invalidates the asserted evidence for adaptive convergence. Together, these findings indicate that the reported genomic signatures of convergence largely reflect the background level of sequence convergence unrelated to the origins of echolocation. PMID:25631925

  10. A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency

    PubMed Central

    O'Reilly, Linda P.; Long, Olivia S.; Cobanoglu, Murat C.; Benson, Joshua A.; Luke, Cliff J.; Miedel, Mark T.; Hale, Pamela; Perlmutter, David H.; Bahar, Ivet; Silverman, Gary A.; Pak, Stephen C.

    2014-01-01

    α1-Antitrypsin deficiency (ATD) is a common genetic disorder that can lead to end-stage liver and lung disease. Although liver transplantation remains the only therapy currently available, manipulation of the proteostasis network (PN) by small molecule therapeutics offers great promise. To accelerate the drug-discovery process for this disease, we first developed a semi-automated high-throughput/content-genome-wide RNAi screen to identify PN modifiers affecting the accumulation of the α1-antitrypsin Z mutant (ATZ) in a Caenorhabditis elegans model of ATD. We identified 104 PN modifiers, and these genes were used in a computational strategy to identify human ortholog–ligand pairs. Based on rigorous selection criteria, we identified four FDA-approved drugs directed against four different PN targets that decreased the accumulation of ATZ in C. elegans. We also tested one of the compounds in a mammalian cell line with similar results. This methodology also proved useful in confirming drug targets in vivo, and predicting the success of combination therapy. We propose that small animal models of genetic disorders combined with genome-wide RNAi screening and computational methods can be used to rapidly, economically and strategically prime the preclinical discovery pipeline for rare and neglected diseases with limited therapeutic options. PMID:24838285

  11. Consistency-based rectification of nonrigid registrations

    PubMed Central

    Gass, Tobias; Székely, Gábor; Goksel, Orcun

    2015-01-01

    Abstract. We present a technique to rectify nonrigid registrations by improving their group-wise consistency, which is a widely used unsupervised measure to assess pair-wise registration quality. While pair-wise registration methods cannot guarantee any group-wise consistency, group-wise approaches typically enforce perfect consistency by registering all images to a common reference. However, errors in individual registrations to the reference then propagate, distorting the mean and accumulating in the pair-wise registrations inferred via the reference. Furthermore, the assumption that perfect correspondences exist is not always true, e.g., for interpatient registration. The proposed consistency-based registration rectification (CBRR) method addresses these issues by minimizing the group-wise inconsistency of all pair-wise registrations using a regularized least-squares algorithm. The regularization controls the adherence to the original registration, which is additionally weighted by the local postregistration similarity. This allows CBRR to adaptively improve consistency while locally preserving accurate pair-wise registrations. We show that the resulting registrations are not only more consistent, but also have lower average transformation error when compared to known transformations in simulated data. On clinical data, we show improvements of up to 50% target registration error in breathing motion estimation from four-dimensional MRI and improvements in atlas-based segmentation quality of up to 65% in terms of mean surface distance in three-dimensional (3-D) CT. Such improvement was observed consistently using different registration algorithms, dimensionality (two-dimensional/3-D), and modalities (MRI/CT). PMID:26158083

  12. Spatially Resolved Genome-wide Transcriptional Profiling Identifies BMP Signaling as Essential Regulator of Zebrafish Cardiomyocyte Regeneration.

    PubMed

    Wu, Chi-Chung; Kruse, Fabian; Vasudevarao, Mohankrishna Dalvoy; Junker, Jan Philipp; Zebrowski, David C; Fischer, Kristin; Noël, Emily S; Grün, Dominic; Berezikov, Eugene; Engel, Felix B; van Oudenaarden, Alexander; Weidinger, Gilbert; Bakkers, Jeroen

    2016-01-11

    In contrast to mammals, zebrafish regenerate heart injuries via proliferation of cardiomyocytes located near the wound border. To identify regulators of cardiomyocyte proliferation, we used spatially resolved RNA sequencing (tomo-seq) and generated a high-resolution genome-wide atlas of gene expression in the regenerating zebrafish heart. Interestingly, we identified two wound border zones with distinct expression profiles, including the re-expression of embryonic cardiac genes and targets of bone morphogenetic protein (BMP) signaling. Endogenous BMP signaling has been reported to be detrimental to mammalian cardiac repair. In contrast, we find that genetic or chemical inhibition of BMP signaling in zebrafish reduces cardiomyocyte dedifferentiation and proliferation, ultimately compromising myocardial regeneration, while bmp2b overexpression is sufficient to enhance it. Our results provide a resource for further studies on the molecular regulation of cardiac regeneration and reveal intriguing differential cellular responses of cardiomyocytes to a conserved signaling pathway in regenerative versus non-regenerative hearts.

  13. Genome-wide identification of long noncoding RNAs in rat models of cardiovascular and renal disease.

    PubMed

    Gopalakrishnan, Kathirvel; Kumarasamy, Sivarajan; Mell, Blair; Joe, Bina

    2015-01-01

    Long noncoding RNAs (lncRNAs) are an emerging class of genomic regulatory molecules reported in various species. In the rat, which is one of the major mammalian model organisms, discovery of lncRNAs on a genome-wide scale is lagging. Renal lncRNA sequencing and lncRNA transcriptome analysis were conducted in 3 rat strains that are widely used in cardiovascular and renal research: the Dahl salt-sensitive rat, the spontaneously hypertensive rat, and the Dahl salt-resistant rat. Through the RNA sequencing approach, 3273 transcripts were identified as rat lncRNAs. A majority of lncRNAs were without predicted target genes. Differential expression of 273 and 749 lncRNAs was detected between Dahl salt-sensitive versus Dahl salt-resistant and Dahl salt-sensitive versus spontaneously hypertensive rat comparisons, respectively. To couple the observed differential expression of lncRNAs with the status of mRNAs, an mRNA transcriptome analysis was conducted. Several cis mRNA genes were coregulated with lncRNAs. Of these, the protein expression status of 4 target genes, Asb3, Chac2, Pex11b, and Sp5, were differentially expressed between the relevant strain comparisons, thereby suggesting that the differentially expressed lncRNAs associated with these genes are candidate genetic determinants of blood pressure. This study serves as a first-generation catalog of rat lncRNAs and illustrates the prioritization of lncRNAs as candidates for complex polygenic traits. PMID:25385761

  14. Impact of high predation risk on genome-wide hippocampal gene expression in snowshoe hares.

    PubMed

    Lavergne, Sophia G; McGowan, Patrick O; Krebs, Charles J; Boonstra, Rudy

    2014-11-01

    The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada's boreal forest. During the 8- to 11-year population cycle, hare densities can fluctuate up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect population numbers not only through direct mortality but also through sublethal effects. The chronic stress hypothesis posits that high predation risk during the decline severely stresses hares, leading to greater stress responses, heightened ability to mobilize cortisol and energy, and a poorer body condition. These effects may result in, or be mediated by, differential gene expression. We used an oligonucleotide microarray designed for a closely-related species, the European rabbit (Oryctolagus cuniculus), to characterize differences in genome-wide hippocampal RNA transcript abundance in wild hares from the Yukon during peak and decline phases of a single cycle. A total of 106 genes were differentially regulated between phases. Array results were validated with quantitative real-time PCR, and mammalian protein sequence similarity was used to infer gene function. In comparison to hares from the peak, decline phase hares showed increased expression of genes involved in metabolic processes and hormone response, and decreased expression of immune response and blood cell formation genes. We found evidence for predation risk effects on the expression of genes whose putative functions correspond with physiological impacts known to be induced by predation risk in snowshoe hares. This study shows, for the first time, a link between changes in demography and alterations in neural RNA transcript abundance in a natural population.

  15. Genome-Wide Detection of Fitness Genes in Uropathogenic Escherichia coli during Systemic Infection

    PubMed Central

    Subashchandrabose, Sargurunathan; Smith, Sara N.; Spurbeck, Rachel R.; Kole, Monica M.; Mobley, Harry L. T.

    2013-01-01

    Uropathogenic Escherichia coli (UPEC) is a leading etiological agent of bacteremia in humans. Virulence mechanisms of UPEC in the context of urinary tract infections have been subjected to extensive research. However, understanding of the fitness mechanisms used by UPEC during bacteremia and systemic infection is limited. A forward genetic screen was utilized to detect transposon insertion mutants with fitness defects during colonization of mouse spleens. An inoculum comprised of 360,000 transposon mutants in the UPEC strain CFT073, cultured from the blood of a patient with pyelonephritis, was used to inoculate mice intravenously. Transposon insertion sites in the inoculum (input) and bacteria colonizing the spleen (output) were identified using high-throughput sequencing of transposon-chromosome junctions. Using frequencies of representation of each insertion mutant in the input and output samples, 242 candidate fitness genes were identified. Co-infection experiments with each of 11 defined mutants and the wild-type strain demonstrated that 82% (9 of 11) of the tested candidate fitness genes were required for optimal fitness in a mouse model of systemic infection. Genes involved in biosynthesis of poly-N-acetyl glucosamine (pgaABCD), major and minor pilin of a type IV pilus (c2394 and c2395), oligopeptide uptake periplasmic-binding protein (oppA), sensitive to antimicrobial peptides (sapABCDF), putative outer membrane receptor (yddB), zinc metallopeptidase (pqqL), a shikimate pathway gene (c1220) and autotransporter serine proteases (pic and vat) were further characterized. Here, we report the first genome-wide identification of genes that contribute to fitness in UPEC during systemic infection in a mammalian host. These fitness factors may represent targets for developing novel therapeutics against UPEC. PMID:24339777

  16. Impact of high predation risk on genome-wide hippocampal gene expression in snowshoe hares.

    PubMed

    Lavergne, Sophia G; McGowan, Patrick O; Krebs, Charles J; Boonstra, Rudy

    2014-11-01

    The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada's boreal forest. During the 8- to 11-year population cycle, hare densities can fluctuate up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect population numbers not only through direct mortality but also through sublethal effects. The chronic stress hypothesis posits that high predation risk during the decline severely stresses hares, leading to greater stress responses, heightened ability to mobilize cortisol and energy, and a poorer body condition. These effects may result in, or be mediated by, differential gene expression. We used an oligonucleotide microarray designed for a closely-related species, the European rabbit (Oryctolagus cuniculus), to characterize differences in genome-wide hippocampal RNA transcript abundance in wild hares from the Yukon during peak and decline phases of a single cycle. A total of 106 genes were differentially regulated between phases. Array results were validated with quantitative real-time PCR, and mammalian protein sequence similarity was used to infer gene function. In comparison to hares from the peak, decline phase hares showed increased expression of genes involved in metabolic processes and hormone response, and decreased expression of immune response and blood cell formation genes. We found evidence for predation risk effects on the expression of genes whose putative functions correspond with physiological impacts known to be induced by predation risk in snowshoe hares. This study shows, for the first time, a link between changes in demography and alterations in neural RNA transcript abundance in a natural population. PMID:25234370

  17. Genome-wide copy number variations in Oryza sativa L.

    PubMed Central

    2013-01-01

    Background Copy number variation (CNV) can lead to intra-specific genome variations. It is not only part of normal genetic variation, but also is the source of phenotypic differences. Rice (Oryza sativa L.) is a model organism with a well-annotated genome, but investigation of CNVs in rice lags behind its mammalian counterparts. Results We comprehensively assayed CNVs using high-density array comparative genomic hybridization in a panel of 20 Asian cultivated rice comprising six indica, three aus, two rayada, two aromatic, three tropical japonica, and four temperate japonica varieties. We used a stringent criterion to identify a total of 2886 high-confidence copy number variable regions (CNVRs), which span 10.28 Mb (or 2.69%) of the rice genome, overlapping 1321 genes. These genes were significantly enriched for specific biological functions involved in cell death, protein phosphorylation, and defense response. Transposable elements (TEs) and other repetitive sequences were identified in the majority of CNVRs. Chromosome 11 showed the greatest enrichment for CNVs. Of subspecies-specific CNVRs, 55.75% and 61.96% were observed in only one cultivar of ssp. indica and ssp. japonica, respectively. Some CNVs with high frequency differences among groups resided in genes underlying rice adaptation. Conclusions Higher recombination rates and the presence of homologous gene clusters are probably predispositions for generation of the higher number of CNVs on chromosome 11 by non-allelic homologous recombination events. The subspecies-specific variants are enriched for rare alleles, which suggests that CNVs are relatively recent events that have arisen within breeding populations. A number of the CNVs identified in this study are candidates for generation of group-specific phenotypes. PMID:24059626

  18. Genome-wide inference of ancestral recombination graphs.

    PubMed

    Rasmussen, Matthew D; Hubisz, Melissa J; Gronau, Ilan; Siepel, Adam

    2014-01-01

    The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the "ancestral recombination graph" (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of [Formula: see text] chromosomes conditional on an ARG of [Formula: see text] chromosomes, an operation we call "threading." Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective sweeps. PMID:24831947

  19. Genome-Wide Inference of Ancestral Recombination Graphs

    PubMed Central

    Rasmussen, Matthew D.; Hubisz, Melissa J.; Gronau, Ilan; Siepel, Adam

    2014-01-01

    The complex correlation structure of a collection of orthologous DNA sequences is uniquely captured by the “ancestral recombination graph” (ARG), a complete record of coalescence and recombination events in the history of the sample. However, existing methods for ARG inference are computationally intensive, highly approximate, or limited to small numbers of sequences, and, as a consequence, explicit ARG inference is rarely used in applied population genomics. Here, we introduce a new algorithm for ARG inference that is efficient enough to apply to dozens of complete mammalian genomes. The key idea of our approach is to sample an ARG of chromosomes conditional on an ARG of chromosomes, an operation we call “threading.” Using techniques based on hidden Markov models, we can perform this threading operation exactly, up to the assumptions of the sequentially Markov coalescent and a discretization of time. An extension allows for threading of subtrees instead of individual sequences. Repeated application of these threading operations results in highly efficient Markov chain Monte Carlo samplers for ARGs. We have implemented these methods in a computer program called ARGweaver. Experiments with simulated data indicate that ARGweaver converges rapidly to the posterior distribution over ARGs and is effective in recovering various features of the ARG for dozens of sequences generated under realistic parameters for human populations. In applications of ARGweaver to 54 human genome sequences from Complete Genomics, we find clear signatures of natural selection, including regions of unusually ancient ancestry associated with balancing selection and reductions in allele age in sites under directional selection. The patterns we observe near protein-coding genes are consistent with a primary influence from background selection rather than hitchhiking, although we cannot rule out a contribution from recurrent selective sweeps. PMID:24831947

  20. Genome-wide microarray analysis of gene expression profiling in major depression and antidepressant therapy.

    PubMed

    Lin, Eugene; Tsai, Shih-Jen

    2016-01-01

    Major depressive disorder (MDD) is a serious health concern worldwide. Currently there are no predictive tests for the effectiveness of any particular antidepressant in an individual patient. Thus, doctors must prescribe antidepressants based on educated guesses. With the recent advent of scientific research, genome-wide gene expression microarray studies are widely utilized to analyze hundreds of thousands of biomarkers by high-throughput technologies. In addition to the candidate-gene approach, the genome-wide approach has recently been employed to investigate the determinants of MDD as well as antidepressant response to therapy. In this review, we mainly focused on gene expression studies with genome-wide approaches using RNA derived from peripheral blood cells. Furthermore, we reviewed their limitations and future directions with respect to the genome-wide gene expression profiling in MDD pathogenesis as well as in antidepressant therapy.

  1. Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

    PubMed Central

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M.; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M.; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U.; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G.; Mattheisen, Manuel; Nöthen, Markus M.

    2015-01-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10−12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region. PMID:25763902

  2. Genome-wide association study and meta-analysis identify ISL1 as genome-wide significant susceptibility gene for bladder exstrophy.

    PubMed

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G; Mattheisen, Manuel; Nöthen, Markus M; Ludwig, Michael; Reutter, Heiko

    2015-03-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.

  3. Genome-wide association mapping in plants exemplified for root growth in Arabidopsis thaliana.

    PubMed

    Slovak, Radka; Göschl, Christian; Seren, Ümit; Busch, Wolfgang

    2015-01-01

    Genome-wide association (GWA) mapping is a powerful technique to address the molecular basis of genotype to phenotype relationships and to map regulators of biological processes. This chapter presents a protocol for genome-wide association mapping in Arabidopsis thaliana using the user-friendly internet application GWAPP, and provides a specific protocol for acquiring root trait data suitable for GWA studies using the semi-automated, high-throughput phenotyping pipeline BRAT for early root growth.

  4. Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.

    PubMed

    Mägi, Reedik; Asimit, Jennifer L; Day-Williams, Aaron G; Zeggini, Eleftheria; Morris, Andrew P

    2012-12-01

    Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits. The majority of reproducible associations within these loci are with common variants, each of modest effect, which together explain only a small proportion of heritability. It has been suggested that much of the unexplained genetic component of complex traits can thus be attributed to rare variation. However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants. Nevertheless, we demonstrate here, by simulation, that imputation from an existing scaffold of genome-wide genotype data up to high-density reference panels has the potential to identify rare variant associations with complex traits, without the need for costly re-sequencing experiments. By application of this approach to genome-wide association studies of seven common complex diseases, imputed up to publicly available reference panels, we identify genome-wide significant evidence of rare variant association in PRDM10 with coronary artery disease and multiple genes in the major histocompatibility complex (MHC) with type 1 diabetes. The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.

  5. Genome-wide association study for the level of serum electrolytes in Italian Large White pigs.

    PubMed

    Bovo, S; Schiavo, G; Mazzoni, G; Dall'Olio, S; Galimberti, G; Calò, D G; Scotti, E; Bertolini, F; Buttazzoni, L; Samorè, A B; Fontanesi, L

    2016-10-01

    Calcium, magnesium and phosphorus are essential electrolytes involved in a large number of biological processes. Imbalance of these minerals in blood may indicate clinically relevant conditions and are important in inferring acute or chronic pathologies in humans and animals. In this work, we carried out a genome-wide association study (GWAS) for the level of these three electrolytes in the serum of 843 performance-tested Italian Large White pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip, and GWAS was carried out using genome-wide efficient mixed-model association. For the level of Ca(2+) , eight single nucleotide polymorphisms (SNPs) were significant, considering a false discovery rate (FDR) < 0.05, and another eight were above the moderate association threshold (Pnominal value  < 5.00E-05). These SNPs are distributed in four porcine chromosomes (SSC): SSC8, SSC11, SSC12 and SSC13. In particular, a few putative different signals of association detected on SSC13 and one on SSC12 were in genes or close to genes involved in calcium metabolism (P2RY1, RAP2B, SLC9A9, C3orf58, TSC22D2, PLCH1 and CACNB1). Only one SNP (on SSC7) and six SNPs (on SSC2 and SSC7) showed moderate association with the level of magnesium and phosphorus respectively. The association signals for these two latter minerals might identify genes not known thus far for playing a role in their biological functions and regulations. In conclusion, our GWAS contributed to increased knowledge on the role that calcium, magnesium and phosphorus may play in the genetically determined physiological mechanisms affecting the natural variability of mineral levels in mammalian blood.

  6. Genome-wide association study for the level of serum electrolytes in Italian Large White pigs.

    PubMed

    Bovo, S; Schiavo, G; Mazzoni, G; Dall'Olio, S; Galimberti, G; Calò, D G; Scotti, E; Bertolini, F; Buttazzoni, L; Samorè, A B; Fontanesi, L

    2016-10-01

    Calcium, magnesium and phosphorus are essential electrolytes involved in a large number of biological processes. Imbalance of these minerals in blood may indicate clinically relevant conditions and are important in inferring acute or chronic pathologies in humans and animals. In this work, we carried out a genome-wide association study (GWAS) for the level of these three electrolytes in the serum of 843 performance-tested Italian Large White pigs. All pigs were genotyped with the Illumina PorcineSNP60 BeadChip, and GWAS was carried out using genome-wide efficient mixed-model association. For the level of Ca(2+) , eight single nucleotide polymorphisms (SNPs) were significant, considering a false discovery rate (FDR) < 0.05, and another eight were above the moderate association threshold (Pnominal value  < 5.00E-05). These SNPs are distributed in four porcine chromosomes (SSC): SSC8, SSC11, SSC12 and SSC13. In particular, a few putative different signals of association detected on SSC13 and one on SSC12 were in genes or close to genes involved in calcium metabolism (P2RY1, RAP2B, SLC9A9, C3orf58, TSC22D2, PLCH1 and CACNB1). Only one SNP (on SSC7) and six SNPs (on SSC2 and SSC7) showed moderate association with the level of magnesium and phosphorus respectively. The association signals for these two latter minerals might identify genes not known thus far for playing a role in their biological functions and regulations. In conclusion, our GWAS contributed to increased knowledge on the role that calcium, magnesium and phosphorus may play in the genetically determined physiological mechanisms affecting the natural variability of mineral levels in mammalian blood. PMID:27296164

  7. Meta-Analysis of Genome-Wide Linkage Studies in Celiac Disease

    PubMed Central

    Forabosco, Paola; Neuhausen, Susan L.; Greco, Luigi; Naluai, Åsa Torinsson; Wijmenga, Cisca; Saavalainen, Päivi; Houlston, Richard S.; Ciclitira, Paul J.; Babron, Marie-Claude; Lewis, Cathryn M.

    2009-01-01

    Objective A meta-analysis of genome-wide linkage studies allows us to summarize the extensive information available from family-based studies, as the field moves into genome-wide association studies. Methods Here we apply the genome scan meta-analysis (GSMA) method, a rank-based, model-free approach, to combine results across eight independent genome-wide linkages performed on celiac disease (CD), including 554 families with over 1,500 affected individuals. We also investigate the agreement between signals we identified from this meta-analysis of linkage studies and those identified from genome-wide association analysis using a hypergeometric distribution. Results Not surprisingly, the most significant result was obtained in the HLA region. Outside the HLA region, suggestive evidence for linkage was obtained at the telomeric region of chromosome 10 (10q26.12-qter; p = 0.00366), and on chromosome 8 (8q22.2-q24.21; p = 0.00491). Testing signals of association and linkage within bins showed no significant evidence for co-localization of results. Conclusion This meta-analysis allowed us to pool the results from available genome-wide linkage studies and to identify novel regions potentially harboring predisposing genetic variation contributing to CD. This study also shows that linkage and association studies may identify different types of disease-predisposing variants. PMID:19622889

  8. Genome-wide identification of human functional DNA using a neutral indel model.

    PubMed

    Lunter, Gerton; Ponting, Chris P; Hein, Jotun

    2006-01-01

    heterogeneous selection, that is, sequence subject to both positive selection with respect to substitutions and purifying selection with respect to indels. The ability to identify elements under heterogeneous selection enables, for the first time, the genome-wide investigation of positive selection on functional elements other than protein-coding genes.

  9. Comparison of false-discovery rate for genome-wide and fine mapping regions.

    PubMed

    Tabangin, Meredith E; Woo, Jessica G; Liu, Chunyan; Nick, Todd G; Martin, Lisa J

    2007-01-01

    With technological advances in high-throughput genotyping, it is not unusual to perform hundreds of thousands of tests for each phenotype. Thus, correction to control type I error is essential. The false-discovery rate (FDR) has been successfully used in genome-wide expression data. However, its performance has not been evaluated for association analysis. Our objective was to analyze the Genetic Analysis Workshop 15 simulated data set, with answers, to evaluate FDR for genome-wide association and fine mapping. In genome-wide analysis, FDR performed well, with good localization of positive results. However, in fine mapping, all tested methods performed poorly, producing a high proportion of significant results. Thus, caution should be used when employing FDR for fine mapping.

  10. Genome-wide alternative polyadenylation in animals: insights from high-throughput technologies.

    PubMed

    Sun, Yu; Fu, Yonggui; Li, Yuxin; Xu, Anlong

    2012-12-01

    Alternative polyadenylation (APA) plays an important role in gene expression by affecting mRNA stability, translation, and translocation in cells. However, genome-wide APA events have only recently been subjected to more systematic analysis with newly developed high-throughput methods. In this review, we focus on the recent technological development of APA analyses on a genome-wide scale, as well as the impact of APA switches on a number of critical biological processes in animals, including cell proliferation, differentiation, and oncogenic transformation. With the highly enlarged scope of genome-wide APA analyses, the APA regulations of various biological processes have increasingly become a new paradigm for the regulation of gene transcription and translation.

  11. A genome wide association study identifies common variants associated with lipid levels in the Chinese population.

    PubMed

    Zhou, Li; He, Meian; Mo, Zengnan; Wu, Chen; Yang, Handong; Yu, Dianke; Yang, Xiaobo; Zhang, Xiaomin; Wang, Yiqin; Sun, Jielin; Gao, Yong; Tan, Aihua; He, Yunfeng; Zhang, Haiying; Qin, Xue; Zhu, Jingwen; Li, Huaixing; Lin, Xu; Zhu, Jiang; Min, Xinwen; Lang, Mingjian; Li, Dongfeng; Zhai, Kan; Chang, Jiang; Tan, Wen; Yuan, Jing; Chen, Weihong; Wang, Youjie; Wei, Sheng; Miao, Xiaoping; Wang, Feng; Fang, Weimin; Liang, Yuan; Deng, Qifei; Dai, Xiayun; Lin, Dafeng; Huang, Suli; Guo, Huan; Lilly Zheng, S; Xu, Jianfeng; Lin, Dongxin; Hu, Frank B; Wu, Tangchun

    2013-01-01

    Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52 × 10(-16), 1.38 × 10(-6) and 5.59 × 10(-9), respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population.

  12. Genome-wide approaches (GWA) in oral and craniofacial diseases research

    PubMed Central

    Kim, H; Gordon, S; Dionne, R

    2012-01-01

    Underlying molecular genetic mechanisms of diseases can be deciphered with unbiased strategies using recently developed technologies enabling genome-wide scale investigations. These technologies have been applied in scanning for genetic variations, gene expression profiles, and epigenetic changes for oral and craniofacial diseases. However, these approaches as applied to oral and craniofacial conditions are in the initial stages, and challenges remain to be overcome, including analysis of high throughput data and their interpretation. Here, we review methodology and studies using genome-wide approaches in oral and craniofacial diseases and suggest future directions. PMID:22913301

  13. Genome-wide association defines more than thirty distinct susceptibility loci for Crohn's disease

    PubMed Central

    Barrett, Jeffrey C.; Hansoul, Sarah; Nicolae, Dan L.; Cho, Judy H.; Duerr, Richard H.; Rioux, John D.; Brant, Steven R.; Silverberg, Mark S.; Taylor, Kent D.; Barmada, M. Michael; Bitton, Alain; Dassopoulos, Themistocles; Datta, Lisa Wu; Green, Todd; Griffiths, Anne M.; Kistner, Emily O.; Murtha, Michael T.; Regueiro, Miguel D.; Rotter, Jerome I.; Schumm, L. Philip; Steinhart, A. Hillary; Targan, Stephan R.; Xavier, Ramnik J.; Libioulle, Cécile; Sandor, Cynthia; Lathrop, Mark; Belaiche, Jacques; Dewit, Olivier; Gut, Ivo; Heath, Simon; Laukens, Debby; Mni, Myriam; Rutgeerts, Paul; Van Gossum, André; Zelenika, Diana; Franchimont, Denis; Hugot, JP; de Vos, Martine; Vermeire, Severine; Louis, Edouard; Cardon, Lon R.; Anderson, Carl A.; Drummond, Hazel; Nimmo, Elaine; Ahmad, Tariq; Prescott, Natalie J; Onnie, Clive M.; Fisher, Sheila A.; Marchini, Jonathan; Ghori, Jilur; Bumpstead, Suzannah; Gwillam, Rhian; Tremelling, Mark; Deloukas, Panos; Mansfield, John; Jewell, Derek; Satsangi, Jack; Mathew, Christopher G.; Parkes, Miles; Georges, Michel; Daly, Mark J.

    2008-01-01

    Several new risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further we have combined the data from three studies (a total of 3,230 cases and 4,829 controls) and performed replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 new loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1, and ITLN1. The expanded molecular understanding of the basis of disease offers promise for informed therapeutic development. PMID:18587394

  14. A population structure and genome-wide association analysis on the USDA soybean germplasm collection

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genotype-phenotype associations within the soybean (Glycine max) germplasm collection could provide valuable information on the frequency and distribution of alleles affecting economically important traits. Here we performed a genome-wide association study (GWAS) for seed protein and oil content in ...

  15. A genome-wide association study platform built on iPlant cyber-infrastructure

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We demonstrated a flexible Genome-Wide Association (GWA) Study (GWAS) platform built upon the iPlant Collaborative Cyber-infrastructure. The platform supports big data management, sharing, and large scale study of both genotype and phenotype data on clusters. End users can add their own analysis too...

  16. Signatures of positive selection in East African Shorthorn Zebu: a genome-wide SNP analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The small East African Shorthorn Zebu is the main indigenous cattle across East Africa. A recent genome wide SNPs analysis has revealed their ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signature of positive selection in their genome, with the aim...

  17. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    PubMed Central

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Chanock, Stephen J.; Wan, Peggy; Sheng, Xin; Pooler, Loreall C.; Van Den Berg, David J.; Le Marchand, Loic; Kolonel, Laurence N.; Henderson, Brian E.; Haiman, Chris A.; Stram, Daniel O.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density. PMID:23468962

  18. CNV-based genome wide association study reveals additional variants contributing to meat quality in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pork quality is important both to the meat processing industry and consumers’ purchasing attitudes. Copy number variation (CNV) is a burgeoning kind of variant that may influence meat quality. Herein, a genome-wide association study (GWAS) was performed between CNVs and meat quality traits in swine....

  19. Genome-wide association study of agronomic traits in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide association study (GWAS) using a global Andean diversity panel (ADP) of 237 genotypes of common bean, Phaseolus vulgaris was conducted to gain insight into the genetic architecture of several agronomic traits controlling phenology, biomass, yield components and seed yield. The panel wa...

  20. Genome-wide association analysis of symbiotic nitrogen fixation in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide association study (GWAS) was conducted to explore the genetic basis of variation for symbiotic nitrogen fixation (SNF) and related traits in the Andean diversity panel (ADP) comprised of 259 common bean (Phaseolus vulgaris) genotypes. The ADP was evaluated for SNF and related traits in...

  1. Genome-wide association as a means to understanding the mammary gland

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Next-generation sequencing and related technologies have facilitated the creation of enormous public databases that catalogue genomic variation. These databases have facilitated a variety of approaches to discover new genes that regulate normal biology as well as disease. Genome wide association (...

  2. Genome-Wide Association Study of Receptive Language Ability of 12-Year-Olds

    ERIC Educational Resources Information Center

    Harlaar, Nicole; Meaburn, Emma L.; Hayiou-Thomas, Marianna E.; Davis, Oliver S. P.; Docherty, Sophia; Hanscombe, Ken B.; Haworth, Claire M. A.; Price, Thomas S.; Trzaskowski, Maciej; Dale, Philip S.; Plomin, Robert

    2014-01-01

    Purpose: Researchers have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. In the current study, the authors attempted to identify some of the genes responsible for the heritability of receptive language ability using a "genome-wide association" approach. Method: The…

  3. Genome-Wide Association Study of Intelligence: Additive Effects of Novel Brain Expressed Genes

    ERIC Educational Resources Information Center

    Loo, Sandra K.; Shtir, Corina; Doyle, Alysa E.; Mick, Eric; McGough, James J.; McCracken, James; Biederman, Joseph; Smalley, Susan L.; Cantor, Rita M.; Faraone, Stephen V.; Nelson, Stanley F.

    2012-01-01

    Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally…

  4. Implementing meta-analysis from genome-wide association studies for pork quality traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pork quality plays an important role in the meat processing industry, thus different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. Howe...

  5. Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Low plasma B-vitamin levels and elevated homocysteine have been associated with cancer, cardiovascular disease, and neurodegenerative disorders. Common variants in FUT2 on chromosome 19q13 were associated with plasma vitamin B12 levels among women in a genome-wide association study (GWAS) in the Nur...

  6. Genome-wide CNV analysis reveals variants associated with growth traits in Bos indicus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Apart from single nucleotide polymorphism (SNP), copy number variation (CNV) is another important type of genetic variation, which may affect growth traits and play key roles for the production of beef cattle. To date, no genome-wide association study (GWAS) for CNV and body traits in be...

  7. Genome-wide computational prediction and analysis of core promoter elements across plant monocots and dicots

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transcription initiation, essential to gene expression regulation, involves recruitment of basal transcription factors to the core promoter elements (CPEs). The distribution of currently known CPEs across plant genomes is largely unknown. This is the first large scale genome-wide report on the compu...

  8. Genome-wide association mapping of partial resistance to Aphanomyces euteiches in pea

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome-wide association mapping has recently emerged as a valuable approach to refine genetic basis of polygenic resistance to plant diseases, which are increasingly used in integrated strategies for durable crop protection. Aphanomyces euteiches is a soil borne pathogen of pea and other legumes wor...

  9. Genome-Wide SNP Calling Using Next Generation Sequencing Data in Tomato

    PubMed Central

    Kim, Ji-Eun; Oh, Sang-Keun; Lee, Jeong-Hee; Lee, Bo-Mi; Jo, Sung-Hwan

    2014-01-01

    The tomato (Solanum lycopersicum L.) is a model plant for genome research in Solanaceae, as well as for studying crop breeding. Genome-wide single nucleotide polymorphisms (SNPs) are a valuable resource in genetic research and breeding. However, to do discovery of genome-wide SNPs, most methods require expensive high-depth sequencing. Here, we describe a method for SNP calling using a modified version of SAMtools that improved its sensitivity. We analyzed 90 Gb of raw sequence data from next-generation sequencing of two resequencing and seven transcriptome data sets from several tomato accessions. Our study identified 4,812,432 non-redundant SNPs. Moreover, the workflow of SNP calling was improved by aligning the reference genome with its own raw data. Using this approach, 131,785 SNPs were discovered from transcriptome data of seven accessions. In addition, 4,680,647 SNPs were identified from the genome of S. pimpinellifolium, which are 60 times more than 71,637 of the PI212816 transcriptome. SNP distribution was compared between the whole genome and transcriptome of S. pimpinellifolium. Moreover, we surveyed the location of SNPs within genic and intergenic regions. Our results indicated that the sufficient genome-wide SNP markers and very sensitive SNP calling method allow for application of marker assisted breeding and genome-wide association studies. PMID:24552708

  10. Software engineering the mixed model for genome-wide association studies on large samples

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mixed models improve the ability to detect phenotype-genotype associations in the presence of population stratification and multiple levels of relatedness in genome-wide association studies (GWAS), but for large data sets the resource consumption becomes impractical. At the same time, the sample siz...

  11. Genome-wide SNP detection, validation, and development of an 8K SNP array for apple

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide...

  12. Genome-wide identification and characterization of simple sequence repeat loci in grape phylloxera, Daktulosphaira vitifoliae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide sequence search was conducted to identify simple sequence repeat (SSR) loci in phylloxera, Daktulosphaira vitifoliae (Fitch), a key grape pest throughout the world. Collectively, 1,524 SSR loci containing mono, di-, tri-, tetra-, penta- and hexanucleotide motifs were identified. Among...

  13. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population

    PubMed Central

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene–environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10−8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  14. Gene-Environment Interactions in Genome-Wide Association Studies: Current Approaches and New Directions

    PubMed Central

    Winham, Stacey J; Biernacka, Joanna M.

    2013-01-01

    Background Complex psychiatric traits have long been thought to be the result of a combination of genetic and environmental factors, and gene-environment interactions are thought to play a crucial role in behavioral phenotypes and the susceptibility and progression of psychiatric disorders. Candidate gene studies to investigate hypothesized gene-environment interactions are now fairly common in human genetic research, and with the shift towards genome-wide association studies, genome-wide gene-environment interaction studies are beginning to emerge. Methods We summarize the basic ideas behind gene-environment interaction, and provide an overview of possible study designs and traditional analysis methods in the context of genome-wide analysis. We then discuss novel approaches beyond the traditional strategy of analyzing the interaction between the environmental factor and each polymorphism individually. Results Two-step filtering approaches that reduce the number of polymorphisms tested for interactions can substantially increase the power of genome-wide gene-environment studies. New analytical methods including data-mining approaches, and gene-level and pathway-level analyses, also have the capacity to improve our understanding of how complex genetic and environmental factors interact to influence psychological and psychiatric traits. Such methods, however, have not yet been utilized much in behavioral and mental health research. Conclusions Although methods to investigate gene-environment interactions are available, there is a need for further development and extension of these methods to identify gene-environment interactions in the context of genome-wide association studies. These novel approaches need to be applied in studies of psychology and psychiatry. PMID:23808649

  15. A genome-wide quantitative trait loci scan of neurocognitive performances in families with schizophrenia.

    PubMed

    Lien, Y-J; Liu, C-M; Faraone, S V; Tsuang, M T; Hwu, H-G; Hsiao, P-C; Chen, W J

    2010-10-01

    Patients with schizophrenia frequently display neurocognitive dysfunction, and genetic studies suggest it to be an endophenotype for schizophrenia. Genetic studies of such traits may thus help elucidate the biological pathways underlying genetic susceptibility to schizophrenia. This study aimed to identify loci influencing neurocognitive performance in schizophrenia. The sample comprised of 1207 affected individuals and 1035 unaffected individuals of Han Chinese ethnicity from 557 sib-pair families co-affected with DSM-IV (Diagnostic and Statistical Manual, Fourth Edition) schizophrenia. Subjects completed a face-to-face semi-structured interview, the continuous performance test (CPT) and the Wisconsin card sorting test (WCST), and were genotyped with 386 microsatellite markers across the genome. A series of autosomal genome-wide multipoint nonparametric quantitative trait loci (QTL) linkage analysis were performed in affected individuals only. Determination of genome-wide empirical significance was performed using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified: 12q24.32 for undegraded CPT hit rate [nonparametric linkage z (NPL-Z) scores = 3.32, genome-wide empirical P = 0.03]. This result was higher than the peak linkage signal obtained in the previous genome-wide scan using a dichotomous diagnosis of schizophrenia. The identification of 12q24.32 as a QTL has not been consistently implicated in previous linkage studies on schizophrenia, which suggests that the analysis of endophenotypes provides additional information from what is seen in analyses that rely on diagnoses. This region with linkage to a particular neurocognitive feature may inform functional hypotheses for further genetic studies for schizophrenia.

  16. A genome-wide approach to children's aggressive behavior: The EAGLE consortium.

    PubMed

    Pappa, Irene; St Pourcain, Beate; Benke, Kelly; Cavadino, Alana; Hakulinen, Christian; Nivard, Michel G; Nolte, Ilja M; Tiesler, Carla M T; Bakermans-Kranenburg, Marian J; Davies, Gareth E; Evans, David M; Geoffroy, Marie-Claude; Grallert, Harald; Groen-Blokhuis, Maria M; Hudziak, James J; Kemp, John P; Keltikangas-Järvinen, Liisa; McMahon, George; Mileva-Seitz, Viara R; Motazedi, Ehsan; Power, Christine; Raitakari, Olli T; Ring, Susan M; Rivadeneira, Fernando; Rodriguez, Alina; Scheet, Paul A; Seppälä, Ilkka; Snieder, Harold; Standl, Marie; Thiering, Elisabeth; Timpson, Nicholas J; Veenstra, René; Velders, Fleur P; Whitehouse, Andrew J O; Smith, George Davey; Heinrich, Joachim; Hypponen, Elina; Lehtimäki, Terho; Middeldorp, Christel M; Oldehinkel, Albertine J; Pennell, Craig E; Boomsma, Dorret I; Tiemeier, Henning

    2016-07-01

    Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

  17. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population.

    PubMed

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene-environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10-8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  18. Genome-wide meta-analyses of smoking behaviors in African Americans.

    PubMed

    David, S P; Hamidovic, A; Chen, G K; Bergen, A W; Wessel, J; Kasberger, J L; Brown, W M; Petruzella, S; Thacker, E L; Kim, Y; Nalls, M A; Tranah, G J; Sung, Y J; Ambrosone, C B; Arnett, D; Bandera, E V; Becker, D M; Becker, L; Berndt, S I; Bernstein, L; Blot, W J; Broeckel, U; Buxbaum, S G; Caporaso, N; Casey, G; Chanock, S J; Deming, S L; Diver, W R; Eaton, C B; Evans, D S; Evans, M K; Fornage, M; Franceschini, N; Harris, T B; Henderson, B E; Hernandez, D G; Hitsman, B; Hu, J J; Hunt, S C; Ingles, S A; John, E M; Kittles, R; Kolb, S; Kolonel, L N; Le Marchand, L; Liu, Y; Lohman, K K; McKnight, B; Millikan, R C; Murphy, A; Neslund-Dudas, C; Nyante, S; Press, M; Psaty, B M; Rao, D C; Redline, S; Rodriguez-Gil, J L; Rybicki, B A; Signorello, L B; Singleton, A B; Smoller, J; Snively, B; Spring, B; Stanford, J L; Strom, S S; Swan, G E; Taylor, K D; Thun, M J; Wilson, A F; Witte, J S; Yamamura, Y; Yanek, L R; Yu, K; Zheng, W; Ziegler, R G; Zonderman, A B; Jorgenson, E; Haiman, C A; Furberg, H

    2012-01-01

    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans. PMID:22832964

  19. Genome-wide meta-analyses of smoking behaviors in African Americans.

    PubMed

    David, S P; Hamidovic, A; Chen, G K; Bergen, A W; Wessel, J; Kasberger, J L; Brown, W M; Petruzella, S; Thacker, E L; Kim, Y; Nalls, M A; Tranah, G J; Sung, Y J; Ambrosone, C B; Arnett, D; Bandera, E V; Becker, D M; Becker, L; Berndt, S I; Bernstein, L; Blot, W J; Broeckel, U; Buxbaum, S G; Caporaso, N; Casey, G; Chanock, S J; Deming, S L; Diver, W R; Eaton, C B; Evans, D S; Evans, M K; Fornage, M; Franceschini, N; Harris, T B; Henderson, B E; Hernandez, D G; Hitsman, B; Hu, J J; Hunt, S C; Ingles, S A; John, E M; Kittles, R; Kolb, S; Kolonel, L N; Le Marchand, L; Liu, Y; Lohman, K K; McKnight, B; Millikan, R C; Murphy, A; Neslund-Dudas, C; Nyante, S; Press, M; Psaty, B M; Rao, D C; Redline, S; Rodriguez-Gil, J L; Rybicki, B A; Signorello, L B; Singleton, A B; Smoller, J; Snively, B; Spring, B; Stanford, J L; Strom, S S; Swan, G E; Taylor, K D; Thun, M J; Wilson, A F; Witte, J S; Yamamura, Y; Yanek, L R; Yu, K; Zheng, W; Ziegler, R G; Zonderman, A B; Jorgenson, E; Haiman, C A; Furberg, H

    2012-05-22

    The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

  20. Bimolecular fluorescence complementation (BiFC) analysis: advances and recent applications for genome-wide interaction studies

    PubMed Central

    Huh, Won-Ki; Park, Hay-Oak

    2015-01-01

    Complex protein networks are involved in nearly all cellular processes. To uncover these vast networks of protein interactions, various high-throughput screening technologies have been developed. Over the last decade, bimolecular fluorescence complementation (BiFC) assay has been widely used to detect protein-protein interactions (PPIs) in living cells. This technique is based on the reconstitution of a fluorescent protein in vivo. Easy quantification of the BiFC signals allows effective cell-based high-throughput screenings for protein-binding partners and drugs that modulate PPIs. Recently, with the development of large screening libraries, BiFC has been effectively applied for genome-wide PPI studies and has uncovered novel protein interactions, providing new insight into protein functions. In this review, we describe the development of reagents and methods used for BiFC-based screens in yeast, plants, and mammalian cells. We also discuss the advantages and drawbacks of these methods and highlight the application of BiFC in large-scale studies. PMID:25772494

  1. Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing.

    PubMed

    Nicod, Jérôme; Davies, Robert W; Cai, Na; Hassett, Carl; Goodstadt, Leo; Cosgrove, Cormac; Yee, Benjamin K; Lionikaite, Vikte; McIntyre, Rebecca E; Remme, Carol Ann; Lodder, Elisabeth M; Gregory, Jennifer S; Hough, Tertius; Joynson, Russell; Phelps, Hayley; Nell, Barbara; Rowe, Clare; Wood, Joe; Walling, Alison; Bopp, Nasrin; Bhomra, Amarjit; Hernandez-Pliego, Polinka; Callebert, Jacques; Aspden, Richard M; Talbot, Nick P; Robbins, Peter A; Harrison, Mark; Fray, Martin; Launay, Jean-Marie; Pinto, Yigal M; Blizard, David A; Bezzina, Connie R; Adams, David J; Franken, Paul; Weaver, Tom; Wells, Sara; Brown, Steve D M; Potter, Paul K; Klenerman, Paul; Lionikas, Arimantas; Mott, Richard; Flint, Jonathan

    2016-08-01

    Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations. PMID:27376238

  2. Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing.

    PubMed

    Nicod, Jérôme; Davies, Robert W; Cai, Na; Hassett, Carl; Goodstadt, Leo; Cosgrove, Cormac; Yee, Benjamin K; Lionikaite, Vikte; McIntyre, Rebecca E; Remme, Carol Ann; Lodder, Elisabeth M; Gregory, Jennifer S; Hough, Tertius; Joynson, Russell; Phelps, Hayley; Nell, Barbara; Rowe, Clare; Wood, Joe; Walling, Alison; Bopp, Nasrin; Bhomra, Amarjit; Hernandez-Pliego, Polinka; Callebert, Jacques; Aspden, Richard M; Talbot, Nick P; Robbins, Peter A; Harrison, Mark; Fray, Martin; Launay, Jean-Marie; Pinto, Yigal M; Blizard, David A; Bezzina, Connie R; Adams, David J; Franken, Paul; Weaver, Tom; Wells, Sara; Brown, Steve D M; Potter, Paul K; Klenerman, Paul; Lionikas, Arimantas; Mott, Richard; Flint, Jonathan

    2016-08-01

    Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

  3. Genome-wide transcriptional analysis of the human cell cycle identifies genes differentially regulated in normal and cancer cells

    PubMed Central

    Bar-Joseph, Ziv; Siegfried, Zahava; Brandeis, Michael; Brors, Benedikt; Lu, Yong; Eils, Roland; Dynlacht, Brian D.; Simon, Itamar

    2008-01-01

    Characterization of the transcriptional regulatory network of the normal cell cycle is essential for understanding the perturbations that lead to cancer. However, the complete set of cycling genes in primary cells has not yet been identified. Here, we report the results of genome-wide expression profiling experiments on synchronized primary human foreskin fibroblasts across the cell cycle. Using a combined experimental and computational approach to deconvolve measured expression values into “single-cell” expression profiles, we were able to overcome the limitations inherent in synchronizing nontransformed mammalian cells. This allowed us to identify 480 periodically expressed genes in primary human foreskin fibroblasts. Analysis of the reconstructed primary cell profiles and comparison with published expression datasets from synchronized transformed cells reveals a large number of genes that cycle exclusively in primary cells. This conclusion was supported by both bioinformatic analysis and experiments performed on other cell types. We suggest that this approach will help pinpoint genetic elements contributing to normal cell growth and cellular transformation. PMID:18195366

  4. Quality control and conduct of genome-wide association meta-analyses

    PubMed Central

    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C; Wood, Andrew R; Locke, Adam E; Mägi, Reedik; Ferreira, Teresa; Fall, Tove; Graff, Mariaelisa; Justice, Anne E; Luan, Jian'an; Gustafsson, Stefan; Randall, Joshua C; Vedantam, Sailaja; Workalemahu, Tsegaselassie; Kilpeläinen, Tuomas O; Scherag, André; Esko, Tonu; Kutalik, Zoltán; Heid, Iris M; Loos, Ruth JF

    2014-01-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for [1] organizational aspects of GWAMAs, and for [2] QC at the study file level, the meta-level across studies, and the meta-analysis output level. Real–world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for use of a powerful and flexible software package called EasyQC. For consortia of comparable size to the GIANT consortium, the present protocol takes a minimum of about 10 months to complete. PMID:24762786

  5. Genome-wide association mapping reveals a rich genetic architecture of complex traits in Oryza sativa

    PubMed Central

    Zhao, Keyan; Tung, Chih-Wei; Eizenga, Georgia C.; Wright, Mark H.; Ali, M. Liakat; Price, Adam H.; Norton, Gareth J.; Islam, M. Rafiqul; Reynolds, Andy; Mezey, Jason; McClung, Anna M.; Bustamante, Carlos D.; McCouch, Susan R.

    2011-01-01

    Asian rice, Oryza sativa is a cultivated, inbreeding species that feeds over half of the world's population. Understanding the genetic basis of diverse physiological, developmental, and morphological traits provides the basis for improving yield, quality and sustainability of rice. Here we show the results of a genome-wide association study based on genotyping 44,100 SNP variants across 413 diverse accessions of O. sativa collected from 82 countries that were systematically phenotyped for 34 traits. Using cross-population-based mapping strategies, we identified dozens of common variants influencing numerous complex traits. Significant heterogeneity was observed in the genetic architecture associated with subpopulation structure and response to environment. This work establishes an open-source translational research platform for genome-wide association studies in rice that directly links molecular variation in genes and metabolic pathways with the germplasm resources needed to accelerate varietal development and crop improvement. PMID:21915109

  6. Genome-wide association analysis identifies six new loci associated with forced vital capacity

    PubMed Central

    Loth, Daan W.; Artigas, María Soler; Gharib, Sina A.; Wain, Louise V.; Franceschini, Nora; Koch, Beate; Pottinger, Tess; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P.; James, Alan L.; Huffman, Jennifer E.; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J.; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kähönen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M.; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K.; Fall, Tove; Viňuela, Ana; Launer, Lenore J.; Loehr, Laura R.; Fornage, Myriam; Li, Guo; Wilk, Jemma B.; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B.; North, Kari E.; Rudnicka, Alicja R.; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F.; Hastie, Nicholas D.; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A.; Pietiläinen, Kirsi H.; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G.; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M.; Wojczynski, Mary; Pouta, Anneli; Johansson, Åsa; Wild, Sarah H.; Ingelsson, Erik; Rivadeneira, Fernando; Völzke, Henry; Hysi, Pirro G.; Eiriksdottir, Gudny; Morrison, Alanna C.; Rotter, Jerome I.; Gao, Wei; Postma, Dirkje S.; White, Wendy B.; Rich, Stephen S.; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J.; Psaty, Bruce M.; Lohman, Kurt; Burchard, Esteban G.; Uitterlinden, André G.; Garcia, Melissa; Joubert, Bonnie R.; McArdle, Wendy L.; Musk, A. Bill; Hansel, Nadia; Heckbert, Susan R.; Zgaga, Lina; van Meurs, Joyce B.J.; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah; Zhao, Jing Hua; Rantanen, Taina; O’Connor, George T.; Ripatti, Samuli; Scott, Rodney J.; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C.; Starr, John M.; Wijmenga, Cisca; Minster, Ryan L.; Lederer, David J.; Pekkanen, Juha; Gyllensten, Ulf; Campbell, Harry; Morris, Andrew P.; Gläser, Sven; Hammond, Christopher J.; Burkart, Kristin M.; Beilby, John; Kritchevsky, Stephen B.; Gudnason, Vilmundur; Hancock, Dana B.; Williams, O. Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F.; Wjst, Matthias; Kim, Woo Jin; Porteous, David J.; Scotland, Generation; Smith, Blair H.; Viljanen, Anne; Heliövaara, Markku; Attia, John R.; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J.; Boezen, H. Marike; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F.; Lind, Lars; Stricker, Bruno H.; Teumer, Alexander; Spector, Timothy D.; Melén, Erik; Peters, Marjolein J.; Lange, Leslie A.; Barr, R. Graham; Bracke, Ken R.; Verhamme, Fien M.; Sung, Joohon; Hiemstra, Pieter S.; Cassano, Patricia A.; Sood, Akshay; Hayward, Caroline; Dupuis, Josée; Hall, Ian P.; Brusselle, Guy G.; Tobin, Martin D.; London, Stephanie J.

    2014-01-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease. PMID:24929828

  7. FINEMAP: efficient variable selection using summary data from genome-wide association studies

    PubMed Central

    Benner, Christian; Spencer, Chris C.A.; Havulinna, Aki S.; Salomaa, Veikko; Ripatti, Samuli; Pirinen, Matti

    2016-01-01

    Motivation: The goal of fine-mapping in genomic regions associated with complex diseases and traits is to identify causal variants that point to molecular mechanisms behind the associations. Recent fine-mapping methods using summary data from genome-wide association studies rely on exhaustive search through all possible causal configurations, which is computationally expensive. Results: We introduce FINEMAP, a software package to efficiently explore a set of the most important causal configurations of the region via a shotgun stochastic search algorithm. We show that FINEMAP produces accurate results in a fraction of processing time of existing approaches and is therefore a promising tool for analyzing growing amounts of data produced in genome-wide association studies and emerging sequencing projects. Availability and implementation: FINEMAP v1.0 is freely available for Mac OS X and Linux at http://www.christianbenner.com. Contact: christian.benner@helsinki.fi or matti.pirinen@helsinki.fi PMID:26773131

  8. A guide to genome-wide association analysis and post-analytic interrogation.

    PubMed

    Reed, Eric; Nunez, Sara; Kulp, David; Qian, Jing; Reilly, Muredach P; Foulkes, Andrea S

    2015-12-10

    This tutorial is a learning resource that outlines the basic process and provides specific software tools for implementing a complete genome-wide association analysis. Approaches to post-analytic visualization and interrogation of potentially novel findings are also presented. Applications are illustrated using the free and open-source R statistical computing and graphics software environment, Bioconductor software for bioinformatics and the UCSC Genome Browser. Complete genome-wide association data on 1401 individuals across 861,473 typed single nucleotide polymorphisms from the PennCATH study of coronary artery disease are used for illustration. All data and code, as well as additional instructional resources, are publicly available through the Open Resources in Statistical Genomics project: http://www.stat-gen.org.

  9. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

    PubMed Central

    Law, Matthew H.; Bishop, D. Timothy; Martin, Nicholas G.; Moses, Eric K.; Song, Fengju; Barrett, Jennifer H.; Kumar, Rajiv; Easton, Douglas F.; Pharoah, Paul D. P.; Swerdlow, Anthony J.; Kypreou, Katerina P.; Taylor, John C.; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Duffy, David L.; Elder, David E.; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Chen, Wei V.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Mann, Graham J.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A.; Radford-Smith, Graham L.; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; Craig, Jamie E.; Schadendorf, Dirk; Simms, Lisa A.; Burdon, Kathryn P.; Nyholt, Dale R.; Pooley, Karen A.; Orr, Nick; Stratigos, Alexander J.; Cust, Anne E.; Ward, Sarah V.; Hayward, Nicholas K.; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M.; Bishop, Julia A. Newton; MacGregor, Stuart; Iles, Mark M.

    2015-01-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology. PMID:26237428

  10. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

    PubMed

    Law, Matthew H; Bishop, D Timothy; Lee, Jeffrey E; Brossard, Myriam; Martin, Nicholas G; Moses, Eric K; Song, Fengju; Barrett, Jennifer H; Kumar, Rajiv; Easton, Douglas F; Pharoah, Paul D P; Swerdlow, Anthony J; Kypreou, Katerina P; Taylor, John C; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dȩbniak, Tadeusz; Duffy, David L; Elder, David E; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Chen, Wei V; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Mann, Graham J; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A; Radford-Smith, Graham L; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; Craig, Jamie E; Schadendorf, Dirk; Simms, Lisa A; Burdon, Kathryn P; Nyholt, Dale R; Pooley, Karen A; Orr, Nick; Stratigos, Alexander J; Cust, Anne E; Ward, Sarah V; Hayward, Nicholas K; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M; Bishop, Julia A Newton; Demenais, Florence; Amos, Christopher I; MacGregor, Stuart; Iles, Mark M

    2015-09-01

    Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology. PMID:26237428

  11. Genome-wide association analysis identifies six new loci associated with forced vital capacity.

    PubMed

    Loth, Daan W; Soler Artigas, María; Gharib, Sina A; Wain, Louise V; Franceschini, Nora; Koch, Beate; Pottinger, Tess D; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P; James, Alan L; Huffman, Jennifer E; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kähönen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K; Fall, Tove; Viñuela, Ana; Launer, Lenore J; Loehr, Laura R; Fornage, Myriam; Li, Guo; Wilk, Jemma B; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B; North, Kari E; Rudnicka, Alicja R; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F; Hastie, Nicholas D; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A; Pietiläinen, Kirsi H; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M; Wojczynski, Mary; Pouta, Anneli; Johansson, Asa; Wild, Sarah H; Ingelsson, Erik; Rivadeneira, Fernando; Völzke, Henry; Hysi, Pirro G; Eiriksdottir, Gudny; Morrison, Alanna C; Rotter, Jerome I; Gao, Wei; Postma, Dirkje S; White, Wendy B; Rich, Stephen S; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J; Psaty, Bruce M; Lohman, Kurt; Burchard, Esteban G; Uitterlinden, André G; Garcia, Melissa; Joubert, Bonnie R; McArdle, Wendy L; Musk, A Bill; Hansel, Nadia; Heckbert, Susan R; Zgaga, Lina; van Meurs, Joyce B J; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah L; Zhao, Jing Hua; Rantanen, Taina; O'Connor, George T; Ripatti, Samuli; Scott, Rodney J; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C; Starr, John M; Wijmenga, Cisca; Minster, Ryan L; Lederer, David J; Pekkanen, Juha; Gyllensten, Ulf; Campbell, Harry; Morris, Andrew P; Gläser, Sven; Hammond, Christopher J; Burkart, Kristin M; Beilby, John; Kritchevsky, Stephen B; Gudnason, Vilmundur; Hancock, Dana B; Williams, O Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F; Wjst, Matthias; Kim, Woo Jin; Porteous, David J; Scotland, Generation; Smith, Blair H; Viljanen, Anne; Heliövaara, Markku; Attia, John R; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J; Boezen, H Marike; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F; Lind, Lars; Stricker, Bruno H; Teumer, Alexander; Spector, Timothy D; Melén, Erik; Peters, Marjolein J; Lange, Leslie A; Barr, R Graham; Bracke, Ken R; Verhamme, Fien M; Sung, Joohon; Hiemstra, Pieter S; Cassano, Patricia A; Sood, Akshay; Hayward, Caroline; Dupuis, Josée; Hall, Ian P; Brusselle, Guy G; Tobin, Martin D; London, Stephanie J

    2014-07-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

  12. Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma

    PubMed Central

    Chahal, Harvind S.; Wu, Wenting; Ransohoff, Katherine J.; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Hinds, David A.; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.

    2016-01-01

    Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10−8, logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC. PMID:27539887

  13. Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics.

    PubMed

    Lundby, Alicia; Rossin, Elizabeth J; Steffensen, Annette B; Acha, Moshe Rav; Newton-Cheh, Christopher; Pfeufer, Arne; Lynch, Stacey N; Olesen, Søren-Peter; Brunak, Søren; Ellinor, Patrick T; Jukema, J Wouter; Trompet, Stella; Ford, Ian; Macfarlane, Peter W; Krijthe, Bouwe P; Hofman, Albert; Uitterlinden, André G; Stricker, Bruno H; Nathoe, Hendrik M; Spiering, Wilko; Daly, Mark J; Asselbergs, Folkert W; van der Harst, Pim; Milan, David J; de Bakker, Paul I W; Lage, Kasper; Olsen, Jesper V

    2014-08-01

    Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT-interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single-nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics. PMID:24952909

  14. Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics

    PubMed Central

    Lundby, Alicia; Rossin, Elizabeth J.; Steffensen, Annette B.; Rav Acha, Moshe; Newton-Cheh, Christopher; Pfeufer, Arne; Lynch, Stacey N.; Olesen, Søren-Peter; Brunak, Søren; Ellinor, Patrick T.; Jukema, J.Wouter; Trompet, Stella; Ford, Ian; Macfarlane, Peter W.; Krijthe, Bouwe P.; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.; Nathoe, Hendrik M.; Spiering, Wilko; Daly, Mark J.; Asselbergs, Folkert W.; van der Harst, Pim; Milan, David J.; de Bakker, Paul I.W.; Lage, Kasper; Olsen, Jesper V.

    2014-01-01

    Genome-wide association studies (GWAS) have identified thousands of loci associated wtih complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes involved in the Mendelian disorder long QT syndrome (LQTS). We integrated the LQTS network with GWAS loci from the corresponding common complex trait, QT interval variation, to identify candidate genes that were subsequently confirmed in Xenopus laevis oocytes and zebrafish. We used the LQTS protein network to filter weak GWAS signals by identifying single nucleotide polymorphisms (SNPs) in proximity to genes in the network supported by strong proteomic evidence. Three SNPs passing this filter reached genome-wide significance after replication genotyping. Overall, we present a general strategy to propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics. PMID:24952909

  15. High-Throughput, Liquid-Based Genome-Wide RNAi Screening in C. elegans.

    PubMed

    O'Reilly, Linda P; Knoerdel, Ryan R; Silverman, Gary A; Pak, Stephen C

    2016-01-01

    RNA interference (RNAi) is a process in which double-stranded RNA (dsRNA) molecules mediate the inhibition of gene expression. RNAi in C. elegans can be achieved by simply feeding animals with bacteria expressing dsRNA against the gene of interest. This "feeding" method has made it possible to conduct genome-wide RNAi experiments for the systematic knockdown and subsequent investigation of almost every single gene in the genome. Historically, these genome-scale RNAi screens have been labor and time intensive. However, recent advances in automated, high-throughput methodologies have allowed the development of more rapid and efficient screening protocols. In this report, we describe a fast and efficient, liquid-based method for genome-wide RNAi screening. PMID:27581291

  16. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.

    PubMed

    Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter Hl; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

    2016-01-01

    Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. PMID:27162171

  17. Identification of Transcribed Enhancers by Genome-Wide Chromatin Immunoprecipitation Sequencing.

    PubMed

    Blinka, Steven; Reimer, Michael H; Pulakanti, Kirthi; Pinello, Luca; Yuan, Guo-Cheng; Rao, Sridhar

    2017-01-01

    Recent work has shown that RNA polymerase II-mediated transcription at distal cis-regulatory elements serves as a mark of highly active enhancers. Production of noncoding RNAs at enhancers, termed eRNAs, correlates with higher expression of genes that the enhancer interacts with; hence, eRNAs provide a new tool to model gene activity in normal and disease tissues. Moreover, this unique class of noncoding RNA has diverse roles in transcriptional regulation. Transcribed enhancers can be identified by a common signature of epigenetic marks by overlaying a series of genome-wide chromatin immunoprecipitation and RNA sequencing datasets. A computational approach to filter non-enhancer elements and other classes of noncoding RNAs is essential to not cloud downstream analysis. Here we present a protocol that combines wet and dry bench methods to accurately identify transcribed enhancers genome-wide as well as an experimental procedure to validate these datasets. PMID:27662872

  18. Quality control and conduct of genome-wide association meta-analyses.

    PubMed

    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C; Wood, Andrew R; Locke, Adam E; Mägi, Reedik; Ferreira, Teresa; Fall, Tove; Graff, Mariaelisa; Justice, Anne E; Luan, Jian'an; Gustafsson, Stefan; Randall, Joshua C; Vedantam, Sailaja; Workalemahu, Tsegaselassie; Kilpeläinen, Tuomas O; Scherag, André; Esko, Tonu; Kutalik, Zoltán; Heid, Iris M; Loos, Ruth J F

    2014-05-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.

  19. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality.

    PubMed

    Kamvar, Zhian N; Brooks, Jonah C; Grünwald, Niklaus J

    2015-01-01

    To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies. PMID:26113860

  20. Genome-wide Mapping of Nucleosome Positioning and DNA Methylation Within Individual DNA Molecules

    PubMed Central

    Liu, Yaping; Lay, Fides D.; Liang, Gangning; Berman, Benjamin P.; Jones, Peter A.; Kelly, Terry

    2012-01-01

    DNA methylation and nucleosome positioning work together to generate chromatin structures that regulate gene expression. Nucleosomes are typically mapped using nuclease digestion requiring significant amounts of material and varying enzyme concentrations. We have developed a method that uses a GpC methyltransferase (M.CviPI) and next generation sequencing to footprint nucleosome positioning genome-wide using less than 1 million cells, which does not suffer from sequence based biases associated with MNase digestion and retains endogenous DNA methylation information. Using a novel bioinformatics pipeline we identify chromatin configurations associated with a variety of functional genomic loci including distinct promoter types, enhancers, insulators, X-inactivated and imprinted genes. Importantly, DNA methylation and nucleosome positioning information are obtained from the same DNA molecule, giving the first genome-wide DNA methylation and nucleosome positioning correlation at the single molecule level that can be used to monitor disease progression and response to therapy.

  1. Genetic Studies on Diabetic Microvascular Complications: Focusing on Genome-Wide Association Studies

    PubMed Central

    Kwak, Soo Heon

    2015-01-01

    Diabetes is a common metabolic disorder with a worldwide prevalence of 8.3% and is the leading cause of visual loss, end-stage renal disease and amputation. Recently, genome-wide association studies (GWASs) have identified genetic risk factors for diabetic microvascular complications of retinopathy, nephropathy, and neuropathy. We summarized the recent findings of GWASs on diabetic microvascular complications and highlighted the challenges and our opinion on future directives. Five GWASs were conducted on diabetic retinopathy, nine on nephropathy, and one on neuropathic pain. The majority of recent GWASs were underpowered and heterogeneous in terms of study design, inclusion criteria and phenotype definition. Therefore, few reached the genome-wide significance threshold and the findings were inconsistent across the studies. Recent GWASs provided novel information on genetic risk factors and the possible pathophysiology of diabetic microvascular complications. However, further collaborative efforts to standardize phenotype definition and increase sample size are necessary for successful genetic studies on diabetic microvascular complications. PMID:26194074

  2. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast

    PubMed Central

    Oud, Bart; Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-01-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages. PMID:22152095

  3. Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.

    PubMed

    Chahal, Harvind S; Wu, Wenting; Ransohoff, Katherine J; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong-Ji; Qureshi, Abrar A; Li, Wen-Qing; Kraft, Peter; Hinds, David A; Tang, Jean Y; Han, Jiali; Sarin, Kavita Y

    2016-01-01

    Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC. PMID:27539887

  4. Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies.

    PubMed

    Xu, P; Wu, X; Wang, B; Luo, J; Liu, Y; Ehlers, J D; Close, T J; Roberts, P A; Lu, Z; Wang, S; Li, G

    2012-07-01

    Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform. PMID:22378357

  5. Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions.

    PubMed

    Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile J W; de Moor, Marleen H M; Madden, Pamela A F; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M

    2013-08-01

    Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. PMID:23211697

  6. Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies.

    PubMed

    Xu, P; Wu, X; Wang, B; Luo, J; Liu, Y; Ehlers, J D; Close, T J; Roberts, P A; Lu, Z; Wang, S; Li, G

    2012-07-01

    Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.

  7. Genome-wide Association and Functional Studies Identify a Role for IGFBP3 in Hip Osteoarthritis

    PubMed Central

    Evans, Daniel S.; Cailotto, Frederic; Parimi, Neeta; Valdes, Ana M.; Castaño-Betancourt, Martha C.; Liu, Youfang; Kaplan, Robert C.; Bidlingmaier, Martin; Vasan, Ramachandran S.; Teumer, Alexander; Tranah, Gregory J.; Nevitt, Michael C.; Cummings, Steven R.; Orwoll, Eric S.; Barrett-Connor, Elizabeth; Renner, Jordan B.; Jordan, Joanne M.; Doherty, Michael; Doherty, Sally A.; Uitterlinden, Andre G.; van Meurs, Joyce B.J.; Spector, Tim D.; Lories, Rik J.; Lane, Nancy E.

    2015-01-01

    Objectives To identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA. Methods The GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (P-value ≤ 5x10−8) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis. Results The A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR = 0.71, P-value = 2x10−8). The association replicated in five studies (OR = 0.92, P-value = 0.020), but the joint analysis of discovery and replication results was not genome-wide significant (P-value = 1x10−6). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (P-value = 4x10−13), suggesting that this SNP or a variant in linkage disequilibrium (LD) could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation. Conclusions Results from GWAS and functional studies provided suggestive links between IGFBP3 and HOA. PMID:24928840

  8. Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics.

    PubMed

    Agrawal, Arpana; Edenberg, Howard J; Gelernter, Joel

    2016-09-01

    Meta-analyses of genome-wide association study data have begun to lead to promising new discoveries for behavioral and psychiatrically relevant phenotypes (e.g., schizophrenia, educational attainment). We outline how this methodology can similarly lead to novel discoveries in genomic studies of substance use disorders, and discuss challenges that will need to be overcome to accomplish this goal. We illustrate our approach with the work of the newly established Substance Use Disorders workgroup of the Psychiatric Genomics Consortium. PMID:27588522

  9. Estimating genome-wide significance for whole-genome sequencing studies.

    PubMed

    Xu, ChangJiang; Tachmazidou, Ioanna; Walter, Klaudia; Ciampi, Antonio; Zeggini, Eleftheria; Greenwood, Celia M T

    2014-05-01

    Although a standard genome-wide significance level has been accepted for the testing of association between common genetic variants and disease, the era of whole-genome sequencing (WGS) requires a new threshold. The allele frequency spectrum of sequence-identified variants is very different from common variants, and the identified rare genetic variation is usually jointly analyzed in a series of genomic windows or regions. In nearby or overlapping windows, these test statistics will be correlated, and the degree of correlation is likely to depend on the choice of window size, overlap, and the test statistic. Furthermore, multiple analyses may be performed using different windows or test statistics. Here we propose an empirical approach for estimating genome-wide significance thresholds for data arising from WGS studies, and we demonstrate that the empirical threshold can be efficiently estimated by extrapolating from calculations performed on a small genomic region. Because analysis of WGS may need to be repeated with different choices of test statistics or windows, this prediction approach makes it computationally feasible to estimate genome-wide significance thresholds for different analysis choices. Based on UK10K whole-genome sequence data, we derive genome-wide significance thresholds ranging between 2.5 × 10(-8) and 8 × 10(-8) for our analytic choices in window-based testing, and thresholds of 0.6 × 10(-8) -1.5 × 10(-8) for a combined analytic strategy of testing common variants using single-SNP tests together with rare variants analyzed with our sliding-window test strategy.

  10. Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder

    PubMed Central

    Xie, Pingxing; Kranzler, Henry R.; Yang, Can; Zhao, Hongyu; Farrer, Lindsay A.; Gelernter, Joel

    2013-01-01

    Background Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate gene association studies have identified few genetic variants that contribute to PTSD risk. Methods We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Results In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance (p = 3.97×10−8). A SNP that maps to the first intron of the Tolloid-Like 1 gene (TLL1) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1, rs6812849 and rs7691872, with p values of 6.3×10−6 and 2.3×10−4, respectively. In the combined sample, rs6812849 had a p value of 3.1 ×10−9. No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results. Conclusions This study identified TLL1 as a new susceptibility gene for PTSD. PMID:23726511

  11. Meta-analysis of 32 genome-wide linkage studies of schizophrenia

    PubMed Central

    Ng, MYM; Levinson, DF; Faraone, SV; Suarez, BK; DeLisi, LE; Arinami, T; Riley, B; Paunio, T; Pulver, AE; Irmansyah; Holmans, PA; Escamilla, M; Wildenauer, DB; Williams, NM; Laurent, C; Mowry, BJ; Brzustowicz, LM; Maziade, M; Sklar, P; Garver, DL; Abecasis, GR; Lerer, B; Fallin, MD; Gurling, HMD; Gejman, PV; Lindholm, E; Moises, HW; Byerley, W; Wijsman, EM; Forabosco, P; Tsuang, MT; Hwu, H-G; Okazaki, Y; Kendler, KS; Wormley, B; Fanous, A; Walsh, D; O’Neill, FA; Peltonen, L; Nestadt, G; Lasseter, VK; Liang, KY; Papadimitriou, GM; Dikeos, DG; Schwab, SG; Owen, MJ; O’Donovan, MC; Norton, N; Hare, E; Raventos, H; Nicolini, H; Albus, M; Maier, W; Nimgaonkar, VL; Terenius, L; Mallet, J; Jay, M; Godard, S; Nertney, D; Alexander, M; Crowe, RR; Silverman, JM; Bassett, AS; Roy, M-A; Mérette, C; Pato, CN; Pato, MT; Roos, J Louw; Kohn, Y; Amann-Zalcenstein, D; Kalsi, G; McQuillin, A; Curtis, D; Brynjolfson, J; Sigmundsson, T; Petursson, H; Sanders, AR; Duan, J; Jazin, E; Myles-Worsley, M; Karayiorgou, M; Lewis, CM

    2009-01-01

    A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. PMID:19349958

  12. Genome-Wide Association Studies and Hepatitis C: Harvesting the Benefits of the Genomic Revolution.

    PubMed

    Eslam, Mohammed; George, Jacob

    2015-11-01

    Utilizing genome-wide association studies (GWASs) to examine the variation in hepatitis C virus (HCV) phenotypes has led to quantum improvements in our understanding of both the genetic basis and the underlying pathogenesis of HCV infection. In this context, the discovery of interferon lambda polymorphisms is unique with far reaching implications that extend well beyond HCV to various other liver and extrahepatic diseases. In this review, we summarize the data on the impact of GWASs on our understanding of HCV disease.

  13. Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

    PubMed

    Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T; Harrison, Tabitha A; Jeon, Jihyoun; Hutter, Carolyn M; Berndt, Sonja I; Brenner, Hermann; Caan, Bette J; Campbell, Peter T; Chang-Claude, Jenny; Chanock, Stephen J; Cheadle, Jeremy P; Curtis, Keith R; Duggan, David; Fisher, David; Fuchs, Charles S; Gala, Manish; Giovannucci, Edward L; Hayes, Richard B; Hoffmeister, Michael; Hsu, Li; Jacobs, Eric J; Jansen, Lina; Kaplan, Richard; Kap, Elisabeth J; Maughan, Timothy S; Potter, John D; Schoen, Robert E; Seminara, Daniela; Slattery, Martha L; West, Hannah; White, Emily; Peters, Ulrike; Newcomb, Polly A

    2016-01-01

    Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. PMID:26586795

  14. Where to begin? Mapping transcription start sites genome-wide in Escherichia coli.

    PubMed

    Wade, Joseph T

    2015-01-01

    Recent genome-wide studies of bacterial transcription have revealed large numbers of promoters located inside genes. In this issue of the Journal of Bacteriology, Thomason and colleagues (J. Bacteriol. 197:18-28, 2015, doi:10.1128/JB.02096-14) map transcription start sites in Escherichia coli on an unprecedented scale. This work provides important insights into the regulation of transcripts that initiate inside genes and sources of variability between studies aimed at identifying these RNAs.

  15. Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.

    PubMed

    Yucesoy, Berran; Kaufman, Kenneth M; Lummus, Zana L; Weirauch, Matthew T; Zhang, Ge; Cartier, André; Boulet, Louis-Philippe; Sastre, Joaquin; Quirce, Santiago; Tarlo, Susan M; Cruz, Maria-Jesus; Munoz, Xavier; Harley, John B; Bernstein, David I

    2015-07-01

    Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10(-14)). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10(-9) and rs2514805, p = 1.22 × 10(-8), respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10(-6)). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies.

  16. Genome-wide contribution of genotype by environment interaction to variation of diabetes-related traits.

    PubMed

    Zheng, Ju-Sheng; Arnett, Donna K; Lee, Yu-Chi; Shen, Jian; Parnell, Laurence D; Smith, Caren E; Richardson, Kris; Li, Duo; Borecki, Ingrid B; Ordovás, José M; Lai, Chao-Qiang

    2013-01-01

    While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-β-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.

  17. Common Variants Confer Susceptibility to Barrett's Esophagus: Insights from the First Genome-Wide Association Studies.

    PubMed

    Palles, Claire; Findlay, John M; Tomlinson, Ian

    2016-01-01

    Eight loci have been identified by the two genome-wide association studies of Barrett's esophagus that have been conducted to date. Esophageal adenocarcinoma cases were included in the second study following evidence that predisposing genetic variants for this cancer overlap with those for Barrett's esophagus. Genes with roles in embryonic development of the foregut are adjacent to 6 of the loci identified (FOXF1, BARX1, FOXP1, GDF7, TBX5, and ALDH1A2). An additional locus maps to a gene with known oncogenic potential (CREB-regulated transcription coactivator 1), but expression quantitative trait data implicates yet another gene involved in esophageal development (PBX4). These results strongly support a model whereby dysregulation of genes involved in esophageal and thoracic development increases susceptibility to Barrett's esophagus and esophageal adenocarcinoma, probably by reducing anatomical antireflux mechanisms. An additional signal at 6p21 in the major histocompatibility complex also reinforces evidence that immune and inflammatory response to reflux is involved in the development of both diseases. All of the variants identified are intronic or intergenic rather than coding and are presumed to be or to mark regulatory variants. As with genome-wide association studies of other diseases, the functional variants at each locus are yet to be identified and the genes affected need confirming. In this chapter as well as discussing the biology behind each genome-wide association signal, we review the requirements for successfully conducting genome-wide association studies and discuss how progress in understanding the genetic variants that contribute to Barrett's esophagus/esophageal adenocarcinoma susceptibility compares to other cancers. PMID:27573776

  18. Genome wide expression profiling of angiogenic signaling and the Heisenberg uncertainty principle.

    PubMed

    Huber, Peter E; Hauser, Kai; Abdollahi, Amir

    2004-11-01

    Genome wide DNA expression profiling coupled with antibody array experiments using endostatin to probe the angiogenic signaling network in human endothelial cells were performed. The results reveal constraints on the measuring process that are of a similar kind as those implied by the uncertainty principle of quantum mechanics as described by Werner Heisenberg. We describe this analogy and argue for its heuristic utility in the conceptualization of angiogenesis as an important step in tumor formation.

  19. Genome-wide association studies for hematological traits in Chinese Sutai pigs

    PubMed Central

    2014-01-01

    Background It has been shown that hematological traits are strongly associated with the metabolism and the immune system in domestic pig. However, little is known about the genetic architecture of hematological traits. To identify quantitative trait loci (QTL) controlling hematological traits, we performed single marker Genome-wide association studies (GWAS) and haplotype analysis for 15 hematological traits in 495 Chinese Sutai pigs. Results We identified 161 significant SNPs including 44 genome-wide significant SNPs associated with 11 hematological traits by single marker GWAS. Most of them were located on SSC2. Meanwhile, we detected 499 significant SNPs containing 154 genome-wide significant SNPs associated with 9 hematological traits by haplotype analysis. Most of the identified loci were located on SSC7 and SSC9. Conclusions We detected 4 SNPs with pleiotropic effects on SSC2 by single marker GWAS and (or) on SSC7 by haplotype analysis. Furthermore, through checking the gene functional annotations, positions and their expression variation, we finally selected 7 genes as potential candidates. Specially, we found that three genes (TRIM58, TRIM26 and TRIM21) of them originated from the same gene family and executed similar function of innate and adaptive immune. The findings will contribute to dissection the immune gene network, further identification of causative mutations underlying the identified QTLs and providing insights into the molecular basis of hematological trait in domestic pig. PMID:24674592

  20. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.

    PubMed

    Wolpin, Brian M; Rizzato, Cosmeri; Kraft, Peter; Kooperberg, Charles; Petersen, Gloria M; Wang, Zhaoming; Arslan, Alan A; Beane-Freeman, Laura; Bracci, Paige M; Buring, Julie; Canzian, Federico; Duell, Eric J; Gallinger, Steven; Giles, Graham G; Goodman, Gary E; Goodman, Phyllis J; Jacobs, Eric J; Kamineni, Aruna; Klein, Alison P; Kolonel, Laurence N; Kulke, Matthew H; Li, Donghui; Malats, Núria; Olson, Sara H; Risch, Harvey A; Sesso, Howard D; Visvanathan, Kala; White, Emily; Zheng, Wei; Abnet, Christian C; Albanes, Demetrius; Andreotti, Gabriella; Austin, Melissa A; Barfield, Richard; Basso, Daniela; Berndt, Sonja I; Boutron-Ruault, Marie-Christine; Brotzman, Michelle; Büchler, Markus W; Bueno-de-Mesquita, H Bas; Bugert, Peter; Burdette, Laurie; Campa, Daniele; Caporaso, Neil E; Capurso, Gabriele; Chung, Charles; Cotterchio, Michelle; Costello, Eithne; Elena, Joanne; Funel, Niccola; Gaziano, J Michael; Giese, Nathalia A; Giovannucci, Edward L; Goggins, Michael; Gorman, Megan J; Gross, Myron; Haiman, Christopher A; Hassan, Manal; Helzlsouer, Kathy J; Henderson, Brian E; Holly, Elizabeth A; Hu, Nan; Hunter, David J; Innocenti, Federico; Jenab, Mazda; Kaaks, Rudolf; Key, Timothy J; Khaw, Kay-Tee; Klein, Eric A; Kogevinas, Manolis; Krogh, Vittorio; Kupcinskas, Juozas; Kurtz, Robert C; LaCroix, Andrea; Landi, Maria T; Landi, Stefano; Le Marchand, Loic; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L; Nakamura, Yusuke; Oberg, Ann L; Owzar, Kouros; Patel, Alpa V; Peeters, Petra H M; Peters, Ulrike; Pezzilli, Raffaele; Piepoli, Ada; Porta, Miquel; Real, Francisco X; Riboli, Elio; Rothman, Nathaniel; Scarpa, Aldo; Shu, Xiao-Ou; Silverman, Debra T; Soucek, Pavel; Sund, Malin; Talar-Wojnarowska, Renata; Taylor, Philip R; Theodoropoulos, George E; Thornquist, Mark; Tjønneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Vodicka, Pavel; Wactawski-Wende, Jean; Wentzensen, Nicolas; Wu, Chen; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Hartge, Patricia; Fuchs, Charles; Chanock, Stephen J; Stolzenberg-Solomon, Rachael S; Amundadottir, Laufey T

    2014-09-01

    We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies. PMID:25086665

  1. Replicability and robustness of genome-wide-association studies for behavioral traits.

    PubMed

    Rietveld, Cornelius A; Conley, Dalton; Eriksson, Nicholas; Esko, Tõnu; Medland, Sarah E; Vinkhuyzen, Anna A E; Yang, Jian; Boardman, Jason D; Chabris, Christopher F; Dawes, Christopher T; Domingue, Benjamin W; Hinds, David A; Johannesson, Magnus; Kiefer, Amy K; Laibson, David; Magnusson, Patrik K E; Mountain, Joanna L; Oskarsson, Sven; Rostapshova, Olga; Teumer, Alexander; Tung, Joyce Y; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-11-01

    A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies.

  2. Genome-Wide Scan of Copy Number Variation in Late-Onset Alzheimer’s Disease

    PubMed Central

    Heinzen, Erin L.; Need, Anna C.; Hayden, Kathleen M.; Chiba-Falek, Ornit; Roses, Allen D.; Strittmatter, Warren J.; Burke, James R.; Hulette, Christine M.; Welsh-Bohmer, Kathleen A.; Goldstein, David B.

    2010-01-01

    Alzheimer’s disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE ε4 risk allele, identified a novel variant that influences disease risk within the APOE ε4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer’s disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In line with previous reports, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation. PMID:20061627

  3. Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension.

    PubMed

    Lu, Xiangfeng; Wang, Laiyuan; Lin, Xu; Huang, Jianfeng; Charles Gu, C; He, Meian; Shen, Hongbing; He, Jiang; Zhu, Jingwen; Li, Huaixing; Hixson, James E; Wu, Tangchun; Dai, Juncheng; Lu, Ling; Shen, Chong; Chen, Shufeng; He, Lin; Mo, Zengnan; Hao, Yongchen; Mo, Xingbo; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Fan, Zhongjie; Li, Ying; Zhao, Liancheng; Li, Hongfan; Lu, Fanghong; Yao, Cailiang; Yu, Lin; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Deng, Ying; Hu, Dongsheng; Zhang, Weidong; Ji, Xu; Guo, Dongshuang; Guo, Zhirong; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Zhou, Xiaoyang; Yan, Weili; Sun, Ningling; Gao, Pingjin; Gu, Dongfeng

    2015-02-01

    Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments. PMID:25249183

  4. Cell-Type-Specific Genome-wide Expression Profiling after Laser Capture Microdissection of Living Tissue

    SciTech Connect

    Marchetti, F; Manohar, C F

    2005-02-09

    The purpose of this technical feasibility study was to develop and evaluate robust microgenomic tools for investigations of genome-wide expression of very small numbers of cells isolated from whole tissue sections. Tissues contain large numbers of cell-types that play varied roles in organ function and responses to endogenous and exogenous toxicants whether bacterial, viral, chemical or radiation. Expression studies of whole tissue biopsy are severely limited because heterogeneous cell-types result in an averaging of molecular signals masking subtle but important changes in gene expression in any one cell type(s) or group of cells. Accurate gene expression analysis requires the study of specific cell types in their tissue environment but without contamination from surrounding cells. Laser capture microdissection (LCM) is a new technology to isolate morphologically distinct cells from tissue sections. Alternative methods are available for isolating single cells but not yet for their reliable genome-wide expression analyses. The tasks of this feasibility project were to: (1) Develop efficient protocols for laser capture microdissection of cells from tissues identified by antibody label, or morphological stain. (2) Develop reproducible gene-transcript analyses techniques for single cell-types and determine the numbers of cells needed for reliable genome-wide analyses. (3) Validate the technology for epithelial and endothelial cells isolated from the gastrointestinal tract of mice.

  5. Genome-wide association study identifies multiple loci associated with bladder cancer risk

    PubMed Central

    Figueroa, Jonine D.; Ye, Yuanqing; Siddiq, Afshan; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Prokunina-Olsson, Ludmila; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Dinney, Colin P.; Malats, Núria; Baris, Dalsu; Purdue, Mark; Jacobs, Eric J.; Albanes, Demetrius; Wang, Zhaoming; Deng, Xiang; Chung, Charles C.; Tang, Wei; Bas Bueno-de-Mesquita, H.; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Kamat, Ashish M.; Lerner, Seth P.; Barton Grossman, H.; Lin, Jie; Gu, Jian; Pu, Xia; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Kogevinas, Manolis; Tardón, Adonina; Serra, Consol; Carrato, Alfredo; García-Closas, Reina; Lloreta, Josep; Schwenn, Molly; Karagas, Margaret R.; Johnson, Alison; Schned, Alan; Armenti, Karla R.; Hosain, G.M.; Andriole, Gerald; Grubb, Robert; Black, Amanda; Ryan Diver, W.; Gapstur, Susan M.; Weinstein, Stephanie J.; Virtamo, Jarmo; Haiman, Chris A.; Landi, Maria T.; Caporaso, Neil; Fraumeni, Joseph F.; Vineis, Paolo; Wu, Xifeng; Silverman, Debra T.; Chanock, Stephen; Rothman, Nathaniel

    2014-01-01

    Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis. PMID:24163127

  6. Meta-analysis of sex-specific genome-wide association studies.

    PubMed

    Magi, Reedik; Lindgren, Cecilia M; Morris, Andrew P

    2010-12-01

    Despite the success of genome-wide association studies, much of the genetic contribution to complex human traits is still unexplained. One potential source of genetic variation that may contribute to this "missing heritability" is that which differs in magnitude and/or direction between males and females, which could result from sexual dimorphism in gene expression. Such sex-differentiated effects are common in model organisms, and are becoming increasingly evident in human complex traits through large-scale male- and female-specific meta-analyses. In this article, we review the methodology for meta-analysis of sex-specific genome-wide association studies, and propose a sex-differentiated test of association with quantitative or dichotomous traits, which allows for heterogeneity of allelic effects between males and females. We perform detailed simulations to compare the power of the proposed sex-differentiated meta-analysis with the more traditional "sex-combined" approach, which is ambivalent to gender. The results of this study highlight only a small loss in power for the sex-differentiated meta-analysis when the allelic effects of the causal variant are the same in males and females. However, over a range of models of heterogeneity in allelic effects between genders, our sex-differentiated meta-analysis strategy offers substantial gains in power, and thus has the potential to discover novel loci contributing effects to complex human traits with existing genome-wide association data.

  7. Multi-instance multi-label distance metric learning for genome-wide protein function prediction.

    PubMed

    Xu, Yonghui; Min, Huaqing; Song, Hengjie; Wu, Qingyao

    2016-08-01

    Multi-instance multi-label (MIML) learning has been proven to be effective for the genome-wide protein function prediction problems where each training example is associated with not only multiple instances but also multiple class labels. To find an appropriate MIML learning method for genome-wide protein function prediction, many studies in the literature attempted to optimize objective functions in which dissimilarity between instances is measured using the Euclidean distance. But in many real applications, Euclidean distance may be unable to capture the intrinsic similarity/dissimilarity in feature space and label space. Unlike other previous approaches, in this paper, we propose to learn a multi-instance multi-label distance metric learning framework (MIMLDML) for genome-wide protein function prediction. Specifically, we learn a Mahalanobis distance to preserve and utilize the intrinsic geometric information of both feature space and label space for MIML learning. In addition, we try to deal with the sparsely labeled data by giving weight to the labeled data. Extensive experiments on seven real-world organisms covering the biological three-domain system (i.e., archaea, bacteria, and eukaryote; Woese et al., 1990) show that the MIMLDML algorithm is superior to most state-of-the-art MIML learning algorithms.

  8. Five endometrial cancer risk loci identified through genome-wide association analysis.

    PubMed

    Cheng, Timothy H T; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica M J; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-06-01

    We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. PMID:27135401

  9. Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population

    PubMed Central

    Gauvin, Héloïse; Moreau, Claudia; Lefebvre, Jean-François; Laprise, Catherine; Vézina, Hélène; Labuda, Damian; Roy-Gagnon, Marie-Hélène

    2014-01-01

    In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6–7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship's variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec. PMID:24129432

  10. Genetic architecture dissection by genome-wide association analysis reveals avian eggshell ultrastructure traits

    PubMed Central

    Duan, Zhongyi; Sun, Congjiao; Shen, ManMan; Wang, Kehua; Yang, Ning; Zheng, Jiangxia; Xu, Guiyun

    2016-01-01

    The ultrastructure of an eggshell is considered the major determinant of eggshell quality, which has biological and economic significance for the avian and poultry industries. However, the interrelationships and genome-wide architecture of eggshell ultrastructure remain to be elucidated. Herein, we measured eggshell thickness (EST), effective layer thickness (ET), mammillary layer thickness (MT), and mammillary density (MD) and conducted genome-wide association studies in 927 F2 hens. The SNP-based heritabilities of eggshell ultrastructure traits were estimated to be 0.39, 0.36, 0.17 and 0.19 for EST, ET, MT and MD, respectively, and a total of 719, 784, 1 and 10 genome-wide significant SNPs were associated with EST, ET, MT and MD, respectively. ABCC9, ITPR2, KCNJ8 and WNK1, which are involved in ion transport, were suggested to be the key genes regulating EST and ET. ITM2C and KNDC1 likely affect MT and MD, respectively. Additionally, there were linear relationships between the chromosome lengths and the variance explained per chromosome for EST (R2 = 0.57) and ET (R2 = 0.67). In conclusion, the interrelationships and genetic architecture of eggshell ultrastructure traits revealed in this study are valuable for our understanding of the avian eggshell and contribute to research on a variety of other calcified shells. PMID:27456605

  11. Population genomic and genome-wide association studies of agroclimatic traits in sorghum.

    PubMed

    Morris, Geoffrey P; Ramu, Punna; Deshpande, Santosh P; Hash, C Thomas; Shah, Trushar; Upadhyaya, Hari D; Riera-Lizarazu, Oscar; Brown, Patrick J; Acharya, Charlotte B; Mitchell, Sharon E; Harriman, James; Glaubitz, Jeffrey C; Buckler, Edward S; Kresovich, Stephen

    2013-01-01

    Accelerating crop improvement in sorghum, a staple food for people in semiarid regions across the developing world, is key to ensuring global food security in the context of climate change. To facilitate gene discovery and molecular breeding in sorghum, we have characterized ~265,000 single nucleotide polymorphisms (SNPs) in 971 worldwide accessions that have adapted to diverse agroclimatic conditions. Using this genome-wide SNP map, we have characterized population structure with respect to geographic origin and morphological type and identified patterns of ancient crop diffusion to diverse agroclimatic regions across Africa and Asia. To better understand the genomic patterns of diversification in sorghum, we quantified variation in nucleotide diversity, linkage disequilibrium, and recombination rates across the genome. Analyzing nucleotide diversity in landraces, we find evidence of selective sweeps around starch metabolism genes, whereas in landrace-derived introgression lines, we find introgressions around known height and maturity loci. To identify additional loci underlying variation in major agroclimatic traits, we performed genome-wide association studies (GWAS) on plant height components and inflorescence architecture. GWAS maps several classical loci for plant height, candidate genes for inflorescence architecture. Finally, we trace the independent spread of multiple haplotypes carrying alleles for short stature or long inflorescence branches. This genome-wide map of SNP variation in sorghum provides a basis for crop improvement through marker-assisted breeding and genomic selection. PMID:23267105

  12. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

    PubMed Central

    Chouraki, V; De Bruijn, RFAG; Chapuis, J; Bis, JC; Reitz, C; Schraen, S; Ibrahim-Verbaas, CA; Grenier-Boley, B; Delay, C; Rogers, R; Demiautte, F; Mounier, A; Fitzpatrick, AL; Berr, C; Dartigues, J-F; Uitterlinden, AG; Hofman, A; Breteler, M; Becker, JT; Lathrop, M; Schupf, N; Alpérovitch, A; Mayeux, R; van Duijn, CM; Buée, L; Amouyel, P; Lopez, OL; Ikram, MA; Tzourio, C; Lambert, J-C

    2014-01-01

    Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides’ functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1–40 and Aβ1–42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10−5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1–42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1–42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites. PMID:24535457

  13. Testing untyped alleles (TUNA)-applications to genome-wide association studies.

    PubMed

    Nicolae, Dan L

    2006-12-01

    The large number of tests performed in analyzing data from genome-wide association studies has a large impact on the power of detecting risk variants, and analytic strategies specifying the optimal set of hypotheses to be tested are necessary. We propose a genome-wide strategy that is based on one degree of freedom tests for all the genotyped variants, and for all the untyped variants for which there is sufficient information in the observed data. The set of untyped variants to be tested is found using multi-locus measures of linkage disequilibrium and haplotype frequencies from a reference database such as HapMap (The International HapMap Consortium [2003] Nature 426:789-796). We introduce a novel statistic for testing differences in allele frequencies for untyped variation that is based on linear combinations of estimable haplotype frequencies. Algorithms for finding the sets of genotyped markers to be used in testing an untyped allele, and ways of incorporating haplotypes observed in the study data but not in the reference database are also described. The proposed testing strategy can be used as the first step in the analysis of genome-wide association data, and, because every performed test is directed to a marker, it can be used to specify the set of polymorphisms to genotype in follow-up studies. The described methodology provides also a tool for joint analysis of data from studies done on different platforms.

  14. A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM

    PubMed Central

    Weiss, Lauren A.; Arking, Dan E.

    2009-01-01

    Summary Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants. PMID:19812673

  15. A twin study of breastfeeding with a preliminary genome wide association scan

    PubMed Central

    Colodro-Conde, L.; Zhu, G.; Power, R. A.; Henders, A.; Heath, A.C.; Madden, P.A.F.; Montgomery, G.W.; Medland, S. E.; Ordoñana, J.R.; Martin, N.G.

    2015-01-01

    Breastfeeding has been an important survival trait during human history, though it has long been recognised that individuals differ in their exact breastfeeding behaviour. Here our aims were, first, to explore to what extent genetic and environmental influences contributed to the individual differences in breastfeeding behaviour; second, to detect possible genetic variants related to breastfeeding; and lastly, to test if the genetic variants associated with breastfeeding have been previously found to be related with breast size. Data were collected from a large community-based cohort of Australian twins, with 3,364 women for the twin modelling analyses and 1,521 of them included in the genome wide association study. Monozygotic twin correlations (rMZ = .52, 95% CI .46 – .57) were larger than dizygotic twin correlations (rDZ = .35, 95% CI .25 – .43) and the best-fitting model was the one composed by additive genetics and unique environmental factors, explaining 53% and 47% of the variance in breastfeeding behaviour, respectively. No breastfeeding-related genetic variants reached genome-wide significance. The polygenic risk score analyses showed no significant results, suggesting breast size does not influence breastfeeding. This study confers a replication of a previous one exploring the sources of variance of breastfeeding and, to our knowledge, is the first one to conduct a Genome-Wide Association Study on breastfeeding and look at the overlap with variants for breast size. PMID:25475840

  16. Population genomic and genome-wide association studies of agroclimatic traits in sorghum

    PubMed Central

    Morris, Geoffrey P.; Ramu, Punna; Deshpande, Santosh P.; Hash, C. Thomas; Shah, Trushar; Upadhyaya, Hari D.; Riera-Lizarazu, Oscar; Brown, Patrick J.; Acharya, Charlotte B.; Mitchell, Sharon E.; Harriman, James; Glaubitz, Jeffrey C.; Buckler, Edward S.; Kresovich, Stephen

    2013-01-01

    Accelerating crop improvement in sorghum, a staple food for people in semiarid regions across the developing world, is key to ensuring global food security in the context of climate change. To facilitate gene discovery and molecular breeding in sorghum, we have characterized ∼265,000 single nucleotide polymorphisms (SNPs) in 971 worldwide accessions that have adapted to diverse agroclimatic conditions. Using this genome-wide SNP map, we have characterized population structure with respect to geographic origin and morphological type and identified patterns of ancient crop diffusion to diverse agroclimatic regions across Africa and Asia. To better understand the genomic patterns of diversification in sorghum, we quantified variation in nucleotide diversity, linkage disequilibrium, and recombination rates across the genome. Analyzing nucleotide diversity in landraces, we find evidence of selective sweeps around starch metabolism genes, whereas in landrace-derived introgression lines, we find introgressions around known height and maturity loci. To identify additional loci underlying variation in major agroclimatic traits, we performed genome-wide association studies (GWAS) on plant height components and inflorescence architecture. GWAS maps several classical loci for plant height, candidate genes for inflorescence architecture. Finally, we trace the independent spread of multiple haplotypes carrying alleles for short stature or long inflorescence branches. This genome-wide map of SNP variation in sorghum provides a basis for crop improvement through marker-assisted breeding and genomic selection. PMID:23267105

  17. NSD1 mutations generate a genome-wide DNA methylation signature

    PubMed Central

    Choufani, S.; Cytrynbaum, C.; Chung, B. H. Y.; Turinsky, A. L.; Grafodatskaya, D.; Chen, Y. A.; Cohen, A. S. A.; Dupuis, L.; Butcher, D. T.; Siu, M. T.; Luk, H. M.; Lo, I. F. M.; Lam, S. T. S.; Caluseriu, O.; Stavropoulos, D. J.; Reardon, W.; Mendoza-Londono, R.; Brudno, M.; Gibson, W. T.; Chitayat, D.; Weksberg, R.

    2015-01-01

    Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/−-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/− signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. PMID:26690673

  18. Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension.

    PubMed

    Lu, Xiangfeng; Wang, Laiyuan; Lin, Xu; Huang, Jianfeng; Charles Gu, C; He, Meian; Shen, Hongbing; He, Jiang; Zhu, Jingwen; Li, Huaixing; Hixson, James E; Wu, Tangchun; Dai, Juncheng; Lu, Ling; Shen, Chong; Chen, Shufeng; He, Lin; Mo, Zengnan; Hao, Yongchen; Mo, Xingbo; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Fan, Zhongjie; Li, Ying; Zhao, Liancheng; Li, Hongfan; Lu, Fanghong; Yao, Cailiang; Yu, Lin; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Deng, Ying; Hu, Dongsheng; Zhang, Weidong; Ji, Xu; Guo, Dongshuang; Guo, Zhirong; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Zhou, Xiaoyang; Yan, Weili; Sun, Ningling; Gao, Pingjin; Gu, Dongfeng

    2015-02-01

    Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.

  19. Assessing the Genome-Wide Effect of Promoter Region Tandem Repeat Natural Variation on Gene Expression

    PubMed Central

    Elmore, Martha H.; Gibbons, John G.; Rokas, Antonis

    2012-01-01

    Copy number polymorphisms of nucleotide tandem repeat (TR) regions, such as microsatellites and minisatellites, are mutationally reversible and highly abundant in eukaryotic genomes. Studies linking TR polymorphism to phenotypic variation have led some to suggest that TR variation modulates and majorly contributes to phenotypic variation; however, studies in which the authors assess the genome-wide impact of TR variation on phenotype are lacking. To address this question, we quantified relationships between polymorphism levels in 143 genome-wide promoter region TRs across 16 isolates of the filamentous fungus Aspergillus flavus and its ecotype Aspergillus oryzae with expression levels of their downstream genes. We found that only 4.3% of relationships tested were significant; these findings were consistent with models in which TRs act as “tuning,” “volume,” or “optimality” “knobs” of phenotype but not with “switch” models. Furthermore, the promoter regions of differentially expressed genes between A. oryzae and A. flavus did not show TR enrichment, suggesting that genome-wide differences in molecular phenotype between the two species are not significantly associated with TRs. Although in some cases TR polymorphisms do contribute to transcript abundance variation, these results argue that at least in this case, TRs might not be major modulators of variation in phenotype. PMID:23275886

  20. Genome-Wide Association Study of the Child Behavior Checklist Dysregulation Profile

    PubMed Central

    Mick, Eric; McGough, James; Loo, Sandra; Doyle, Alysa E.; Wozniak, Janet; Wilens, Timothy E.; Smalley, Susan; McCracken, James; Biederman, Joseph; Faraone, Stephen V.

    2011-01-01

    Objective A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile comprised of the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for later psychopathology, including severe mood problems and aggressive behavior. We have conducted a genome-wide association study of the CBCL-DP in children with attention-deficit/hyperactivity disorder (ADHD). Method Families were ascertained at Massachusetts General Hospital and University of California, Los Angeles. Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. Genome-wide association analyses were conducted with the MQFAM multivariate extension of PLINK. Results CBCL data were available for 341 ADHD offspring from 339 ADHD affected trio families from the UCLA (N=128) and the MGH (N=213) sites. We found no genome-wide statistically significant associations but identified several plausible candidate genes among findings at p<5E-05: TMEM132D, LRRC7, SEMA3A, ALK, and STIP1. Conclusions We found suggestive evidence for developmentally expressed genes operant in hippocampal dependent memory and learning with the CBCL-DP. PMID:21784300

  1. Anxiety genetics – findings from cross-species genome-wide approaches

    PubMed Central

    2013-01-01

    Anxiety disorders are complex diseases, which often occur in combination with major depression, alcohol use disorder, or general medical conditions. Anxiety disorders were the most common mental disorders within the EU states in 2010 with 14% prevalence. Anxiety disorders are triggered by environmental factors in genetically susceptible individuals, and therefore genetic research offers a great route to unravel molecular basis of these diseases. As anxiety is an evolutionarily conserved response, mouse models can be used to carry out genome-wide searches for specific genes in a setting that controls for the environmental factors. In this review, we discuss translational approaches that aim to bridge results from unbiased genome-wide screens using mouse models to anxiety disorders in humans. Several methods, such as quantitative trait locus mapping, gene expression profiling, and proteomics, have been used in various mouse models of anxiety to identify genes that regulate anxiety or play a role in maintaining pathological anxiety. We first discuss briefly the evolutionary background of anxiety, which justifies cross-species approaches. We then describe how several genes have been identified through genome-wide methods in mouse models and subsequently investigated in human anxiety disorder samples as candidate genes. These studies have led to the identification of completely novel biological pathways that regulate anxiety in mice and humans, and that can be further investigated as targets for therapy. PMID:23659354

  2. Unraveling the genetic etiology of adult antisocial behavior: a genome-wide association study.

    PubMed

    Tielbeek, Jorim J; Medland, Sarah E; Benyamin, Beben; Byrne, Enda M; Heath, Andrew C; Madden, Pamela A F; Martin, Nicholas G; Wray, Naomi R; Verweij, Karin J H

    2012-01-01

    Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10(-5)) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies. PMID:23077488

  3. Genome-wide signatures of male-mediated migration shaping the Indian gene pool.

    PubMed

    ArunKumar, GaneshPrasad; Tatarinova, Tatiana V; Duty, Jeff; Rollo, Debra; Syama, Adhikarla; Arun, Varatharajan Santhakumari; Kavitha, Valampuri John; Triska, Petr; Greenspan, Bennett; Wells, R Spencer; Pitchappan, Ramasamy

    2015-09-01

    Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India.

  4. Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder

    PubMed Central

    Neale, Benjamin M; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schäfer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J.L.; Langely, Kate; O’Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective Although twin and family studies have shown Attention Deficit/Hyperactivity Disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association scans (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children’s Hospital of Philadelphia (CHOP), b) phase I of the International Multicenter ADHD Genetics project (IMAGE), c) phase II of IMAGE (IMAGE II), and d) the Pfizer funded study from the University of California, Los Angeles, Washington University and the Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases and 2,455 controls. For each study, we imputed HapMap SNPs, computed association test statistics and transformed them to Z-scores, and then combined weighted Z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g. rare ones, account for much of the disorder’s heritability. PMID:20732625

  5. Unraveling the Genetic Etiology of Adult Antisocial Behavior: A Genome-Wide Association Study

    PubMed Central

    Tielbeek, Jorim J.; Medland, Sarah E.; Benyamin, Beben; Byrne, Enda M.; Heath, Andrew C.; Madden, Pamela A. F.; Martin, Nicholas G.; Wray, Naomi R.; Verweij, Karin J. H.

    2012-01-01

    Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10−5) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies. PMID:23077488

  6. Genome-wide linkage disequilibrium in nine-spined stickleback populations.

    PubMed

    Yang, Ji; Shikano, Takahito; Li, Meng-Hua; Merilä, Juha

    2014-08-12

    Variation in the extent and magnitude of genome-wide linkage disequilibrium (LD) among populations residing in different habitats has seldom been studied in wild vertebrates. We used a total of 109 microsatellite markers to quantify the level and patterns of genome-wide LD in 13 Fennoscandian nine-spined stickleback (Pungitius pungitius) populations from four (viz. marine, lake, pond, and river) different habitat types. In general, high magnitude (D' > 0.5) of LD was found both in freshwater and marine populations, and the magnitude of LD was significantly greater in inland freshwater than in marine populations. Interestingly, three coastal freshwater populations located in close geographic proximity to the marine populations exhibited similar LD patterns and genetic diversity as their marine neighbors. The greater levels of LD in inland freshwater compared with marine and costal freshwater populations can be explained in terms of their contrasting demographic histories: founder events, long-term isolation, small effective sizes, and population bottlenecks are factors likely to have contributed to the high levels of LD in the inland freshwater populations. In general, these findings shed new light on the patterns and extent of variation in genome-wide LD, as well as the ecological and evolutionary factors driving them.

  7. Revisiting the classification of curtoviruses based on genome-wide pairwise identity.

    PubMed

    Varsani, Arvind; Martin, Darren P; Navas-Castillo, Jesús; Moriones, Enrique; Hernández-Zepeda, Cecilia; Idris, Ali; Murilo Zerbini, F; Brown, Judith K

    2014-07-01

    Members of the genus Curtovirus (family Geminiviridae) are important pathogens of many wild and cultivated plant species. Until recently, relatively few full curtovirus genomes have been characterised. However, with the 19 full genome sequences now available in public databases, we revisit the proposed curtovirus species and strain classification criteria. Using pairwise identities coupled with phylogenetic evidence, revised species and strain demarcation guidelines have been instituted. Specifically, we have established 77 % genome-wide pairwise identity as a species demarcation threshold and 94 % genome-wide pairwise identity as a strain demarcation threshold. Hence, whereas curtovirus sequences with >77 % genome-wide pairwise identity would be classified as belonging to the same species, those sharing >94 % identity would be classified as belonging to the same strain. We provide step-by-step guidelines to facilitate the classification of newly discovered curtovirus full genome sequences and a set of defined criteria for naming new species and strains. The revision yields three curtovirus species: Beet curly top virus (BCTV), Spinach severe surly top virus (SpSCTV) and Horseradish curly top virus (HrCTV). PMID:24463952

  8. Characterization and Correction of Error in Genome-Wide IBD Estimation for Samples with Population Structure

    PubMed Central

    Morrison, Jean

    2014-01-01

    The proportion of the genome that is shared identical by descent (IBD) between pairs of individuals is often estimated in studies involving genome-wide SNP data. These estimates can be used to check pedigrees, estimate heritability, and adjust association analyses. We focus on the method of moments technique as implemented in PLINK [Purcell et al., 2007] and other software that estimates the proportions of the genome at which two individuals share 0, 1, or 2 alleles IBD. This technique is based on the assumption that the study sample is drawn from a single, homogeneous, randomly mating population. This assumption is violated if pedigree founders are drawn from multiple populations or include admixed individuals. In the presence of population structure, the method of moments estimator has an inflated variance and can be biased because it relies on sample-based allele frequency estimates. In the case of the PLINK estimator, which truncates genome-wide sharing estimates at zero and one to generate biologically interpretable results, the bias is most often towards over-estimation of relatedness between ancestrally similar individuals. Using simulated pedigrees, we are able to demonstrate and quantify the behavior of the PLINK method of moments estimator under different population structure conditions. We also propose a simple method based on SNP pruning for improving genome-wide IBD estimates when the assumption of a single, homogeneous population is violated. PMID:23740691

  9. Genetic architecture dissection by genome-wide association analysis reveals avian eggshell ultrastructure traits.

    PubMed

    Duan, Zhongyi; Sun, Congjiao; Shen, ManMan; Wang, Kehua; Yang, Ning; Zheng, Jiangxia; Xu, Guiyun

    2016-01-01

    The ultrastructure of an eggshell is considered the major determinant of eggshell quality, which has biological and economic significance for the avian and poultry industries. However, the interrelationships and genome-wide architecture of eggshell ultrastructure remain to be elucidated. Herein, we measured eggshell thickness (EST), effective layer thickness (ET), mammillary layer thickness (MT), and mammillary density (MD) and conducted genome-wide association studies in 927 F2 hens. The SNP-based heritabilities of eggshell ultrastructure traits were estimated to be 0.39, 0.36, 0.17 and 0.19 for EST, ET, MT and MD, respectively, and a total of 719, 784, 1 and 10 genome-wide significant SNPs were associated with EST, ET, MT and MD, respectively. ABCC9, ITPR2, KCNJ8 and WNK1, which are involved in ion transport, were suggested to be the key genes regulating EST and ET. ITM2C and KNDC1 likely affect MT and MD, respectively. Additionally, there were linear relationships between the chromosome lengths and the variance explained per chromosome for EST (R(2) = 0.57) and ET (R(2) = 0.67). In conclusion, the interrelationships and genetic architecture of eggshell ultrastructure traits revealed in this study are valuable for our understanding of the avian eggshell and contribute to research on a variety of other calcified shells. PMID:27456605

  10. Genome-Wide Association Study for Wool Production Traits in a Chinese Merino Sheep Population

    PubMed Central

    Wang, Zhipeng; Zhang, Hui; Yang, Hua; Wang, Shouzhi; Rong, Enguang; Pei, Wenyu; Li, Hui; Wang, Ning

    2014-01-01

    Genome-wide association studies (GWAS) provide a powerful approach for identifying quantitative trait loci without prior knowledge of location or function. To identify loci associated with wool production traits, we performed a genome-wide association study on a total of 765 Chinese Merino sheep (JunKen type) genotyped with 50 K single nucleotide polymorphisms (SNPs). In the present study, five wool production traits were examined: fiber diameter, fiber diameter coefficient of variation, fineness dispersion, staple length and crimp. We detected 28 genome-wide significant SNPs for fiber diameter, fiber diameter coefficient of variation, fineness dispersion, and crimp trait in the Chinese Merino sheep. About 43% of the significant SNP markers were located within known or predicted genes, including YWHAZ, KRTCAP3, TSPEAR, PIK3R4, KIF16B, PTPN3, GPRC5A, DDX47, TCF9, TPTE2, EPHA5 and NBEA genes. Our results not only confirm the results of previous reports, but also provide a suite of novel SNP markers and candidate genes associated with wool traits. Our findings will be useful for exploring the genetic control of wool traits in sheep. PMID:25268383

  11. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.

    PubMed

    Chouraki, V; De Bruijn, R F A G; Chapuis, J; Bis, J C; Reitz, C; Schraen, S; Ibrahim-Verbaas, C A; Grenier-Boley, B; Delay, C; Rogers, R; Demiautte, F; Mounier, A; Fitzpatrick, A L; Berr, C; Dartigues, J-F; Uitterlinden, A G; Hofman, A; Breteler, M; Becker, J T; Lathrop, M; Schupf, N; Alpérovitch, A; Mayeux, R; van Duijn, C M; Buée, L; Amouyel, P; Lopez, O L; Ikram, M A; Tzourio, C; Lambert, J-C

    2014-12-01

    Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

  12. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

    PubMed Central

    Smolonska, Joanna; Koppelman, Gerard H.; Wijmenga, Cisca; Vonk, Judith M.; Zanen, Pieter; Bruinenberg, Marcel; Curjuric, Ivan; Imboden, Medea; Thun, Gian-Andri; Franke, Lude; Probst-Hensch, Nicole M.; Nürnberg, Peter; Riemersma, Roland A.; van Schayck, Onno; Loth, Daan W.; Bruselle, Guy G.; Stricker, Bruno H; Hofman, Albert; Uitterlinden, André G.; Lahousse, Lies; London, Stephanie J.; Loehr, Laura R.; Manichaikul, Ani; Barr, R. Graham; Donohue, Kathleen M.; Rich, Stephen S.; Pare, Peter; Bossé, Yohan; Hao, Ke; van den Berge, Maarten; Groen, Harry J.M.; Lammers, Jan-Willem J.; Mali, Willem; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution. PMID:24993907

  13. High-fidelity CRISPR-Cas9 variants with undetectable genome-wide off-targets

    PubMed Central

    Kleinstiver, Benjamin P.; Pattanayak, Vikram; Prew, Michelle S.; Tsai, Shengdar Q.; Nguyen, Nhu; Zheng, Zongli; Joung, J. Keith

    2015-01-01

    CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations. Existing strategies for reducing genome-wide off-targets of the broadly used Streptococcus pyogenes Cas9 (SpCas9) are imperfect, possessing only partial or unproven efficacies and other limitations that constrain their use. Here we describe SpCas9-HF1, a high-fidelity variant harboring alterations designed to reduce non-specific DNA contacts. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with >85% of single-guide RNAs (sgRNAs) tested in human cells. Strikingly, with sgRNAs targeted to standard non-repetitive sequences, SpCas9-HF1 rendered all or nearly all off-target events undetectable by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off-targets induced by SpCas9-HF1 were not detected. With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other RNA-guided nucleases. PMID:26735016

  14. Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules

    PubMed Central

    Kelly, Theresa K.; Liu, Yaping; Lay, Fides D.; Liang, Gangning; Berman, Benjamin P.; Jones, Peter A.

    2012-01-01

    DNA methylation and nucleosome positioning work together to generate chromatin structures that regulate gene expression. Nucleosomes are typically mapped using nuclease digestion requiring significant amounts of material and varying enzyme concentrations. We have developed a method (NOMe-seq) that uses a GpC methyltransferase (M.CviPI) and next generation sequencing to generate a high resolution footprint of nucleosome positioning genome-wide using less than 1 million cells while retaining endogenous DNA methylation information from the same DNA strand. Using a novel bioinformatics pipeline, we show a striking anti-correlation between nucleosome occupancy and DNA methylation at CTCF regions that is not present at promoters. We further show that the extent of nucleosome depletion at promoters is directly correlated to expression level and can accommodate multiple nucleosomes and provide genome-wide evidence that expressed non-CpG island promoters are nucleosome-depleted. Importantly, NOMe-seq obtains DNA methylation and nucleosome positioning information from the same DNA molecule, giving the first genome-wide DNA methylation and nucleosome positioning correlation at the single molecule, and thus, single cell level, that can be used to monitor disease progression and response to therapy. PMID:22960375

  15. Genome-wide meta-analysis of longitudinal alcohol consumption across youth and early adulthood

    PubMed Central

    Adkins, Daniel E.; Clark, Shaunna L.; Copeland, William E.; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A.; Silberg, Judy; Brown, Tyson H.; Fergusson, David M.; Horwood, L. John; Eaves, Lindon; van den Oord, Edwin J.C.G.; Sullivan, Patrick F.; Costello, E. J.

    2016-01-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse and dependence increasing across adolescence and peaking in early adulthood. Here we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three, longitudinal community samples (N=2,126, obs=12,166). Consumption repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and 6 others met our “suggestive” criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms including neurotransmission, xenobiotic pharmacodynamics and nuclear hormone receptors. These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies. PMID:26081443

  16. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    PubMed

    Wang, Yu; Li, Wei; Xia, Yingying; Wang, Chongzhi; Tang, Y Tom; Guo, Wenying; Li, Jinliang; Zhao, Xia; Sun, Yepeng; Hu, Juan; Zhen, Hefu; Zhang, Xiandong; Chen, Chao; Shi, Yujian; Li, Lin; Cao, Hongzhi; Du, Hongli; Li, Jian

    2014-01-01

    Copy-number variations (CNV), loss of heterozygosity (LOH), and uniparental disomy (UPD) are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS) require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS), is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs). In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information. PMID:25919136

  17. Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population.

    PubMed

    Gauvin, Héloïse; Moreau, Claudia; Lefebvre, Jean-François; Laprise, Catherine; Vézina, Hélène; Labuda, Damian; Roy-Gagnon, Marie-Hélène

    2014-06-01

    In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6-7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship's variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec.

  18. Genome-wide association study of personality traits in bipolar patients

    PubMed Central

    Alliey-Rodriguez, Ney; Zhang, Dandan; Badner, Judith A.; Lahey, Benjamin B.; Zhang, Xiaotong; Dinwiddie, Stephen; Romanos, Benjamin; Plenys, Natalie; Liu, Chunyu; Gershon, Elliot S.

    2011-01-01

    Objective Genome-wide association study was carried out on personality traits among bipolar patients as possible endophenotypes for gene discovery in bipolar disorder. Methods The subscales of Cloninger’s Temperament and Character Inventory (TCI) and the Zuckerman–Kuhlman Personality Questionnaire (ZKPQ) were used as quantitative phenotypes. The genotyping platform was the Affymetrix 6.0 SNP array. The sample consisted of 944 individuals for TCI and 1007 for ZKPQ, all of European ancestry, diagnosed with bipolar disorder by Diagnostic and Statistical Manual of Mental Disorders-IV criteria. Results Genome-wide significant association was found for two subscales of the TCI, rs10479334 with the ‘Social Acceptance versus Social Intolerance’ subscale (Bonferroni P = 0.014) in an intergenic region, and rs9419788 with the ‘Spiritual Acceptance versus Rational Materialism’ subscale (Bonferroni P = 0.036) in PLCE1 gene. Although genome-wide significance was not reached for ZKPQ scales, lowest P values pinpointed to genes, RXRG for Sensation Seeking, GRM7 and ITK for Neuroticism Anxiety, and SPTLC3 gene for Aggression Hostility. Conclusion After correction for the 25 subscales in TCI and four scales plus two subscales in ZKPQ, phenotype-wide significance was not reached. PMID:21368711

  19. Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.

    PubMed

    Kutalik, Zoltán; Benyamin, Beben; Bergmann, Sven; Mooser, Vincent; Waeber, Gérard; Montgomery, Grant W; Martin, Nicholas G; Madden, Pamela A F; Heath, Andrew C; Beckmann, Jacques S; Vollenweider, Peter; Marques-Vidal, Pedro; Whitfield, John B

    2011-09-15

    Polysaccharide sidechains attached to proteins play important roles in cell-cell and receptor-ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 × 10(-9), 4 × 10(-39), 5.5 × 10(-43), respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure.

  20. Genome-wide signatures of male-mediated migration shaping the Indian gene pool.

    PubMed

    ArunKumar, GaneshPrasad; Tatarinova, Tatiana V; Duty, Jeff; Rollo, Debra; Syama, Adhikarla; Arun, Varatharajan Santhakumari; Kavitha, Valampuri John; Triska, Petr; Greenspan, Bennett; Wells, R Spencer; Pitchappan, Ramasamy

    2015-09-01

    Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India. PMID:25994871

  1. Replicability and robustness of genome-wide-association studies for behavioral traits.

    PubMed

    Rietveld, Cornelius A; Conley, Dalton; Eriksson, Nicholas; Esko, Tõnu; Medland, Sarah E; Vinkhuyzen, Anna A E; Yang, Jian; Boardman, Jason D; Chabris, Christopher F; Dawes, Christopher T; Domingue, Benjamin W; Hinds, David A; Johannesson, Magnus; Kiefer, Amy K; Laibson, David; Magnusson, Patrik K E; Mountain, Joanna L; Oskarsson, Sven; Rostapshova, Olga; Teumer, Alexander; Tung, Joyce Y; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-11-01

    A recent genome-wide-association study of educational attainment identified three single-nucleotide polymorphisms (SNPs) whose associations, despite their small effect sizes (each R (2) ≈ 0.02%), reached genome-wide significance (p < 5 × 10(-8)) in a large discovery sample and were replicated in an independent sample (p < .05). The study also reported associations between educational attainment and indices of SNPs called "polygenic scores." In three studies, we evaluated the robustness of these findings. Study 1 showed that the associations with all three SNPs were replicated in another large (N = 34,428) independent sample. We also found that the scores remained predictive (R (2) ≈ 2%) in regressions with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered genome-wide-association studies can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing factor explaining the striking contrast between our results and the disappointing replication record of most candidate-gene studies. PMID:25287667

  2. On the Analysis of a Repeated Measure Design in Genome-Wide Association Analysis

    PubMed Central

    Lee, Young; Park, Suyeon; Moon, Sanghoon; Lee, Juyoung; Elston, Robert C.; Lee, Woojoo; Won, Sungho

    2014-01-01

    Longitudinal data enables detecting the effect of aging/time, and as a repeated measures design is statistically more efficient compared to cross-sectional data if the correlations between repeated measurements are not large. In particular, when genotyping cost is more expensive than phenotyping cost, the collection of longitudinal data can be an efficient strategy for genetic association analysis. However, in spite of these advantages, genome-wide association studies (GWAS) with longitudinal data have rarely been analyzed taking this into account. In this report, we calculate the required sample size to achieve 80% power at the genome-wide significance level for both longitudinal and cross-sectional data, and compare their statistical efficiency. Furthermore, we analyzed the GWAS of eight phenotypes with three observations on each individual in the Korean Association Resource (KARE). A linear mixed model allowing for the correlations between observations for each individual was applied to analyze the longitudinal data, and linear regression was used to analyze the first observation on each individual as cross-sectional data. We found 12 novel genome-wide significant disease susceptibility loci that were then confirmed in the Health Examination cohort, as well as some significant interactions between age/sex and SNPs. PMID:25464127

  3. A genome-wide linkage and association scan reveals novel loci for autism.

    PubMed

    Weiss, Lauren A; Arking, Dan E; Daly, Mark J; Chakravarti, Aravinda

    2009-10-01

    Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

  4. Genome-wide evidence for speciation with gene flow in Heliconius butterflies.

    PubMed

    Martin, Simon H; Dasmahapatra, Kanchon K; Nadeau, Nicola J; Salazar, Camilo; Walters, James R; Simpson, Fraser; Blaxter, Mark; Manica, Andrea; Mallet, James; Jiggins, Chris D

    2013-11-01

    Most speciation events probably occur gradually, without complete and immediate reproductive isolation, but the full extent of gene flow between diverging species has rarely been characterized on a genome-wide scale. Documenting the extent and timing of admixture between diverging species can clarify the role of geographic isolation in speciation. Here we use new methodology to quantify admixture at different stages of divergence in Heliconius butterflies, based on whole-genome sequences of 31 individuals. Comparisons between sympatric and allopatric populations of H. melpomene, H. cydno, and H. timareta revealed a genome-wide trend of increased shared variation in sympatry, indicative of pervasive interspecific gene flow. Up to 40% of 100-kb genomic windows clustered by geography rather than by species, demonstrating that a very substantial fraction of the genome has been shared between sympatric species. Analyses of genetic variation shared over different time intervals suggested that admixture between these species has continued since early in speciation. Alleles shared between species during recent time intervals displayed higher levels of linkage disequilibrium than those shared over longer time intervals, suggesting that this admixture took place at multiple points during divergence and is probably ongoing. The signal of admixture was significantly reduced around loci controlling divergent wing patterns, as well as throughout the Z chromosome, consistent with strong selection for Müllerian mimicry and with known Z-linked hybrid incompatibility. Overall these results show that species divergence can occur in the face of persistent and genome-wide admixture over long periods of time.

  5. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

    PubMed Central

    Loukola, Anu; Buchwald, Jadwiga; Gupta, Richa; Palviainen, Teemu; Hällfors, Jenni; Tikkanen, Emmi; Korhonen, Tellervo; Ollikainen, Miina; Sarin, Antti-Pekka; Ripatti, Samuli; Lehtimäki, Terho; Raitakari, Olli; Salomaa, Veikko; Rose, Richard J.; Tyndale, Rachel F.; Kaprio, Jaakko

    2015-01-01

    Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence

  6. Population Stratification in the Context of Diverse Epidemiologic Surveys Sans Genome-Wide Data

    PubMed Central

    Oetjens, Matthew T.; Brown-Gentry, Kristin; Goodloe, Robert; Dilks, Holli H.; Crawford, Dana C.

    2016-01-01

    Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n = 14,998) were extracted from biospecimens from consented NHANES participants between 1991–1994 (NHANES III, phase 2) and 1999–2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We as the Epidemiologic Architecture for Genes Linked to Environment study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999–2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so

  7. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

    PubMed Central

    2014-01-01

    Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the

  8. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism.

    PubMed

    Loukola, Anu; Buchwald, Jadwiga; Gupta, Richa; Palviainen, Teemu; Hällfors, Jenni; Tikkanen, Emmi; Korhonen, Tellervo; Ollikainen, Miina; Sarin, Antti-Pekka; Ripatti, Samuli; Lehtimäki, Terho; Raitakari, Olli; Salomaa, Veikko; Rose, Richard J; Tyndale, Rachel F; Kaprio, Jaakko

    2015-01-01

    Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70-0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence

  9. Population Stratification in the Context of Diverse Epidemiologic Surveys Sans Genome-Wide Data.

    PubMed

    Oetjens, Matthew T; Brown-Gentry, Kristin; Goodloe, Robert; Dilks, Holli H; Crawford, Dana C

    2016-01-01

    Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n = 14,998) were extracted from biospecimens from consented NHANES participants between 1991-1994 (NHANES III, phase 2) and 1999-2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We as the Epidemiologic Architecture for Genes Linked to Environment study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999-2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so for

  10. The National Longitudinal Study of Adolescent to Adult Health (Add Health) Sibling Pairs Genome-Wide Data

    PubMed Central

    McQueen, Matthew B.; Boardman, Jason D.; Domingue, Benjamin W.; Smolen, Andrew; Tabor, Joyce; Killeya-Jones, Ley; Halpern, Carolyn T.; Whitsel, Eric A.; MullanHarris, Kathleen

    2014-01-01

    Here we provide a detailed description of the genome-wide information available on the National Longitudinal Study of Adolescent to Adult Health (Add Health) sibling pair subsample (Harris et al., 2012). A total of 2020 samples were genotyped (including duplicates) arising from 1946 Add Health individuals from the sibling pairs subsample. After various steps for quality control (QC) and quality assurance (QA), we have high quality genome-wide data available on 1,888 individuals. In this report, we first highlight theQC and QA steps that were taken to prune the data of poorly performing samples and genetic markers. We further estimate the pairwise biological relationships using genome-wide data and compare those estimates to the assumed relationships in Add Health. Additionally, using genome-wide data from knownregional reference populations from Europe, West Africa, North and South America, Japan and China, weestimate the relative genetic ancestry of the respondents. Finally, rather than conducting a traditional cross-sectional genome-wide association study (GWAS) of body mass index (BMI), we opted to utilize the extensivepublicly available genome-wide information to conduct a weighted genome-wide association study (GWAS) of longitudinal BMI while accounting for both family and ethnic variation. PMID:25378290

  11. Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries

    PubMed Central

    Baurley, James W.; Edlund, Christopher K.; Pardamean, Carissa I.; Conti, David V.; Krasnow, Ruth; Javitz, Harold S.; Hops, Hyman; Swan, Gary E.; Benowitz, Neal L.

    2016-01-01

    Introduction: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3′-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. Methods: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. Results: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5). Conclusions: This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan

  12. Genome-Wide Identification of Chromatin Transitional Regions Reveals Diverse Mechanisms Defining the Boundary of Facultative Heterochromatin

    PubMed Central

    Li, Guangyao; Zhou, Lei

    2013-01-01

    Due to the self-propagating nature of the heterochromatic modification H3K27me3, chromatin barrier activities are required to demarcate the boundary and prevent it from encroaching into euchromatic regions. Studies in Drosophila and vertebrate systems have revealed several important chromatin barrier elements and their respective binding factors. However, epigenomic data indicate that the binding of these factors are not exclusive to chromatin boundaries. To gain a comprehensive understanding of facultative heterochromatin boundaries, we developed a two-tiered method to identify the Chromatin Transitional Region (CTR), i.e. the nucleosomal region that shows the greatest transition rate of the H3K27me3 modification as revealed by ChIP-Seq. This approach was applied to identify CTRs in Drosophila S2 cells and human HeLa cells. Although many insulator proteins have been characterized in Drosophila, less than half of the CTRs in S2 cells are associated with known insulator proteins, indicating unknown mechanisms remain to be characterized. Our analysis also revealed that the peak binding of insulator proteins are usually 1–2 nucleosomes away from the CTR. Comparison of CTR-associated insulator protein binding sites vs. those in heterochromatic region revealed that boundary-associated binding sites are distinctively flanked by nucleosome destabilizing sequences, which correlates with significant decreased nucleosome density and increased binding intensities of co-factors. Interestingly, several subgroups of boundaries have enhanced H3.3 incorporation but reduced nucleosome turnover rate. Our genome-wide study reveals that diverse mechanisms are employed to define the boundaries of facultative heterochromatin. In both Drosophila and mammalian systems, only a small fraction of insulator protein binding sites co-localize with H3K27me3 boundaries. However, boundary-associated insulator binding sites are distinctively flanked by nucleosome destabilizing sequences, which

  13. Genome-Wide Localization Study of Yeast Pex11 Identifies Peroxisome–Mitochondria Interactions through the ERMES Complex

    PubMed Central

    Mattiazzi Ušaj, M.; Brložnik, M.; Kaferle, P.; Žitnik, M.; Wolinski, H.; Leitner, F.; Kohlwein, S.D.; Zupan, B.; Petrovič, U.

    2015-01-01

    Pex11 is a peroxin that regulates the number of peroxisomes in eukaryotic cells. Recently, it was found that a mutation in one of the three mammalian paralogs, PEX11β, results in a neurological disorder. The molecular function of Pex11, however, is not known. Saccharomyces cerevisiae Pex11 has been shown to recruit to peroxisomes the mitochondrial fission machinery, thus enabling proliferation of peroxisomes. This process is essential for efficient fatty acid β-oxidation. In this study, we used high-content microscopy on a genome-wide scale to determine the subcellular localization pattern of yeast Pex11 in all non-essential gene deletion mutants, as well as in temperature-sensitive essential gene mutants. Pex11 localization and morphology of peroxisomes was profoundly affected by mutations in 104 different genes that were functionally classified. A group of genes encompassing MDM10, MDM12 and MDM34 that encode the mitochondrial and cytosolic components of the ERMES complex was analyzed in greater detail. Deletion of these genes caused a specifically altered Pex11 localization pattern, whereas deletion of MMM1, the gene encoding the fourth, endoplasmic-reticulum-associated component of the complex, did not result in an altered Pex11 localization or peroxisome morphology phenotype. Moreover, we found that Pex11 and Mdm34 physically interact and that Pex11 plays a role in establishing the contact sites between peroxisomes and mitochondria through the ERMES complex. Based on these results, we propose that the mitochondrial/cytosolic components of the ERMES complex establish a direct interaction between mitochondria and peroxisomes through Pex11. PMID:25769804

  14. Genome-Wide Localization Study of Yeast Pex11 Identifies Peroxisome-Mitochondria Interactions through the ERMES Complex.

    PubMed

    Mattiazzi Ušaj, M; Brložnik, M; Kaferle, P; Žitnik, M; Wolinski, H; Leitner, F; Kohlwein, S D; Zupan, B; Petrovič, U

    2015-06-01

    Pex11 is a peroxin that regulates the number of peroxisomes in eukaryotic cells. Recently, it was found that a mutation in one of the three mammalian paralogs, PEX11β, results in a neurological disorder. The molecular function of Pex11, however, is not known. Saccharomyces cerevisiae Pex11 has been shown to recruit to peroxisomes the mitochondrial fission machinery, thus enabling proliferation of peroxisomes. This process is essential for efficient fatty acid β-oxidation. In this study, we used high-content microscopy on a genome-wide scale to determine the subcellular localization pattern of yeast Pex11 in all non-essential gene deletion mutants, as well as in temperature-sensitive essential gene mutants. Pex11 localization and morphology of peroxisomes was profoundly affected by mutations in 104 different genes that were functionally classified. A group of genes encompassing MDM10, MDM12 and MDM34 that encode the mitochondrial and cytosolic components of the ERMES complex was analyzed in greater detail. Deletion of these genes caused a specifically altered Pex11 localization pattern, whereas deletion of MMM1, the gene encoding the fourth, endoplasmic-reticulum-associated component of the complex, did not result in an altered Pex11 localization or peroxisome morphology phenotype. Moreover, we found that Pex11 and Mdm34 physically interact and that Pex11 plays a role in establishing the contact sites between peroxisomes and mitochondria through the ERMES complex. Based on these results, we propose that the mitochondrial/cytosolic components of the ERMES complex establish a direct interaction between mitochondria and peroxisomes through Pex11.

  15. Genome-wide sequencing to identify the cause of hereditary cancer syndromes: with examples from familial pancreatic cancer.

    PubMed

    Roberts, Nicholas J; Klein, Alison P

    2013-11-01

    Advances in our understanding of the human genome and next-generation technologies have facilitated the use of genome-wide sequencing to decipher the genetic basis of Mendelian disease and hereditary cancer syndromes. However, the application of genome-wide sequencing in hereditary cancer syndromes has had mixed success, in part, due to complex nature of the underlying genetic architecture. In this review we discuss the use of genome-wide sequencing in both Mendelian diseases and hereditary cancer syndromes, highlighting the potential and challenges of this approach using familial pancreatic cancer as an example. PMID:23196058

  16. Disruptive selection without genome-wide evolution across a migratory divide.

    PubMed

    von Rönn, Jan A C; Shafer, Aaron B A; Wolf, Jochen B W

    2016-06-01

    Transcontinental migration is a fascinating example of how animals can respond to climatic oscillation. Yet, quantitative data on fitness components are scarce, and the resulting population genetic consequences are poorly understood. Migratory divides, hybrid zones with a transition in migratory behaviour, provide a natural setting to investigate the micro-evolutionary dynamics induced by migration under sympatric conditions. Here, we studied the effects of migratory programme on survival, trait evolution and genome-wide patterns of population differentiation in a migratory divide of European barn swallows. We sampled a total of 824 individuals from both allopatric European populations wintering in central and southern Africa, respectively, along with two mixed populations from within the migratory divide. While most morphological characters varied by latitude consistent with Bergmann's rule, wing length co-varied with distance to wintering grounds. Survival data collected during a 5-year period provided strong evidence that this covariance is repeatedly generated by disruptive selection against intermediate phenotypes. Yet, selection-induced divergence did not translate into genome-wide genetic differentiation as assessed by microsatellites, mtDNA and >20 000 genome-wide SNP markers; nor did we find evidence of local genomic selection between migratory types. Among breeding populations, a single outlier locus mapped to the BUB1 gene with a role in mitotic and meiotic organization. Overall, this study provides evidence for an adaptive response to variation in migration behaviour continuously eroded by gene flow under current conditions of nonassortative mating. It supports the theoretical prediction that population differentiation is difficult to achieve under conditions of gene flow despite measurable disruptive selection. PMID:26749140

  17. Genome-wide association study of infectious bovine keratoconjunctivitis in Angus cattle

    PubMed Central

    2013-01-01

    Background Infectious Bovine Keratoconjunctivitis (IBK) in beef cattle, commonly known as pinkeye, is a bacterial disease caused by Moraxellabovis. IBK is characterized by excessive tearing and ulceration of the cornea. Perforation of the cornea may also occur in severe cases. IBK is considered the most important ocular disease in cattle production, due to the decreased growth performance of infected individuals and its subsequent economic effects. IBK is an economically important, lowly heritable categorical disease trait. Mass selection of unaffected animals has not been successful at reducing disease incidence. Genome-wide studies can determine chromosomal regions associated with IBK susceptibility. The objective of the study was to detect single-nucleotide polymorphism (SNP) markers in linkage disequilibrium (LD) with genetic variants associated with IBK in American Angus cattle. Results The proportion of phenotypic variance explained by markers was 0.06 in the whole genome analysis of IBK incidence classified as two, three or nine categories. Whole-genome analysis using any categorisation of (two, three or nine) IBK scores showed that locations on chromosomes 2, 12, 13 and 21 were associated with IBK disease. The genomic locations on chromosomes 13 and 21 overlap with QTLs associated with Bovine spongiform encephalopathy, clinical mastitis or somatic cell count. Conclusions Results of these genome-wide analyses indicated that if the underlying genetic factors confer not only IBK susceptibility but also IBK severity, treating IBK phenotypes as a two-categorical trait can cause information loss in the genome-wide analysis. These results help our overall understanding of the genetics of IBK and have the potential to provide information for future use in breeding schemes. PMID:23530766

  18. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

    PubMed Central

    Wolpin, Brian M.; Rizzato, Cosmeri; Kraft, Peter; Kooperberg, Charles; Petersen, Gloria M.; Wang, Zhaoming; Arslan, Alan A.; Beane-Freeman, Laura; Bracci, Paige M.; Buring, Julie; Canzian, Federico; Duell, Eric J.; Gallinger, Steven; Giles, Graham G.; Goodman, Gary E.; Goodman, Phyllis J.; Jacobs, Eric J.; Kamineni, Aruna; Klein, Alison P.; Kolonel, Laurence N.; Kulke, Matthew H.; Li, Donghui; Malats, Núria; Olson, Sara H.; Risch, Harvey A.; Sesso, Howard D.; Visvanathan, Kala; White, Emily; Zheng, Wei; Abnet, Christian C.; Albanes, Demetrius; Andreotti, Gabriella; Austin, Melissa A.; Barfield, Richard; Basso, Daniela; Berndt, Sonja I.; Boutron-Ruault, Marie-Christine; Brotzman, Michelle; Büchler, Markus W.; Bueno-de-Mesquita, H. Bas; Bugert, Peter; Burdette, Laurie; Campa, Daniele; Caporaso, Neil E.; Capurso, Gabriele; Chung, Charles; Cotterchio, Michelle; Costello, Eithne; Elena, Joanne; Funel, Niccola; Gaziano, J. Michael; Giese, Nathalia A.; Giovannucci, Edward L.; Goggins, Michael; Gorman, Megan J.; Gross, Myron; Haiman, Christopher A.; Hassan, Manal; Helzlsouer, Kathy J.; Henderson, Brian E.; Holly, Elizabeth A.; Hu, Nan; Hunter, David J.; Innocenti, Federico; Jenab, Mazda; Kaaks, Rudolf; Key, Timothy J.; Khaw, Kay-Tee; Klein, Eric A.; Kogevinas, Manolis; Krogh, Vittorio; Kupcinskas, Juozas; Kurtz, Robert C.; LaCroix, Andrea; Landi, Maria T.; Landi, Stefano; Le Marchand, Loic; Mambrini, Andrea; Mannisto, Satu; Milne, Roger L.; Nakamura, Yusuke; Oberg, Ann L.; Owzar, Kouros; Patel, Alpa V.; Peeters, Petra H. M.; Peters, Ulrike; Pezzilli, Raffaele; Piepoli, Ada; Porta, Miquel; Real, Francisco X.; Riboli, Elio; Rothman, Nathaniel; Scarpa, Aldo; Shu, Xiao-Ou; Silverman, Debra T.; Soucek, Pavel; Sund, Malin; Talar-Wojnarowska, Renata; Taylor, Philip R.; Theodoropoulos, George E.; Thornquist, Mark; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Vodicka, Pavel; Wactawski-Wende, Jean; Wentzensen, Nicolas; Wu, Chen; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Hartge, Patricia; Fuchs, Charles; Chanock, Stephen J.

    2014-01-01

    We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies. PMID:25086665

  19. Genome-wide transcriptional profiling reveals molecular signatures of secondary xylem differentiation in Populus tomentosa.

    PubMed

    Yang, X H; Li, X G; Li, B L; Zhang, D Q

    2014-11-11

    Wood formation occurs via cell division, primary cell wall and secondary wall formation, and programmed cell death in the vascular cambium. Transcriptional profiling of secondary xylem differentiation is essential for understanding the molecular mechanisms underlying wood formation. Differential gene expression in secondary xylem differentiation of Populus has been previously investigated using cDNA microarray analysis. However, little is known about the molecular mechanisms from a genome-wide perspective. In this study, the Affymetrix poplar genome chips containing 61,413 probes were used to investigate the changes in the transcriptome during secondary xylem differentiation in Chinese white poplar (Populus tomentosa). Two xylem tissues (newly formed and lignified) were sampled for genome-wide transcriptional profiling. In total, 6843 genes (~11%) were identified with differential expression in the two xylem tissues. Many genes involved in cell division, primary wall modification, and cellulose synthesis were preferentially expressed in the newly formed xylem. In contrast, many genes, including 4-coumarate:cinnamate-4-hydroxylase (C4H), 4-coumarate:CoA ligase (4CL), cinnamyl alcohol dehydrogenase (CAD), and caffeoyl CoA 3-O-methyltransferase (CCoAOMT), associated with lignin biosynthesis were more transcribed in the lignified xylem. The two xylem tissues also showed differential expression of genes related to various hormones; thus, the secondary xylem differentiation could be regulated by hormone signaling. Furthermore, many transcription factor genes were preferentially expressed in the lignified xylem, suggesting that wood lignification involves extensive transcription regulation. The genome-wide transcriptional profiling of secondary xylem differentiation could provide additional insights into the molecular basis of wood formation in poplar species.

  20. Genome-wide landscape of liver X receptor chromatin binding and gene regulation in human macrophages

    PubMed Central

    2012-01-01

    Background The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided. Results We performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions. Conclusions This first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis. The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319. PMID:22292898

  1. Genome-wide evidence for speciation with gene flow in Heliconius butterflies

    PubMed Central

    Martin, Simon H.; Dasmahapatra, Kanchon K.; Nadeau, Nicola J.; Salazar, Camilo; Walters, James R.; Simpson, Fraser; Blaxter, Mark; Manica, Andrea; Mallet, James; Jiggins, Chris D.

    2013-01-01

    Most speciation events probably occur gradually, without complete and immediate reproductive isolation, but the full extent of gene flow between diverging species has rarely been characterized on a genome-wide scale. Documenting the extent and timing of admixture between diverging species can clarify the role of geographic isolation in speciation. Here we use new methodology to quantify admixture at different stages of divergence in Heliconius butterflies, based on whole-genome sequences of 31 individuals. Comparisons between sympatric and allopatric populations of H. melpomene, H. cydno, and H. timareta revealed a genome-wide trend of increased shared variation in sympatry, indicative of pervasive interspecific gene flow. Up to 40% of 100-kb genomic windows clustered by geography rather than by species, demonstrating that a very substantial fraction of the genome has been shared between sympatric species. Analyses of genetic variation shared over different time intervals suggested that admixture between these species has continued since early in speciation. Alleles shared between species during recent time intervals displayed higher levels of linkage disequilibrium than those shared over longer time intervals, suggesting that this admixture took place at multiple points during divergence and is probably ongoing. The signal of admixture was significantly reduced around loci controlling divergent wing patterns, as well as throughout the Z chromosome, consistent with strong selection for Müllerian mimicry and with known Z-linked hybrid incompatibility. Overall these results show that species divergence can occur in the face of persistent and genome-wide admixture over long periods of time. PMID:24045163

  2. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

    PubMed Central

    Raffensperger, Zachary D.; Heike, Carrie L.; Cunningham, Michael L.; Hecht, Jacqueline T.; Kau, Chung How; Moreno, Lina M.; Wehby, George L.; Murray, Jeffrey C.; Laurie, Cecelia A.; Laurie, Cathy C.; Santorico, Stephanie; Klein, Ophir; Feingold, Eleanor; Hallgrimsson, Benedikt; Spritz, Richard A.; Marazita, Mary L.; Weinberg, Seth M.

    2016-01-01

    Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis. PMID:27560520

  3. FVGWAS: Fast Voxelwise Genome Wide Association Analysis of Large-scale Imaging Genetic Data 1

    PubMed Central

    Huang, Meiyan; Nichols, Thomas; Huang, Chao; Yang, Yu; Lu, Zhaohua; Feng, Qianjing; Knickmeyer, Rebecca C; Zhu, Hongtu

    2015-01-01

    More and more large-scale imaging genetic studies are being widely conducted to collect a rich set of imaging, genetic, and clinical data to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. Several major big-data challenges arise from testing genome-wide (NC > 12 million known variants) associations with signals at millions of locations (NV ~ 106) in the brain from thousands of subjects (n ~ 103). The aim of this paper is to develop a Fast Voxelwise Genome Wide Association analysiS (FVGWAS) framework to e ciently carry out whole-genome analyses of whole-brain data. FVGWAS consists of three components including a heteroscedastic linear model, a global sure independence screening (G-SIS) procedure, and a detection procedure based on wild bootstrap methods. Specifically, for standard linear association, the computational complexity is O(nNV NC) for voxelwise genome wide association analysis (VGWAS) method compared with O((NC + NV)n2) for FVGWAS. Simulation studies show that FVGWAS is an effcient method of searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. Finally, we have successfully applied FVGWAS to a large-scale imaging genetic data analysis of ADNI data with 708 subjects, 193,275 voxels in RAVENS maps, and 501,584 SNPs, and the total processing time was 203,645 seconds for a single CPU. Our FVG-WAS may be a valuable statistical toolbox for large-scale imaging genetic analysis as the field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing. PMID:26025292

  4. Genome-Wide Association Study in Immunocompetent Patients with Delayed Hypersensitivity to Sulfonamide Antimicrobials

    PubMed Central

    Motsinger-Reif, Alison; Dickey, Allison; Yale, Steven; Trepanier, Lauren A.

    2016-01-01

    Background Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. Objective The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Methods Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to “probable” drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. Results For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n = 16), and this may be a false positive finding. No other significant associations were found for the subgroups. Conclusions No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. PMID:27272151

  5. Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell

    PubMed Central

    Peng, Zhaofeng; Wang, Linlin; Du, Linqing; Niu, Wenbin; Sun, Yingpu

    2016-01-01

    Polycystic ovary syndrome (PCOS) affects approximately 7% of the reproductive-age women. A growing body of evidence indicated that epigenetic mechanisms contributed to the development of PCOS. The role of DNA modification in human PCOS ovary granulosa cell is still unknown in PCOS progression. Global DNA methylation and hydroxymethylation were detected between PCOS’ and controls’ granulosa cell. Genome-wide DNA methylation was profiled to investigate the putative function of DNA methylaiton. Selected genes expressions were analyzed between PCOS’ and controls’ granulosa cell. Our results showed that the granulosa cell global DNA methylation of PCOS patients was significant higher than the controls’. The global DNA hydroxymethylation showed low level and no statistical difference between PCOS and control. 6936 differentially methylated CpG sites were identified between control and PCOS-obesity. 12245 differential methylated CpG sites were detected between control and PCOS-nonobesity group. 5202 methylated CpG sites were significantly differential between PCOS-obesity and PCOS-nonobesity group. Our results showed that DNA methylation not hydroxymethylation altered genome-wide in PCOS granulosa cell. The different methylation genes were enriched in development protein, transcription factor activity, alternative splicing, sequence-specific DNA binding and embryonic morphogenesis. YWHAQ, NCF2, DHRS9 and SCNA were up-regulation in PCOS-obesity patients with no significance different between control and PCOS-nonobesity patients, which may be activated by lower DNA methylaiton. Global and genome-wide DNA methylation alteration may contribute to different genes expression and PCOS clinical pathology. PMID:27056885

  6. Genome-Wide Significant Association between Alcohol Dependence and a Variant in the ADH Gene Cluster

    PubMed Central

    Frank, Josef; Cichon, Sven; Treutlein, Jens; Ridinger, Monika; Mattheisen, Manuel; Hoffmann, Per; Herms, Stefan; Wodarz, Norbert; Soyka, Michael; Zill, Peter; Maier, Wolfgang; Mössner, Rainald; Gaebel, Wolfgang; Dahmen, Norbert; Scherbaum, Norbert; Schmäl, Christine; Steffens, Michael; Lucae, Susanne; Ising, Marcus; Müller-Myhsok, Bertram; Nöthen, Markus M; Mann, Karl; Kiefer, Falk; Rietschel, Marcella

    2011-01-01

    Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1,333 male in-patients with severe DSM-IV AD and 2,168 controls. These included 487 patients and 1,358 controls from a previous GWAS study by our group. All individuals were of German descent. Single marker tests and a polygenic score based analysis to assess the combined contribution of multiple markers with small effects were performed. The SNP rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance (p=1.27E–8; OR=1.46). Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (p=1.24E–7, OR=1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score based approach produced a significant result (p=9.66E–9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result suggests that many more AD susceptibility genes still await identification. PMID:22004471

  7. Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations

    PubMed Central

    Bendall, Matthew L; Stevens, Sarah LR; Chan, Leong-Keat; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Froula, Jeff; Kang, Dongwan; Tringe, Susannah G; Bertilsson, Stefan; Moran, Mary A; Shade, Ashley; Newton, Ryan J; McMahon, Katherine D; Malmstrom, Rex R

    2016-01-01

    Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005–2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the ‘ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment. PMID:26744812

  8. Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder.

    PubMed

    Brevik, Erlend J; van Donkelaar, Marjolein M J; Weber, Heike; Sánchez-Mora, Cristina; Jacob, Christian; Rivero, Olga; Kittel-Schneider, Sarah; Garcia-Martínez, Iris; Aebi, Marcel; van Hulzen, Kimm; Cormand, Bru; Ramos-Quiroga, Josep A; Lesch, Klaus-Peter; Reif, Andreas; Ribasés, Marta; Franke, Barbara; Posserud, Maj-Britt; Johansson, Stefan; Lundervold, Astri J; Haavik, Jan; Zayats, Tetyana

    2016-07-01

    Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

  9. Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network.

    PubMed

    Chen, Zhao; Tang, Hua; Qayyum, Rehan; Schick, Ursula M; Nalls, Michael A; Handsaker, Robert; Li, Jin; Lu, Yingchang; Yanek, Lisa R; Keating, Brendan; Meng, Yan; van Rooij, Frank J A; Okada, Yukinori; Kubo, Michiaki; Rasmussen-Torvik, Laura; Keller, Margaux F; Lange, Leslie; Evans, Michele; Bottinger, Erwin P; Linderman, Michael D; Ruderfer, Douglas M; Hakonarson, Hakon; Papanicolaou, George; Zonderman, Alan B; Gottesman, Omri; Thomson, Cynthia; Ziv, Elad; Singleton, Andrew B; Loos, Ruth J F; Sleiman, Patrick M A; Ganesh, Santhi; McCarroll, Steven; Becker, Diane M; Wilson, James G; Lettre, Guillaume; Reiner, Alexander P

    2013-06-15

    Laboratory red blood cell (RBC) measurements are clinically important, heritable and differ among ethnic groups. To identify genetic variants that contribute to RBC phenotypes in African Americans (AAs), we conducted a genome-wide association study in up to ~16 500 AAs. The alpha-globin locus on chromosome 16pter [lead SNP rs13335629 in ITFG3 gene; P < 1E-13 for hemoglobin (Hgb), RBC count, mean corpuscular volume (MCV), MCH and MCHC] and the G6PD locus on Xq28 [lead SNP rs1050828; P < 1E - 13 for Hgb, hematocrit (Hct), MCV, RBC count and red cell distribution width (RDW)] were each associated with multiple RBC traits. At the alpha-globin region, both the common African 3.7 kb deletion and common single nucleotide polymorphisms (SNPs) appear to contribute independently to RBC phenotypes among AAs. In the 2p21 region, we identified a novel variant of PRKCE distinctly associated with Hct in AAs. In a genome-wide admixture mapping scan, local European ancestry at the 6p22 region containing HFE and LRRC16A was associated with higher Hgb. LRRC16A has been previously associated with the platelet count and mean platelet volume in AAs, but not with Hgb. Finally, we extended to AAs the findings of association of erythrocyte traits with several loci previously reported in Europeans and/or Asians, including CD164 and HBS1L-MYB. In summary, this large-scale genome-wide analysis in AAs has extended the importance of several RBC-associated genetic loci to AAs and identified allelic heterogeneity and pleiotropy at several previously known genetic loci associated with blood cell traits in AAs.

  10. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

    PubMed

    Shaffer, John R; Orlova, Ekaterina; Lee, Myoung Keun; Leslie, Elizabeth J; Raffensperger, Zachary D; Heike, Carrie L; Cunningham, Michael L; Hecht, Jacqueline T; Kau, Chung How; Nidey, Nichole L; Moreno, Lina M; Wehby, George L; Murray, Jeffrey C; Laurie, Cecelia A; Laurie, Cathy C; Cole, Joanne; Ferrara, Tracey; Santorico, Stephanie; Klein, Ophir; Mio, Washington; Feingold, Eleanor; Hallgrimsson, Benedikt; Spritz, Richard A; Marazita, Mary L; Weinberg, Seth M

    2016-08-01

    Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10-8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

  11. Genome-wide single nucleotide polymorphisms reveal population history and adaptive divergence in wild guppies.

    PubMed

    Willing, Eva-Maria; Bentzen, Paul; van Oosterhout, Cock; Hoffmann, Margarete; Cable, Joanne; Breden, Felix; Weigel, Detlef; Dreyer, Christine

    2010-03-01

    Adaptation of guppies (Poecilia reticulata) to contrasting upland and lowland habitats has been extensively studied with respect to behaviour, morphology and life history traits. Yet population history has not been studied at the whole-genome level. Although single nucleotide polymorphisms (SNPs) are the most abundant form of variation in many genomes and consequently very informative for a genome-wide picture of standing natural variation in populations, genome-wide SNP data are rarely available for wild vertebrates. Here we use genetically mapped SNP markers to comprehensively survey genetic variation within and among naturally occurring guppy populations from a wide geographic range in Trinidad and Venezuela. Results from three different clustering methods, Neighbor-net, principal component analysis (PCA) and Bayesian analysis show that the population substructure agrees with geographic separation and largely with previously hypothesized patterns of historical colonization. Within major drainages (Caroni, Oropouche and Northern), populations are genetically similar, but those in different geographic regions are highly divergent from one another, with some indications of ancient shared polymorphisms. Clear genomic signatures of a previous introduction experiment were seen, and we detected additional potential admixture events. Headwater populations were significantly less heterozygous than downstream populations. Pairwise F(ST) values revealed marked differences in allele frequencies among populations from different regions, and also among populations within the same region. F(ST) outlier methods indicated some regions of the genome as being under directional selection. Overall, this study demonstrates the power of a genome-wide SNP data set to inform for studies on natural variation, adaptation and evolution of wild populations.

  12. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

    PubMed

    Shaffer, John R; Orlova, Ekaterina; Lee, Myoung Keun; Leslie, Elizabeth J; Raffensperger, Zachary D; Heike, Carrie L; Cunningham, Michael L; Hecht, Jacqueline T; Kau, Chung How; Nidey, Nichole L; Moreno, Lina M; Wehby, George L; Murray, Jeffrey C; Laurie, Cecelia A; Laurie, Cathy C; Cole, Joanne; Ferrara, Tracey; Santorico, Stephanie; Klein, Ophir; Mio, Washington; Feingold, Eleanor; Hallgrimsson, Benedikt; Spritz, Richard A; Marazita, Mary L; Weinberg, Seth M

    2016-08-01

    Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10-8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis. PMID:27560520

  13. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2013-01-01

    Objective . Genes likely play a substantial role in the etiology of attention-deficit hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies have not identified a genome-wide significant association. We have conducted a third, independent multi-site GWAS of DSM-IV-TR ADHD. Method . Families were ascertained at Massachusetts General Hospital (MGH, N=309 trios), Washington University at St Louis (WASH-U, N=272 trios), and University of California at Los Angeles (UCLA, N=156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results . Our smallest p-value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08) but one of the 20 most significant associations was located in a candidate gene of interest for ADHD, (SLC9A9, rs9810857, p=6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusion . We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. PMID:20732626

  14. Meta-analysis of genome-wide association studies of anxiety disorders

    PubMed Central

    Otowa, Takeshi; Hek, Karin; Lee, Minyoung; Byrne, Enda M.; Mirza, Saira S.; Nivard, Michel G.; Bigdeli, Timothy; Aggen, Steven H.; Adkins, Daniel; Wolen, Aaron; Fanous, Ayman; Keller, Matthew C.; Castelao, Enrique; Kutalik, Zoltan; Van der Auwera, Sandra; Homuth, Georg; Nauck, Matthias; Teumer, Alexander; Milaneschi, Yuri; Hottenga, Jouke-Jan; Direk, Nese; Hofman, Albert; Uitterlinden, Andre; Mulder, Cornelis L.; Henders, Anjali K.; Medland, Sarah E.; Gordon, Scott; Heath, Andrew C.; Madden, Pamela A.F.; Pergadia, Michelle; van der Most, Peter J.; Nolte, Ilja M.; van Oort, Floor V.A.; Hartman, Catharina A.; Oldehinkel, Albertine J.; Preisig, Martin; Grabe, Hans Jörgen; Middeldorp, Christel M.; Penninx, Brenda WJH; Boomsma, Dorret; Martin, Nicholas G.; Montgomery, Grant; Maher, Brion S.; van den Oord, Edwin J.; Wray, Naomi R.; Tiemeier, Henning; Hettema, John M.

    2015-01-01

    Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders. PMID:26754954

  15. Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder.

    PubMed

    Brevik, Erlend J; van Donkelaar, Marjolein M J; Weber, Heike; Sánchez-Mora, Cristina; Jacob, Christian; Rivero, Olga; Kittel-Schneider, Sarah; Garcia-Martínez, Iris; Aebi, Marcel; van Hulzen, Kimm; Cormand, Bru; Ramos-Quiroga, Josep A; Lesch, Klaus-Peter; Reif, Andreas; Ribasés, Marta; Franke, Barbara; Posserud, Maj-Britt; Johansson, Stefan; Lundervold, Astri J; Haavik, Jan; Zayats, Tetyana

    2016-07-01

    Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P < 5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27021288

  16. Siblings with Ischemic Stroke Study (SWISS): Results of a Genome-wide Scan for Stroke Loci

    PubMed Central

    Meschia, James F.; Nalls, Michael; Matarin, Mar; Brott, Thomas G.; Brown, Robert D.; Hardy, John; Kissela, Brett; Rich, Stephen S.; Singleton, Andrew; Hernandez, Dena; Ferrucci, Luigi; Pearce, Kerra; Keller, Margaret; Worrall, Bradford B.

    2011-01-01

    Background and Purpose Ischemic stroke has a strong familial component to risk. The Siblings with Ischemic Stroke Study (SWISS) is a genome-wide family-based analysis that included use of imputed genotypes. SWISS was conducted to examine associations between SNPs and risk of stroke and stroke subtypes within pairs. Methods SWISS enrolled 312 probands with ischemic stroke across 70 US and Canadian centers. Affected siblings were ascertained by centers and confirmed by central record review; unaffected siblings were ascertained by telephone contact. Ischemic stroke was subtyped using TOAST criteria. Genotyping was performed using an Illumina 610 quad array (probands) and an Illumina linkage V array (affected siblings). SNPs were imputed using 1000 Genomes Project data and MACH software. Family-based association analyses were conducted using the sibling-transmission disequilibrium test. Results For all pairs, the correlation of age at stroke within pairs of affected siblings was r = 0.83 (95%CI, 0.78 to 0.86; P < 2.2×10−16). The correlation did not differ substantially by subtype. The concordance of stroke subtypes among affected pairs was 33.8% (kappa = 0.13; P = 5.06×10−4) and did not differ by age at stroke in the proband. Although no SNP achieved genome-wide significance for risk of ischemic stroke, there was clustering of the most associated SNPs on chromosomes 3p (NOS1) and 6p. Conclusions Stroke subtype and age at stroke in affected sibling pairs exhibit significant clustering. No individual SNP reached genome-wide significance. However, two promising candidate loci were identified, including one that contains NOS1, though these risk loci warrant further examination in larger sample collections. PMID:21940970

  17. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

    PubMed

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang; Wilson, Robert S; De Jager, Philip L; Yu, Lei; Singleton, Andrew B; Harris, Tamara; Mosley, Thomas H; Pinto, Jayant M; Bennett, David A; Chen, Honglei

    2015-11-01

    Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases. PMID:26632684

  18. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster.

    PubMed

    Frank, Josef; Cichon, Sven; Treutlein, Jens; Ridinger, Monika; Mattheisen, Manuel; Hoffmann, Per; Herms, Stefan; Wodarz, Norbert; Soyka, Michael; Zill, Peter; Maier, Wolfgang; Mössner, Rainald; Gaebel, Wolfgang; Dahmen, Norbert; Scherbaum, Norbert; Schmäl, Christine; Steffens, Michael; Lucae, Susanne; Ising, Marcus; Müller-Myhsok, Bertram; Nöthen, Markus M; Mann, Karl; Kiefer, Falk; Rietschel, Marcella

    2012-01-01

    Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.

  19. Genome-Wide Expression Profiles Identify Potential Targets for Gene by Environment Interactions in Asthma Severity

    PubMed Central

    Sordillo, Joanne E; Kelly, Roxanne; Bunyavanich, Supinda; McGeachie, Michael; Qiu, Weiliang; Croteau-Chonka, Damien C.; Soto-Quiros, Manuel; Avila, Lydiana; Celedón, Juan C.; Brehm, John M.; Weiss, Scott T; Gold, Diane R; Litonjua, Augusto A

    2015-01-01

    Background Gene by environment interaction (G × E) studies utilizing GWAS data are often underpowered after adjustment for multiple comparisons. Differential gene expression, in response to the exposure of interest, may capture the most biologically relevant genes at the genome-wide level. Methods We used differential genome-wide expression profiles from the Home Allergens and Asthma Birth cohort in response to Der f 1 allergen (sensitized vs. non-sensitized) to inform a G × E study of dust mite exposure and asthma severity. Polymorphisms in differentially expressed genes were identified in GWAS data from CAMP, a clinical trial in childhood asthmatics. Home dust mite allergen (< or ≥ 10µg/g dust) was assessed at baseline, and (≥ 1) severe asthma exacerbation (emergency room (ER) visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica (GACRS) study, and a Puerto Rico/Connecticut asthma cohortwere used for replication. Results IL-9, IL-5 and PRG2 expression was up-regulated in Der f 1 stimulated PBMCs from dust mite sensitized individuals (adj. p value <0.04). IL-9 polymorphisms (rs11741137, rs2069885, rs1859430) showed evidence for interaction with dust mite in CAMP (p=0.02 to 0.03), with replication in GACRS (p=0.04). Subjects with the dominant genotype for these IL-9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to elevated dust mite. Conclusions Genome-wide differential gene expression in response to dust mite allergen identified IL-9, a biologically plausible gene target that may interact with environmental dust mite to increase severe asthma exacerbations in children. PMID:25913104

  20. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

    PubMed Central

    Jahanshad, Neda; Rajagopalan, Priya; Hua, Xue; Hibar, Derrek P.; Nir, Talia M.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew J.; Green, Robert C.; Weiner, Michael W.; Medland, Sarah E.; Montgomery, Grant W.; Hansell, Narelle K.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Thompson, Paul M.; Weiner, Michael; Aisen, Paul; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowski, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Liu, Enchi; Green, Robert C.; Montine, Tom; Petersen, Ronald; Aisen, Paul; Gamst, Anthony; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Beckett, Laurel; Harvey, Danielle; Gamst, Anthony; Donohue, Michael; Kornak, John; Jack, Clifford R.; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Jagust, William; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Morris, John; Cairns, Nigel J.; Taylor-Reinwald, Lisa; Trojanowki, J.Q.; Shaw, Les; Lee, Virginia M.Y.; Korecka, Magdalena; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Saykin, Andrew J.; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Khachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Petersen, Ronald; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Coleman, R. Edward; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Lu, Po H.; Bartzokis, George; Silverman, Daniel H.S.; Graff-Radford, Neill R.; Parfitt, Francine; Johnson, Heather; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Herring, Scott; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging-Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O.; Wolday, Saba; Bwayo, Salome K.; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabeth; Rachinsky, Irina; Rogers, John; Kertesz, Andrew; Drost, Dick

    2013-01-01

    Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases. PMID:23471985

  1. Genome-wide patterns of promoter sharing and co-expression in bovine skeletal muscle

    PubMed Central

    2011-01-01

    Background Gene regulation by transcription factors (TF) is species, tissue and time specific. To better understand how the genetic code controls gene expression in bovine muscle we associated gene expression data from developing Longissimus thoracis et lumborum skeletal muscle with bovine promoter sequence information. Results We created a highly conserved genome-wide promoter landscape comprising 87,408 interactions relating 333 TFs with their 9,242 predicted target genes (TGs). We discovered that the complete set of predicted TGs share an average of 2.75 predicted TF binding sites (TFBSs) and that the average co-expression between a TF and its predicted TGs is higher than the average co-expression between the same TF and all genes. Conversely, pairs of TFs sharing predicted TGs showed a co-expression correlation higher that pairs of TFs not sharing TGs. Finally, we exploited the co-occurrence of predicted TFBS in the context of muscle-derived functionally-coherent modules including cell cycle, mitochondria, immune system, fat metabolism, muscle/glycolysis, and ribosome. Our findings enabled us to reverse engineer a regulatory network of core processes, and correctly identified the involvement of E2F1, GATA2 and NFKB1 in the regulation of cell cycle, fat, and muscle/glycolysis, respectively. Conclusion The pivotal implication of our research is two-fold: (1) there exists a robust genome-wide expression signal between TFs and their predicted TGs in cattle muscle consistent with the extent of promoter sharing; and (2) this signal can be exploited to recover the cellular mechanisms underpinning transcription regulation of muscle structure and development in bovine. Our study represents the first genome-wide report linking tissue specific co-expression to co-regulation in a non-model vertebrate. PMID:21226902

  2. Genome-wide analysis of zygotic linkage disequilibrium and its components in crossbred cattle

    PubMed Central

    2012-01-01

    Background Linkage disequilibrium (LD) between genes at linked or independent loci can occur at gametic and zygotic levels known asgametic LD and zygotic LD, respectively. Gametic LD is well known for its roles in fine-scale mapping of quantitative trait loci, genomic selection and evolutionary inference. The less-well studied is the zygotic LD and its components that can be also estimated directly from the unphased SNPs. Results This study was set up to investigate the genome-wide extent and patterns of zygotic LD and its components in a crossbred cattle population using the genomic data from the Illumina BovineSNP50 beadchip. The animal population arose from repeated crossbreeding of multiple breeds and selection for growth and cow reproduction. The study showed that similar genomic structures in gametic and zygotic LD were observed, with zygotic LD decaying faster than gametic LD over marker distance. The trigenic and quadrigenic disequilibria were generally two- to three-fold smaller than the usual digenic disequilibria (gametic or composite LD). There was less power of testing for these high-order genic disequilibria than for the digenic disequilibria. The power estimates decreased with the marker distance between markers though the decay trend is more obvious for the digenic disequilibria than for high-order disequilibria. Conclusions This study is the first major genome-wide survey of all non-allelic associations between pairs of SNPs in a cattle population. Such analysis allows us to assess the relative importance of gametic LD vs. all other non-allelic genic LDs regardless of whether or not the population is in HWE. The observed predominance of digenic LD (gametic or composite LD) coupled with insignificant high-order trigenic and quadrigenic disequilibria supports the current intensive focus on the use of high-density SNP markers for genome-wide association studies and genomic selection activities in the cattle population. PMID:22827586

  3. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

    PubMed

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang; Wilson, Robert S; De Jager, Philip L; Yu, Lei; Singleton, Andrew B; Harris, Tamara; Mosley, Thomas H; Pinto, Jayant M; Bennett, David A; Chen, Honglei

    2015-11-01

    Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta < 1 × 10). Of these, 2 SNPs at chromosome 17q21.31 (rs199443 in NSF, P = 3.02 × 10; and rs2732614 in KIAA1267-LRRC37A, P = 6.65 × 10) exhibited cis effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P < 1 × 10). Gene-based and pathway-enrichment analyses further implicated MAPT in regulating the sense of smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.

  4. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity.

    PubMed

    Jahanshad, Neda; Rajagopalan, Priya; Hua, Xue; Hibar, Derrek P; Nir, Talia M; Toga, Arthur W; Jack, Clifford R; Saykin, Andrew J; Green, Robert C; Weiner, Michael W; Medland, Sarah E; Montgomery, Grant W; Hansell, Narelle K; McMahon, Katie L; de Zubicaray, Greig I; Martin, Nicholas G; Wright, Margaret J; Thompson, Paul M

    2013-03-19

    Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

  5. Genome-Wide Analysis of DNA Methylation and Cigarette Smoking in a Chinese Population

    PubMed Central

    Zhu, Xiaoyan; Li, Jun; Deng, Siyun; Yu, Kuai; Liu, Xuezhen; Deng, Qifei; Sun, Huizhen; Zhang, Xiaomin; He, Meian; Guo, Huan; Chen, Weihong; Yuan, Jing; Zhang, Bing; Kuang, Dan; He, Xiaosheng; Bai, Yansen; Han, Xu; Liu, Bing; Li, Xiaoliang; Yang, Liangle; Jiang, Haijing; Zhang, Yizhi; Hu, Jie; Cheng, Longxian; Luo, Xiaoting; Mei, Wenhua; Zhou, Zhiming; Sun, Shunchang; Zhang, Liyun; Liu, Chuanyao; Guo, Yanjun; Zhang, Zhihong; Hu, Frank B.; Liang, Liming; Wu, Tangchun

    2016-01-01

    Background: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. Objectives: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. Methods: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. Results: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. Conclusion: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. Citation: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ

  6. Genome-wide analysis of methylation in bovine clones by methylated DNA immunoprecipitation (MeDIP).

    PubMed

    Kiefer, Hélène

    2015-01-01

    Methylated DNA immunoprecipitation (MeDIP), when coupled to high-throughput sequencing or microarray hybridization, allows for the identification of methylated loci at a genome-wide scale. Genomic regions affected by incomplete reprogramming after nuclear transfer can potentially be delineated by comparing the MeDIP profiles of bovine clones and non-clones. This chapter presents a MeDIP protocol largely inspired from Mohn and colleagues (Mohn et al., Methods Mol Biol 507:55-64, 2009), with PCR primers specific for cattle, and when possible, overviews of experimental designs adapted to the comparison between clones and non-clones.

  7. Genome-wide measurement of histone H3 replacement dynamics in yeast.

    PubMed

    Rando, Oliver J

    2011-01-01

    Chromatin plays critical roles in processes governed in different timescales - responses to environmental changes require rapid plasticity, while long-term stability through multiple cell generations requires epigenetically heritable chromatin. Understanding the dynamic behavior of chromatin is of great interest for fields ranging from transcriptional regulation through meiosis and gametogenesis. Here, we describe a protocol for measuring histone replacement rates genome wide in the budding yeast Saccharomyces cerevisiae. With suitable modifications, this protocol could be applied to other organisms, or to replacement dynamics of other DNA-associated proteins.

  8. Genome-wide association scans for Type 2 diabetes: new insights into biology and therapy.

    PubMed

    McCarthy, Mark I; Zeggini, Eleftheria

    2007-12-01

    Type 2 diabetes is a complex, multifactorial disease, for which genetic and environmental factors jointly determine susceptibility. Disentangling the genetic aetiology of Type 2 diabetes has proven a challenging task, rewarded, until recently, with only limited success. However, the field of Type 2 diabetes genetics has been transformed over the past few months, with the publication of six genome-wide association scans, leading to the establishment of novel genomic regions that harbour disease susceptibility loci. Here, we provide an overview of the main recent findings and discuss their significance in providing biological insights and their translational implications.

  9. Reverse Engineering of Genome-wide Gene Regulatory Networks from Gene Expression Data.

    PubMed

    Liu, Zhi-Ping

    2015-02-01

    Transcriptional regulation plays vital roles in many fundamental biological processes. Reverse engineering of genome-wide regulatory networks from high-throughput transcriptomic data provides a promising way to characterize the global scenario of regulatory relationships between regulators and their targets. In this review, we summarize and categorize the main frameworks and methods currently available for inferring transcriptional regulatory networks from microarray gene expression profiling data. We overview each of strategies and introduce representative methods respectively. Their assumptions, advantages, shortcomings, and possible improvements and extensions are also clarified and commented.

  10. Insights into RNA structure and function from genome-wide studies.

    PubMed

    Mortimer, Stefanie A; Kidwell, Mary Anne; Doudna, Jennifer A

    2014-07-01

    A comprehensive understanding of RNA structure will provide fundamental insights into the cellular function of both coding and non-coding RNAs. Although many RNA structures have been analysed by traditional biophysical and biochemical methods, the low-throughput nature of these approaches has prevented investigation of the vast majority of cellular transcripts. Triggered by advances in sequencing technology, genome-wide approaches for probing the transcriptome are beginning to reveal how RNA structure affects each step of protein expression and RNA stability. In this Review, we discuss the emerging relationships between RNA structure and the regulation of gene expression. PMID:24821474

  11. Genome-wide analysis and identification of genes related to expansin gene family in indica rice.

    PubMed

    Hemalatha, N; Rajesh, M K; Narayanan, N K

    2011-01-01

    In this study, we carried out genome-wide analyses to explore expansin gene family in the genome of indica rice. Reference nucleotides were chosen as query sequences for searches in the indica rice genome database. Clones having genomic sequences similar to expansin were taken and converted to amino acid sequences. Putative sequences were subjected to PROSITE and Pfam databases, and 21 signature-sequences-related expansin gene family was obtained. The presence of transmembrane domains was also predicted for all 21 expansin proteins. A phylogenetic tree was generated from the alignments of the proteins sequences to examine the phylogenetic relationship of indica rice expansin proteins.

  12. Inferring Where and When Replication Initiates from Genome-Wide Replication Timing Data

    NASA Astrophysics Data System (ADS)

    Baker, A.; Audit, B.; Yang, S. C.-H.; Bechhoefer, J.; Arneodo, A.

    2012-06-01

    Based on an analogy between DNA replication and one dimensional nucleation-and-growth processes, various attempts to infer the local initiation rate I(x,t) of DNA replication origins from replication timing data have been developed in the framework of phase transition kinetics theories. These works have all used curve-fit strategies to estimate I(x,t) from genome-wide replication timing data. Here, we show how to invert analytically the Kolmogorov-Johnson-Mehl-Avrami model and extract I(x,t) directly. Tests on both simulated and experimental budding-yeast data confirm the location and firing-time distribution of replication origins.

  13. Genome-Wide Chromatin Immunoprecipitation in Candida albicans and Other Yeasts

    PubMed Central

    Lohse, Matthew B.; Kongsomboonvech, Pisiwat; Madrigal, Maria; Hernday, Aaron D.; Nobile, Clarissa J.

    2016-01-01

    Chromatin immunoprecipitation experiments are critical to investigating the interactions between DNA and a wide range of nuclear proteins within a cell or biological sample. In this chapter we outline an optimized protocol for genome-wide chromatin immunoprecipitation that has been used successfully for several distinct morphological forms of numerous yeast species, and include an optimized method for amplification of chromatin immunoprecipitated DNA samples and hybridization to a high-density oligonucleotide tiling microarray. We also provide detailed suggestions on how to analyze the complex data obtained from these experiments. PMID:26483022

  14. Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Kim, Deog Kyeom; Cho, Michael H.; Hersh, Craig P.; Lomas, David A.; Miller, Bruce E.; Kong, Xiangyang; Bakke, Per; Gulsvik, Amund; Agustí, Alvar; Wouters, Emiel; Celli, Bartolome; Coxson, Harvey; Vestbo, Jørgen; MacNee, William; Yates, Julie C.; Rennard, Stephen; Litonjua, Augusto; Qiu, Weiliang; Beaty, Terri H.; Crapo, James D.; Riley, John H.; Tal-Singer, Ruth

    2012-01-01

    Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD. Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated. Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts. Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552). PMID

  15. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

    PubMed Central

    Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue; Kosoy, Roman; Lu, Yan; Bianchi, Ilaria; Podda, Mauro; Xu, Chun; Xie, Gang; Macciardi, Fabio; Selmi, Carlo; Lupoli, Sara; Shigeta, Russell; Ransom, Michael; Lleo, Ana; Lee, Annette T; Mason, Andrew L; Myers, Robert P; Peltekian, Kevork M; Ghent, Cameron N; Bernuzzi, Francesca; Zuin, Massimo; Rosina, Floriano; Borghesio, Elisabetta; Floreani, Annarosa; Lazzari, Roberta; Niro, Grazia; Andriulli, Angelo; Muratori, Luigi; Muratori, Paolo; Almasio, Piero L; Andreone, Pietro; Margotti, Marzia; Brunetto, Maurizia; Coco, Barbara; Alvaro, Domenico; Bragazzi, Maria C; Marra, Fabio; Pisano, Alessandro; Rigamonti, Cristina; Colombo, Massimo; Marzioni, Marco; Benedetti, Antonio; Fabris, Luca; Strazzabosco, Mario; Portincasa, Piero; Palmieri, Vincenzo O; Tiribelli, Claudio; Croce, Lory; Bruno, Savino; Rossi, Sonia; Vinci, Maria; Prisco, Cleofe; Mattalia, Alberto; Toniutto, Pierluigi; Picciotto, Antonio; Galli, Andrea; Ferrari, Carlo; Colombo, Silvia; Casella, Giovanni; Morini, Lorenzo; Caporaso, Nicola; Colli, Agostino; Spinzi, Giancarlo; Montanari, Renzo; Gregersen, Peter K; Heathcote, E Jenny; Hirschfield, Gideon M; Siminovitch, Katherine A; Amos, Christopher I; Gershwin, M Eric; Seldin, Michael F

    2011-01-01

    A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38). PMID:20639880

  16. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

    PubMed Central

    Melum, Espen; Franke, Andre; Schramm, Christoph; Weismüller, Tobias J; Gotthardt, Daniel Nils; Offner, Felix A; Juran, Brian D; Laerdahl, Jon K; Labi, Verena; Björnsson, Einar; Weersma, Rinse K; Henckaerts, Liesbet; Teufel, Andreas; Rust, Christian; Ellinghaus, Eva; Balschun, Tobias; Boberg, Kirsten Muri; Ellinghaus, David; Bergquist, Annika; Sauer, Peter; Ryu, Euijung; Hov, Johannes Roksund; Wedemeyer, Jochen; Lindkvist, Björn; Wittig, Michael; Porte, Robert J; Holm, Kristian; Gieger, Christian; Wichmann, H-Erich; Stokkers, Pieter; Ponsioen, Cyriel Y; Runz, Heiko; Stiehl, Adolf; Wijmenga, Cisca; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Villunger, Andreas; Schrumpf, Erik; Lazaridis, Konstantinos N; Manns, Michael P; Schreiber, Stefan; Karlsen, Tom H

    2015-01-01

    Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). PMID:21151127

  17. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

    PubMed

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A; Barnes, Michael R; Li, Xiaohui; Warren, Helen R; Chasman, Daniel I; Zhou, Kaixin; Arsenault, Benoit J; Donnelly, Louise A; Wiggins, Kerri L; Avery, Christy L; Griffin, Paula; Feng, QiPing; Taylor, Kent D; Li, Guo; Evans, Daniel S; Smith, Albert V; de Keyser, Catherine E; Johnson, Andrew D; de Craen, Anton J M; Stott, David J; Buckley, Brendan M; Ford, Ian; Westendorp, Rudi G J; Slagboom, P Eline; Sattar, Naveed; Munroe, Patricia B; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y-D Ida; Nickerson, Deborah A; Smith, Joshua D; Dubé, Marie Pierre; Boekholdt, S Matthijs; Hovingh, G Kees; Kastelein, John J P; McKeigue, Paul M; Betteridge, John; Neil, Andrew; Durrington, Paul N; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C; Rice, Kenneth; Smith, Nicholas L; Lumley, Thomas; Whitsel, Eric A; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S; O'Donnell, Christopher J; Vasan, Ramachandran S; Wei, Wei-Qi; Wilke, Russell A; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M; Stafford, Jeanette M; Ding, Jingzhong; Herrington, David M; Kritchevsky, Stephen B; Eiriksdottir, Gudny; Launer, Leonore J; Harris, Tamara B; Chu, Audrey Y; Giulianini, Franco; MacFadyen, Jean G; Barratt, Bryan J; Nyberg, Fredrik; Stricker, Bruno H; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H; Ridker, Paul M; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C; Ballantyne, Christie M; Rotter, Jerome I; Adrienne Cupples, L; Psaty, Bruce M; Palmer, Colin N A; Tardif, Jean-Claude; Colhoun, Helen M; Hitman, Graham; Krauss, Ronald M; Wouter Jukema, J; Caulfield, Mark J

    2014-10-28

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

  18. Defining and improving the genome-wide specificities of CRISPR-Cas9 nucleases.

    PubMed

    Tsai, Shengdar Q; Joung, J Keith

    2016-05-01

    CRISPR-Cas9 RNA-guided nucleases are a transformative technology for biology, genetics and medicine owing to the simplicity with which they can be programmed to cleave specific DNA target sites in living cells and organisms. However, to translate these powerful molecular tools into safe, effective clinical applications, it is of crucial importance to carefully define and improve their genome-wide specificities. Here, we outline our state-of-the-art understanding of target DNA recognition and cleavage by CRISPR-Cas9 nucleases, methods to determine and improve their specificities, and key considerations for how to evaluate and reduce off-target effects for research and therapeutic applications.

  19. Brewing yeast genomes and genome-wide expression and proteome profiling during fermentation.

    PubMed

    Smart, Katherine A

    2007-11-01

    The genome structure, ancestry and instability of the brewing yeast strains have received considerable attention. The hybrid nature of brewing lager yeast strains provides adaptive potential but yields genome instability which can adversely affect fermentation performance. The requirement to differentiate between production strains and assess master cultures for genomic instability has led to significant adoption of specialized molecular tool kits by the industry. Furthermore, the development of genome-wide transcriptional and protein expression technologies has generated significant interest from brewers. The opportunity presented to explore, and the concurrent requirement to understand both, the constraints and potential of their strains to generate existing and new products during fermentation is discussed.

  20. Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma

    PubMed Central

    Yucesoy, Berran; Kaufman, Kenneth M.; Lummus, Zana L.; Weirauch, Matthew T.; Zhang, Ge; Cartier, André; Boulet, Louis-Philippe; Sastre, Joaquin; Quirce, Santiago; Tarlo, Susan M.; Cruz, Maria-Jesus; Munoz, Xavier; Harley, John B.; Bernstein, David I.

    2015-01-01

    Diisocyanates, reactive chemicals used to produce polyurethane products, are the most common causes of occupational asthma. The aim of this study is to identify susceptibility gene variants that could contribute to the pathogenesis of diisocyanate asthma (DA) using a Genome-Wide Association Study (GWAS) approach. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed in 74 diisocyanate-exposed workers with DA and 824 healthy controls using Omni-2.5 and Omni-5 SNP microarrays. We identified 11 SNPs that exceeded genome-wide significance; the strongest association was for the rs12913832 SNP located on chromosome 15, which has been mapped to the HERC2 gene (p = 6.94 × 10−14). Strong associations were also found for SNPs near the ODZ3 and CDH17 genes on chromosomes 4 and 8 (rs908084, p = 8.59 × 10−9 and rs2514805, p = 1.22 × 10−8, respectively). We also prioritized 38 SNPs with suggestive genome-wide significance (p < 1 × 10−6). Among them, 17 SNPs map to the PITPNC1, ACMSD, ZBTB16, ODZ3, and CDH17 gene loci. Functional genomics data indicate that 2 of the suggestive SNPs (rs2446823 and rs2446824) are located within putative binding sites for the CCAAT/Enhancer Binding Protein (CEBP) and Hepatocyte Nuclear Factor 4, Alpha transcription factors (TFs), respectively. This study identified SNPs mapping to the HERC2, CDH17, and ODZ3 genes as potential susceptibility loci for DA. Pathway analysis indicated that these genes are associated with antigen processing and presentation, and other immune pathways. Overlap of 2 suggestive SNPs with likely TF binding sites suggests possible roles in disruption of gene regulation. These results provide new insights into the genetic architecture of DA and serve as a basis for future functional and mechanistic studies. PMID:25918132

  1. Genome-wide hydroxymethylcytosine pattern changes in response to oxidative stress

    PubMed Central

    Delatte, Benjamin; Jeschke, Jana; Defrance, Matthieu; Bachman, Martin; Creppe, Catherine; Calonne, Emilie; Bizet, Martin; Deplus, Rachel; Marroquí, Laura; Libin, Myriam; Ravichandran, Mirunalini; Mascart, Françoise; Eizirik, Decio L.; Murrell, Adele; Jurkowski, Tomasz P.; Fuks, François

    2015-01-01

    The TET enzymes convert methylcytosine to the newly discovered base hydroxymethylcytosine. While recent reports suggest that TETs may play a role in response to oxidative stress, this role remains uncertain, and results lack in vivo models. Here we show a global decrease of hydroxymethylcytosine in cells treated with buthionine sulfoximine, and in mice depleted for the major antioxidant enzymes GPx1 and 2. Furthermore, genome-wide profiling revealed differentially hydroxymethylated regions in coding genes, and intriguingly in microRNA genes, both involved in response to oxidative stress. These results thus suggest a profound effect of in vivo oxidative stress on the global hydroxymethylome. PMID:26239807

  2. Genome-wide Association Studies from the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative | Office of Cancer Genomics

    Cancer.gov

    CGEMS identifies common inherited genetic variations associated with a number of cancers, including breast and prostate. Data from these genome-wide association studies (GWAS) are available through the Division of Cancer Epidemiology & Genetics website.

  3. GStream: improving SNP and CNV coverage on genome-wide association studies.

    PubMed

    Alonso, Arnald; Marsal, Sara; Tortosa, Raül; Canela-Xandri, Oriol; Julià, Antonio

    2013-01-01

    We present GStream, a method that combines genome-wide SNP and CNV genotyping in the Illumina microarray platform with unprecedented accuracy. This new method outperforms previous well-established SNP genotyping software. More importantly, the CNV calling algorithm of GStream dramatically improves the results obtained by previous state-of-the-art methods and yields an accuracy that is close to that obtained by purely CNV-oriented technologies like Comparative Genomic Hybridization (CGH). We demonstrate the superior performance of GStream using microarray data generated from HapMap samples. Using the reference CNV calls generated by the 1000 Genomes Project (1KGP) and well-known studies on whole genome CNV characterization based either on CGH or genotyping microarray technologies, we show that GStream can increase the number of reliably detected variants up to 25% compared to previously developed methods. Furthermore, the increased genome coverage provided by GStream allows the discovery of CNVs in close linkage disequilibrium with SNPs, previously associated with disease risk in published Genome-Wide Association Studies (GWAS). These results could provide important insights into the biological mechanism underlying the detected disease risk association. With GStream, large-scale GWAS will not only benefit from the combined genotyping of SNPs and CNVs at an unprecedented accuracy, but will also take advantage of the computational efficiency of the method.

  4. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

    PubMed

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Smith, G D; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-08-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

  5. A genome-wide CRISPR library for high-throughput genetic screening in Drosophila cells.

    PubMed

    Bassett, Andrew R; Kong, Lesheng; Liu, Ji-Long

    2015-06-20

    The simplicity of the CRISPR/Cas9 system of genome engineering has opened up the possibility of performing genome-wide targeted mutagenesis in cell lines, enabling screening for cellular phenotypes resulting from genetic aberrations. Drosophila cells have proven to be highly effective in identifying genes involved in cellular processes through similar screens using partial knockdown by RNAi. This is in part due to the lower degree of redundancy between genes in this organism, whilst still maintaining highly conserved gene networks and orthologs of many human disease-causing genes. The ability of CRISPR to generate genetic loss of function mutations not only increases the magnitude of any effect over currently employed RNAi techniques, but allows analysis over longer periods of time which can be critical for certain phenotypes. In this study, we have designed and built a genome-wide CRISPR library covering 13,501 genes, among which 8989 genes are targeted by three or more independent single guide RNAs (sgRNAs). Moreover, we describe strategies to monitor the population of guide RNAs by high throughput sequencing (HTS). We hope that this library will provide an invaluable resource for the community to screen loss of function mutations for cellular phenotypes, and as a source of guide RNA designs for future studies. PMID:26165496

  6. Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours

    PubMed Central

    Melin, Malin; Murén, Eva; Gustafson, Ulla; Starkey, Mike; Borge, Kaja Sverdrup; Lingaas, Frode; Saellström, Sara; Rönnberg, Henrik; Lindblad-Toh, Kerstin

    2016-01-01

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients. PMID:27158822

  7. Genome-wide association study identifies three novel loci for type 2 diabetes.

    PubMed

    Hara, Kazuo; Fujita, Hayato; Johnson, Todd A; Yamauchi, Toshimasa; Yasuda, Kazuki; Horikoshi, Momoko; Peng, Chen; Hu, Cheng; Ma, Ronald C W; Imamura, Minako; Iwata, Minoru; Tsunoda, Tatsuhiko; Morizono, Takashi; Shojima, Nobuhiro; So, Wing Yee; Leung, Ting Fan; Kwan, Patrick; Zhang, Rong; Wang, Jie; Yu, Weihui; Maegawa, Hiroshi; Hirose, Hiroshi; Kaku, Kohei; Ito, Chikako; Watada, Hirotaka; Tanaka, Yasushi; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Jia, Weiping; Chan, Juliana C N; Teo, Yik Ying; Shyong, Tai E; Kamatani, Naoyuki; Kubo, Michiaki; Maeda, Shiro; Kadowaki, Takashi

    2014-01-01

    Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases and 34 814 controls) identified three new loci with genome-wide significance, which were MIR129-LEP [rs791595; risk allele = A; risk allele frequency (RAF) = 0.080; P = 2.55 × 10(-13); odds ratio (OR) = 1.17], GPSM1 [rs11787792; risk allele = A; RAF = 0.874; P = 1.74 × 10(-10); OR = 1.15] and SLC16A13 (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases. PMID:23945395

  8. Insect herbivory elicits genome-wide alternative splicing responses in Nicotiana attenuata.

    PubMed

    Ling, Zhihao; Zhou, Wenwu; Baldwin, Ian T; Xu, Shuqing

    2015-10-01

    Changes in gene expression and alternative splicing (AS) are involved in many responses to abiotic and biotic stresses in eukaryotic organisms. In response to attack and oviposition by insect herbivores, plants elicit rapid changes in gene expression which are essential for the activation of plant defenses; however, the herbivory-induced changes in AS remain unstudied. Using mRNA sequencing, we performed a genome-wide analysis on tobacco hornworm (Manduca sexta) feeding-induced AS in both leaves and roots of Nicotiana attenuata. Feeding by M. sexta for 5 h reduced total AS events by 7.3% in leaves but increased them in roots by 8.0% and significantly changed AS patterns in leaves and roots of existing AS genes. Feeding by M. sexta also resulted in increased (in roots) and decreased (in leaves) transcript levels of the serine/arginine-rich (SR) proteins that are involved in the AS machinery of plants and induced changes in SR gene expression that were jasmonic acid (JA)-independent in leaves but JA-dependent in roots. Changes in AS and gene expression elicited by M. sexta feeding were regulated independently in both tissues. This study provides genome-wide evidence that insect herbivory induces changes not only in the levels of gene expression but also in their splicing, which might contribute to defense against and/or tolerance of herbivory. PMID:26306554

  9. 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

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

    PubMed Central

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

    2014-01-01

    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

  11. Genome-wide association scan suggests basis for microtia in Awassi sheep.

    PubMed

    Jawasreh, K; Boettcher, P J; Stella, A

    2016-08-01

    Hereditary underdevelopment of the ear, a condition also known as microtia, has been observed in several sheep breeds as well as in humans and other species. Its genetic basis in sheep is unknown. The Awassi sheep, a breed native to southwest Asia, carries this phenotype and was targeted for molecular characterization via a genome-wide association study. DNA samples were collected from sheep in Jordan. Eight affected and 12 normal individuals were genotyped with the Illumina OvineSNP50(®) chip. Multilocus analyses failed to identify any genotypic association. In contrast, a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago. Many of the earless sheep breeds may thus share the causative mutation, especially within the subgroup of fat-tailed, wool sheep.

  12. [Strategies of genome-wide association study based on high-throughput sequencing].

    PubMed

    Zhou, Jiapeng; Pei, Zhiyong; Chen, Yubao; Chen, Runsheng

    2014-11-01

    Genome-wide association studies (GWASs) have been playing an important role on human complex diseases. Generally speaking, GWAS tries to detect the relationship between genome-wide genetic variants and measurable traits in the population level. Although fruitful, array-based GWASs still exist some problems, for example, the so-called missing heritability--significantly associated SNPs can only explain a small part of phenotypic variation. Other problems include that, in some traits, significantly associated SNPs in one study are hard to be repeated by other studies; and that the functions of significantly associated SNPs are often difficult to interpret. High-throughput sequencing, also known as next-generation sequencing (NGS), could be one of the most promising technologies to solve those problems by quickly producing accurate variations in a high-throughput way. NGS-based GWASs (NGS-GWAS), to some extent, provide a better solution compared with traditional array-based GWASs. We systematically review the strategies and methods for NGS-GWASs, pick out the most feasible and efficient strategies and methods for NGS-GWASs, and discuss their applications in personalized medicine. PMID:25567868

  13. Natural CMT2 Variation Is Associated With Genome-Wide Methylation Changes and Temperature Seasonality

    PubMed Central

    Shen, Xia; De Jonge, Jennifer; Forsberg, Simon K. G.; Pettersson, Mats E.; Sheng, Zheya; Hennig, Lars; Carlborg, Örjan

    2014-01-01

    As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature-stress. PMID:25503602

  14. GStream: Improving SNP and CNV Coverage on Genome-Wide Association Studies

    PubMed Central

    Alonso, Arnald; Marsal, Sara; Tortosa, Raül; Canela-Xandri, Oriol; Julià, Antonio

    2013-01-01

    We present GStream, a method that combines genome-wide SNP and CNV genotyping in the Illumina microarray platform with unprecedented accuracy. This new method outperforms previous well-established SNP genotyping software. More importantly, the CNV calling algorithm of GStream dramatically improves the results obtained by previous state-of-the-art methods and yields an accuracy that is close to that obtained by purely CNV-oriented technologies like Comparative Genomic Hybridization (CGH). We demonstrate the superior performance of GStream using microarray data generated from HapMap samples. Using the reference CNV calls generated by the 1000 Genomes Project (1KGP) and well-known studies on whole genome CNV characterization based either on CGH or genotyping microarray technologies, we show that GStream can increase the number of reliably detected variants up to 25% compared to previously developed methods. Furthermore, the increased genome coverage provided by GStream allows the discovery of CNVs in close linkage disequilibrium with SNPs, previously associated with disease risk in published Genome-Wide Association Studies (GWAS). These results could provide important insights into the biological mechanism underlying the detected disease risk association. With GStream, large-scale GWAS will not only benefit from the combined genotyping of SNPs and CNVs at an unprecedented accuracy, but will also take advantage of the computational efficiency of the method. PMID:23844243

  15. Genome-wide microsatellite characterization and marker development in the sequenced Brassica crop species.

    PubMed

    Shi, Jiaqin; Huang, Shunmou; Zhan, Jiepeng; Yu, Jingyin; Wang, Xinfa; Hua, Wei; Liu, Shengyi; Liu, Guihua; Wang, Hanzhong

    2014-02-01

    Although much research has been conducted, the pattern of microsatellite distribution has remained ambiguous, and the development/utilization of microsatellite markers has still been limited/inefficient in Brassica, due to the lack of genome sequences. In view of this, we conducted genome-wide microsatellite characterization and marker development in three recently sequenced Brassica crops: Brassica rapa, Brassica oleracea and Brassica napus. The analysed microsatellite characteristics of these Brassica species were highly similar or almost identical, which suggests that the pattern of microsatellite distribution is likely conservative in Brassica. The genomic distribution of microsatellites was highly non-uniform and positively or negatively correlated with genes or transposable elements, respectively. Of the total of 115 869, 185 662 and 356 522 simple sequence repeat (SSR) markers developed with high frequencies (408.2, 343.8 and 356.2 per Mb or one every 2.45, 2.91 and 2.81 kb, respectively), most represented new SSR markers, the majority had determined physical positions, and a large number were genic or putative single-locus SSR markers. We also constructed a comprehensive database for the newly developed SSR markers, which was integrated with public Brassica SSR markers and annotated genome components. The genome-wide SSR markers developed in this study provide a useful tool to extend the annotated genome resources of sequenced Brassica species to genetic study/breeding in different Brassica species.

  16. Methods for Investigating Gene-Environment Interactions in Candidate Pathway and Genome-Wide Association Studies

    PubMed Central

    Thomas, Duncan

    2010-01-01

    Despite the considerable enthusiasm about the yield of novel and replicated discoveries of genetic associations from the new generation of genome-wide association studies (GWAS), the proportion of the heritability of most complex diseases that have been studied to date remains small. Some of this “dark matter” could be due to gene-environment (G×E) interactions or more complex pathways involving multiple genes and exposures. We review the basic epidemiologic study design and statistical analysis approaches to studying G×E interactions individually and then consider more comprehensive approaches to studying entire pathways or GWAS data. In addition to the usual issues in genetic association studies, particular care is needed in exposure assessment and very large sample sizes are required. Although hypothesis-driven pathway-based and “agnostic” GWAS approaches are generally viewed as opposite poles, we suggest that the two can be usefully married using hierarchical modeling strategies that exploit external pathway knowledge in mining genome-wide data. PMID:20070199

  17. Estimating genome-wide heterozygosity: effects of demographic history and marker type

    PubMed Central

    Miller, J M; Malenfant, R M; David, P; Davis, C S; Poissant, J; Hogg, J T; Festa-Bianchet, M; Coltman, D W

    2014-01-01

    Heterozygosity–fitness correlations (HFCs) are often used to link individual genetic variation to differences in fitness. However, most studies examining HFCs find weak or no correlations. Here, we derive broad theoretical predictions about how many loci are needed to adequately measure genomic heterozygosity assuming different levels of identity disequilibrium (ID), a proxy for inbreeding. We then evaluate the expected ability to detect HFCs using an empirical data set of 200 microsatellites and 412 single nucleotide polymorphisms (SNPs) genotyped in two populations of bighorn sheep (Ovis canadensis), with different demographic histories. In both populations, heterozygosity was significantly correlated across marker types, although the strength of the correlation was weaker in a native population compared with one founded via translocation and later supplemented with additional individuals. Despite being bi-allelic, SNPs had similar correlations to genome-wide heterozygosity as microsatellites in both populations. For both marker types, this association became stronger and less variable as more markers were considered. Both populations had significant levels of ID; however, estimates were an order of magnitude lower in the native population. As with heterozygosity, SNPs performed similarly to microsatellites, and precision and accuracy of the estimates of ID increased as more loci were considered. Although dependent on the demographic history of the population considered, these results illustrate that genome-wide heterozygosity, and therefore HFCs, are best measured by a large number of markers, a feat now more realistically accomplished with SNPs than microsatellites. PMID:24149650

  18. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci.

    PubMed

    Stahl, Eli A; Raychaudhuri, Soumya; Remmers, Elaine F; Xie, Gang; Eyre, Stephen; Thomson, Brian P; Li, Yonghong; Kurreeman, Fina A S; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I; Ardlie, Kristin G; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P; Catanese, Joseph J; Coblyn, Jonathan; Coenen, Marieke J H; Costenbader, Karen H; Criswell, Lindsey A; Crusius, J Bart A; Cui, Jing; de Bakker, Paul I W; De Jager, Philip L; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J; Huizinga, Tom W J; Kastner, Daniel L; Ke, Xiayi; Lee, Annette T; Liu, Xiangdong; Martin, Paul; Morgan, Ann W; Padyukov, Leonid; Posthumus, Marcel D; Radstake, Timothy R D J; Reid, David M; Seielstad, Mark; Seldin, Michael F; Shadick, Nancy A; Steer, Sophia; Tak, Paul P; Thomson, Wendy; van der Helm-van Mil, Annette H M; van der Horst-Bruinsma, Irene E; van der Schoot, C Ellen; van Riel, Piet L C M; Weinblatt, Michael E; Wilson, Anthony G; Wolbink, Gert Jan; Wordsworth, B Paul; Wijmenga, Cisca; Karlson, Elizabeth W; Toes, Rene E M; de Vries, Niek; Begovich, Ann B; Worthington, Jane; Siminovitch, Katherine A; Gregersen, Peter K; Klareskog, Lars; Plenge, Robert M

    2010-06-01

    To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles. PMID:20453842

  19. HITS-CLIP yields genome-wide insights into brain alternative RNA processing

    NASA Astrophysics Data System (ADS)

    Licatalosi, Donny D.; Mele, Aldo; Fak, John J.; Ule, Jernej; Kayikci, Melis; Chi, Sung Wook; Clark, Tyson A.; Schweitzer, Anthony C.; Blume, John E.; Wang, Xuning; Darnell, Jennifer C.; Darnell, Robert B.

    2008-11-01

    Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

  20. A Genome-Wide Survey of Date Palm Cultivars Supports Two Major Subpopulations in Phoenix dactylifera

    PubMed Central

    Mathew, Lisa S.; Seidel, Michael A.; George, Binu; Mathew, Sweety; Spannagl, Manuel; Haberer, Georg; Torres, Maria F.; Al-Dous, Eman K.; Al-Azwani, Eman K.; Diboun, Ilhem; Krueger, Robert R.; Mayer, Klaus F. X.; Mohamoud, Yasmin Ali; Suhre, Karsten; Malek, Joel A.

    2015-01-01

    The date palm (Phoenix dactylifera L.) is one of the oldest cultivated trees and is intimately tied to the history of human civilization. There are hundreds of commercial cultivars with distinct fruit shapes, colors, and sizes growing mainly in arid lands from the west of North Africa to India. The origin of date palm domestication is still uncertain, and few studies have attempted to document genetic diversity across multiple regions. We conducted genotyping-by-sequencing on 70 female cultivar samples from across the date palm–growing regions, including four Phoenix species as the outgroup. Here, for the first time, we generate genome-wide genotyping data for 13,000–65,000 SNPs in a diverse set of date palm fruit and leaf samples. Our analysis provides the first genome-wide evidence confirming recent findings that the date palm cultivars segregate into two main regions of shared genetic background from North Africa and the Arabian Gulf. We identify genomic regions with high densities of geographically segregating SNPs and also observe higher levels of allele fixation on the recently described X-chromosome than on the autosomes. Our results fit a model with two centers of earliest cultivation including date palms autochthonous to North Africa. These results adjust our understanding of human agriculture history and will provide the foundation for more directed functional studies and a better understanding of genetic diversity in date palm. PMID:25957276

  1. Genome-wide association studies in preterm birth: implications for the practicing obstetrician-gynaecologist.

    PubMed

    Dolan, Siobhan M; Christiaens, Inge

    2013-01-01

    Preterm birth has the highest mortality and morbidity of all pregnancy complications. The burden of preterm birth on public health worldwide is enormous, yet there are few effective means to prevent a preterm delivery. To date, much of its etiology is unexplained, but genetic predisposition is thought to play a major role. In the upcoming year, the international Preterm Birth Genome Project (PGP) consortium plans to publish a large genome wide association study in early preterm birth. Genome-wide association studies (GWAS) are designed to identify common genetic variants that influence health and disease. Despite the many challenges that are involved, GWAS can be an important discovery tool, revealing genetic variations that are associated with preterm birth. It is highly unlikely that findings of a GWAS can be directly translated into clinical practice in the short run. Nonetheless, it will help us to better understand the etiology of preterm birth and the GWAS results will generate new hypotheses for further research, thus enhancing our understanding of preterm birth and informing prevention efforts in the long run. PMID:23445776

  2. [Analysis of population stratification using random SNPs in genome-wide association studies].

    PubMed

    Cao, Zong-Fu; Ma, Chuan-Xiang; Wang, Lei; Cai, Bin

    2010-09-01

    Since population genetic STRUCTURE can increase false-positive rate in genome-wide association studies (GWAS) for complex diseases, the effect of population stratification should be taken into account in GWAS. However, the effect of randomly selected SNPs in population stratification analysis is underdetermined. In this study, based on the genotype data generated on Genome-Wide Human SNP Array 6.0 from unrelated individuals of HapMap Phase2, we randomly selected SNPs that were evenly distributed across the whole-genome, and acquired Ancestry Informative Markers (AIMs) by the method of f value and allelic Fisher exact test. F-statistics and STRUCTURE analysis based on the select different sets of SNPs were used to evaluate the effect of distinguishing the populations from HapMap Phase3. We found that randomly selected SNPs that were evenly distributed across the whole-genome were able to be used to identify the population structure. This study further indicated that more than 3 000 randomly selected SNPs that were evenly distributed across the whole-genome were substituted for AIMs in population stratification analysis, when there were no available AIMs for spe-cific populations.

  3. Partitioning heritability by functional annotation using genome-wide association summary statistics.

    PubMed

    Finucane, Hilary K; Bulik-Sullivan, Brendan; Gusev, Alexander; Trynka, Gosia; Reshef, Yakir; Loh, Po-Ru; Anttila, Verneri; Xu, Han; Zang, Chongzhi; Farh, Kyle; Ripke, Stephan; Day, Felix R; Purcell, Shaun; Stahl, Eli; Lindstrom, Sara; Perry, John R B; Okada, Yukinori; Raychaudhuri, Soumya; Daly, Mark J; Patterson, Nick; Neale, Benjamin M; Price, Alkes L

    2015-11-01

    Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior. PMID:26414678

  4. Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas.

    PubMed

    Deitz, Kevin C; Athrey, Giridhar A; Jawara, Musa; Overgaard, Hans J; Matias, Abrahan; Slotman, Michel A

    2016-01-01

    Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq) from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression. PMID:27466271

  5. Genome-wide analysis of homeobox gene family in legumes: identification, gene duplication and expression profiling.

    PubMed

    Bhattacharjee, Annapurna; Ghangal, Rajesh; Garg, Rohini; Jain, Mukesh

    2015-01-01

    Homeobox genes encode transcription factors that are known to play a major role in different aspects of plant growth and development. In the present study, we identified homeobox genes belonging to 14 different classes in five legume species, including chickpea, soybean, Medicago, Lotus and pigeonpea. The characteristic differences within homeodomain sequences among various classes of homeobox gene family were quite evident. Genome-wide expression analysis using publicly available datasets (RNA-seq and microarray) indicated that homeobox genes are differentially expressed in various tissues/developmental stages and under stress conditions in different legumes. We validated the differential expression of selected chickpea homeobox genes via quantitative reverse transcription polymerase chain reaction. Genome duplication analysis in soybean indicated that segmental duplication has significantly contributed in the expansion of homeobox gene family. The Ka/Ks ratio of duplicated homeobox genes in soybean showed that several members of this family have undergone purifying selection. Moreover, expression profiling indicated that duplicated genes might have been retained due to sub-functionalization. The genome-wide identification and comprehensive gene expression profiling of homeobox gene family members in legumes will provide opportunities for functional analysis to unravel their exact role in plant growth and development.

  6. Differential network analysis reveals the genome-wide landscape of estrogen receptor modulation in hormonal cancers

    PubMed Central

    Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Hsu, Pei-Yin; Lu, Tzu-Pin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Huang, Tim H.-M.; Chuang, Eric Y.; Chen, Yidong

    2016-01-01

    Several mutual information (MI)-based algorithms have been developed to identify dynamic gene-gene and function-function interactions governed by key modulators (genes, proteins, etc.). Due to intensive computation, however, these methods rely heavily on prior knowledge and are limited in genome-wide analysis. We present the modulated gene/gene set interaction (MAGIC) analysis to systematically identify genome-wide modulation of interaction networks. Based on a novel statistical test employing conjugate Fisher transformations of correlation coefficients, MAGIC features fast computation and adaption to variations of clinical cohorts. In simulated datasets MAGIC achieved greatly improved computation efficiency and overall superior performance than the MI-based method. We applied MAGIC to construct the estrogen receptor (ER) modulated gene and gene set (representing biological function) interaction networks in breast cancer. Several novel interaction hubs and functional interactions were discovered. ER+ dependent interaction between TGFβ and NFκB was further shown to be associated with patient survival. The findings were verified in independent datasets. Using MAGIC, we also assessed the essential roles of ER modulation in another hormonal cancer, ovarian cancer. Overall, MAGIC is a systematic framework for comprehensively identifying and constructing the modulated interaction networks in a whole-genome landscape. MATLAB implementation of MAGIC is available for academic uses at https://github.com/chiuyc/MAGIC. PMID:26972162

  7. Genome-wide analysis of host factors in nodavirus RNA replication.

    PubMed

    Hao, Linhui; Lindenbach, Brett; Wang, Xiaofeng; Dye, Billy; Kushner, David; He, Qiuling; Newton, Michael; Ahlquist, Paul

    2014-01-01

    Flock House virus (FHV), the best studied of the animal nodaviruses, has been used as a model for positive-strand RNA virus research. As one approach to identify host genes that affect FHV RNA replication, we performed a genome-wide analysis using a yeast single gene deletion library and a modified, reporter gene-expressing FHV derivative. A total of 4,491 yeast deletion mutants were tested for their ability to support FHV replication. Candidates for host genes modulating FHV replication were selected based on the initial genome-wide reporter gene assay and validated in repeated Northern blot assays for their ability to support wild type FHV RNA1 replication. Overall, 65 deletion strains were confirmed to show significant changes in the replication of both FHV genomic RNA1 and sub-genomic RNA3 with a false discovery rate of 5%. Among them, eight genes support FHV replication, since their deletion significantly reduced viral RNA accumulation, while 57 genes limit FHV replication, since their deletion increased FHV RNA accumulation. Of the gene products implicated in affecting FHV replication, three are localized to mitochondria, where FHV RNA replication occurs, 16 normally reside in the nucleus and may have indirect roles in FHV replication, and the remaining 46 are in the cytoplasm, with functions enriched in translation, RNA processing and trafficking. PMID:24752411

  8. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations.

    PubMed

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-04-21

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition.

  9. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells

    PubMed Central

    Pirola, Luciano; Balcerczyk, Aneta; Tothill, Richard W.; Haviv, Izhak; Kaspi, Antony; Lunke, Sebastian; Ziemann, Mark; Karagiannis, Tom; Tonna, Stephen; Kowalczyk, Adam; Beresford-Smith, Bryan; Macintyre, Geoff; Kelong, Ma; Hongyu, Zhang; Zhu, Jingde; El-Osta, Assam

    2011-01-01

    Emerging evidence suggests that poor glycemic control mediates post-translational modifications to the H3 histone tail. We are only beginning to understand the dynamic role of some of the diverse epigenetic changes mediated by hyperglycemia at single loci, yet elevated glucose levels are thought to regulate genome-wide changes, and this still remains poorly understood. In this article we describe genome-wide histone H3K9/K14 hyperacetylation and DNA methylation maps conferred by hyperglycemia in primary human vascular cells. Chromatin immunoprecipitation (ChIP) as well as CpG methylation (CpG) assays, followed by massive parallel sequencing (ChIP-seq and CpG-seq) identified unique hyperacetylation and CpG methylation signatures with proximal and distal patterns of regionalization associative with gene expression. Ingenuity knowledge-based pathway and gene ontology analyses indicate that hyperglycemia significantly affects human vascular chromatin with the transcriptional up-regulation of genes involved in metabolic and cardiovascular disease. We have generated the first installment of a reference collection of hyperglycemia-induced chromatin modifications using robust and reproducible platforms that allow parallel sequencing-by-synthesis of immunopurified content. We uncover that hyperglycemia-mediated induction of genes and pathways associated with endothelial dysfunction occur through modulation of acetylated H3K9/K14 inversely correlated with methyl-CpG content. PMID:21890681

  10. Genome-wide interaction analysis reveals replicated epistatic effects on brain structure

    PubMed Central

    Hibar, Derrek P.; Stein, Jason L.; Jahanshad, Neda; Kohannim, Omid; Hua, Xue; Toga, Arthur W.; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicholas G.; Wright, Margaret J.; Weiner, Michael W.; Thompson, Paul M.

    2015-01-01

    The discovery of several genes that affect risk for Alzheimer's disease ignited a worldwide search for Single Nucleotide Polymorphisms (SNPs), common genetic variants that affect the brain. Genome-wide search of all possible SNP-SNP interactions is challenging and rarely attempted, due to the complexity of conducting ∼1011 pairwise statistical tests. However, recent advances in machine learning, e.g., iterative sure independence screening (SIS), make it possible to analyze datasets with vastly more predictors than observations. Using an implementation of the SIS algorithm (called EPISIS), we performed a genome-wide interaction analysis testing all possible SNP-SNP interactions affecting regional brain volumes measured on MRI and mapped using tensor-based morphometry. We identified a significant SNP-SNP interaction between rs1345203 and rs1213205 that explains 1.9% of the variance in temporal lobe volume. We mapped the whole-brain, voxelwise effects of the interaction in the ADNI dataset and separately in an independent replication dataset of healthy twins (QTIM). Each additional loading in the interaction effect was associated with ∼5% greater brain regional brain volume (a protective effect) in both ADNI and QTIM samples. PMID:25264344

  11. Comparison of genome-wide selection strategies to identify furfural tolerance genes in Escherichia coli.

    PubMed

    Glebes, Tirzah Y; Sandoval, Nicholas R; Gillis, Jacob H; Gill, Ryan T

    2015-01-01

    Engineering both feedstock and product tolerance is important for transitioning towards next-generation biofuels derived from renewable sources. Tolerance to chemical inhibitors typically results in complex phenotypes, for which multiple genetic changes must often be made to confer tolerance. Here, we performed a genome-wide search for furfural-tolerant alleles using the TRackable Multiplex Recombineering (TRMR) method (Warner et al. (2010), Nature Biotechnology), which uses chromosomally integrated mutations directed towards increased or decreased expression of virtually every gene in Escherichia coli. We employed various growth selection strategies to assess the role of selection design towards growth enrichments. We also compared genes with increased fitness from our TRMR selection to those from a previously reported genome-wide identification study of furfural tolerance genes using a plasmid-based genomic library approach (Glebes et al. (2014) PLOS ONE). In several cases, growth improvements were observed for the chromosomally integrated promoter/RBS mutations but not for the plasmid-based overexpression constructs. Through this assessment, four novel tolerance genes, ahpC, yhjH, rna, and dicA, were identified and confirmed for their effect on improving growth in the presence of furfural.

  12. Heavy metals induce oxidative stress and genome-wide modulation in transcriptome of rice root.

    PubMed

    Dubey, Sonali; Shri, Manju; Misra, Prashant; Lakhwani, Deepika; Bag, Sumit Kumar; Asif, Mehar H; Trivedi, Prabodh Kumar; Tripathi, Rudro Deo; Chakrabarty, Debasis

    2014-06-01

    Industrial growth, ecological disturbances and agricultural practices have contaminated the soil and water with many harmful compounds, including heavy metals. These heavy metals affect growth and development of plants as well as cause severe human health hazards through food chain contamination. In past, studies have been made to identify biochemical and molecular networks associated with heavy metal toxicity and uptake in plants. Studies suggested that most of the physiological and molecular processes affected by different heavy metals are similar to those affected by other abiotic stresses. To identify common and unique responses by different metals, we have studied biochemical and genome-wide modulation in transcriptome of rice (IR-64 cultivar) root after exposure to cadmium (Cd), arsenate [As(V)], lead (Pb) and chromium [Cr(VI)] in hydroponic condition. We observed that root tissue shows variable responses for antioxidant enzyme system for different heavy metals. Genome-wide expression analysis suggests variable number of genes differentially expressed in root in response to As(V), Cd, Pb and Cr(VI) stresses. In addition to unique genes, each heavy metal modulated expression of a large number of common genes. Study also identified cis-acting regions of the promoters which can be determinants for the modulated expression of the genes in response to different heavy metals. Our study advances understanding related to various processes and networks which might be responsible for heavy metal stresses, accumulation and detoxification. PMID:24553786

  13. Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours.

    PubMed

    Melin, Malin; Rivera, Patricio; Arendt, Maja; Elvers, Ingegerd; Murén, Eva; Gustafson, Ulla; Starkey, Mike; Borge, Kaja Sverdrup; Lingaas, Frode; Häggström, Jens; Saellström, Sara; Rönnberg, Henrik; Lindblad-Toh, Kerstin

    2016-05-01

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients. PMID:27158822

  14. Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris.

    PubMed

    Navarini, Alexander A; Simpson, Michael A; Weale, Michael; Knight, Jo; Carlavan, Isabelle; Reiniche, Pascale; Burden, David A; Layton, Alison; Bataille, Veronique; Allen, Michael; Pleass, Robert; Pink, Andrew; Creamer, Daniel; English, John; Munn, Stephanie; Walton, Shernaz; Willis, Carolyn; Déret, Sophie; Voegel, Johannes J; Spector, Tim; Smith, Catherine H; Trembath, Richard C; Barker, Jonathan N

    2014-01-01

    Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10(-11), odds ratio (OR) = 1.20), 5q11.2 (rs38055, P(combined) = 4.58 × 10(-9), OR = 1.17) and 1q41 (rs1159268, P(combined) = 4.08 × 10(-8), OR = 1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne.

  15. Genome-Wide DNA Methylation Patterns and Transcription Analysis in Sheep Muscle

    PubMed Central

    Couldrey, Christine; Brauning, Rudiger; Bracegirdle, Jeremy; Maclean, Paul; Henderson, Harold V.; McEwan, John C.

    2014-01-01

    DNA methylation plays a central role in regulating many aspects of growth and development in mammals through regulating gene expression. The development of next generation sequencing technologies have paved the way for genome-wide, high resolution analysis of DNA methylation landscapes using methodology known as reduced representation bisulfite sequencing (RRBS). While RRBS has proven to be effective in understanding DNA methylation landscapes in humans, mice, and rats, to date, few studies have utilised this powerful method for investigating DNA methylation in agricultural animals. Here we describe the utilisation of RRBS to investigate DNA methylation in sheep Longissimus dorsi muscles. RRBS analysis of ∼1% of the genome from Longissimus dorsi muscles provided data of suitably high precision and accuracy for DNA methylation analysis, at all levels of resolution from genome-wide to individual nucleotides. Combining RRBS data with mRNAseq data allowed the sheep Longissimus dorsi muscle methylome to be compared with methylomes from other species. While some species differences were identified, many similarities were observed between DNA methylation patterns in sheep and other more commonly studied species. The RRBS data presented here highlights the complexity of epigenetic regulation of genes. However, the similarities observed across species are promising, in that knowledge gained from epigenetic studies in human and mice may be applied, with caution, to agricultural species. The ability to accurately measure DNA methylation in agricultural animals will contribute an additional layer of information to the genetic analyses currently being used to maximise production gains in these species. PMID:25010796

  16. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    SciTech Connect

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMahon, Katherine D.; Malmstrom, Rex R.

    2014-06-18

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ‘ecotype model’ of diversification, but not previously observed in natural populations.

  17. Genome-wide patterns of genetic polymorphism and signatures of selection in Plasmodium vivax.

    PubMed

    Cornejo, Omar E; Fisher, David; Escalante, Ananias A

    2014-12-17

    Plasmodium vivax is the most prevalent human malaria parasite outside of Africa. Yet, studies aimed to identify genes with signatures consistent with natural selection are rare. Here, we present a comparative analysis of the pattern of genetic variation of five sequenced isolates of P. vivax and its divergence with two closely related species, Plasmodium cynomolgi and Plasmodium knowlesi, using a set of orthologous genes. In contrast to Plasmodium falciparum, the parasite that causes the most lethal form of human malaria, we did not find significant constraints on the evolution of synonymous sites genome wide in P. vivax. The comparative analysis of polymorphism and divergence across loci allowed us to identify 87 genes with patterns consistent with positive selection, including genes involved in the "exportome" of P. vivax, which are potentially involved in evasion of the host immune system. Nevertheless, we have found a pattern of polymorphism genome wide that is consistent with a significant amount of constraint on the replacement changes and prevalent negative selection. Our analyses also show that silent polymorphism tends to be larger toward the ends of the chromosomes, where many genes involved in antigenicity are located, suggesting that natural selection acts not only by shaping the patterns of variation within the genes but it also affects genome organization.

  18. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    SciTech Connect

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMcahon, Katherine D.; Mamlstrom, Rex R.

    2014-05-12

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ecotype model? of diversification, but not previously observed in natural populations.

  19. Ancestry informative markers for distinguishing between Thai populations based on genome-wide association datasets.

    PubMed

    Vongpaisarnsin, Kornkiat; Listman, Jennifer Beth; Malison, Robert T; Gelernter, Joel

    2015-07-01

    The main purpose of this work was to identify a set of AIMs that stratify the genetic structure and diversity of the Thai population from a high-throughput autosomal genome-wide association study. In this study, more than one million SNPs from the international HapMap database and the Thai depression genome-wide association study have been examined to identify ancestry informative markers (AIMs) that distinguish between Thai populations. An efficient strategy is proposed to identify and characterize such SNPs and to test high-resolution SNP data from international HapMap populations. The best AIMs are identified to stratify the population and to infer genetic ancestry structure. A total of 124 AIMs were clearly clustered geographically across the continent, whereas only 89 AIMs stratified the Thai population from East Asian populations. Finally, a set of 273 AIMs was able to distinguish northern from southern Thai subpopulations. These markers will be of particular value in identifying the ethnic origins in regions where matching by self-reports is unavailable or unreliable, which usually occurs in real forensic cases.

  20. Genome-wide analysis of alternative splicing during human heart development

    PubMed Central

    Wang, He; Chen, Yanmei; Li, Xinzhong; Chen, Guojun; Zhong, Lintao; Chen, Gangbing; Liao, Yulin; Liao, Wangjun; Bin, Jianping

    2016-01-01

    Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA). A significant difference of AS patterns was found between foetal and adult hearts. The predicted difference in AS events was further confirmed using quantitative reverse transcription-polymerase chain reaction analysis of human heart samples. Functional foetal-specific AS event analysis showed enrichment associated with cell proliferation-related pathways including cell cycle, whereas adult-specific AS events were associated with protein synthesis. Furthermore, 42.6% of foetal-specific AS events showed significant changes in gene expression levels between foetal and adult hearts. Genes exhibiting both foetal-specific AS and differential expression were highly enriched in cell cycle-associated functions. In conclusion, we provided a genome-wide profiling of AS transitions between foetal and adult hearts and proposed that AS transitions and deferential gene expression may play determinative roles in human heart development. PMID:27752099

  1. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations

    PubMed Central

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-01-01

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition. PMID:27097669

  2. Genome-wide association studies for multiple diseases of the German Shepherd Dog

    PubMed Central

    Tsai, Kate L.; Noorai, Rooksana E.; Starr-Moss, Alison N.; Quignon, Pascale; Rinz, Caitlin J.; Ostrander, Elaine A.; Steiner, Jörg M.; Murphy, Keith E.

    2012-01-01

    The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3. Results for DM confirm a major locus encompassing SOD1, in which an associated point mutation was previously identified, but do not suggest modifier loci. Several SNPs on Chr 12 are associated with ME and a 4.7 Mb haplotype block is present in affected dogs. Analysis of additional ME cases for a SNP within the haplotype provides further support for this association. Results for PAA indicate more complex genetic underpinnings. Several regions on multiple chromosomes reach genome-wide significance. However, no major locus is apparent and only two associated haplotype blocks, on Chrs 7 and 12 are observed. These data suggest that PAA may be governed by multiple loci with small effects, or it may be a heterogeneous disorder. PMID:22105877

  3. CONAN: copy number variation analysis software for genome-wide association studies

    PubMed Central

    2010-01-01

    Background Genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs) promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs. Results CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data. Conclusions CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at. PMID:20546565

  4. Genome-wide association for sensitivity to chronic oxidative stress in Drosophila melanogaster.

    PubMed

    Jordan, Katherine W; Craver, Kyle L; Magwire, Michael M; Cubilla, Carmen E; Mackay, Trudy F C; Anholt, Robert R H

    2012-01-01

    Reactive oxygen species (ROS) are a common byproduct of mitochondrial energy metabolism, and can also be induced by exogenous sources, including UV light, radiation, and environmental toxins. ROS generation is essential for maintaining homeostasis by triggering cellular signaling pathways and host defense mechanisms. However, an imbalance of ROS induces oxidative stress and cellular death and is associated with human disease, including age-related locomotor impairment. To identify genes affecting sensitivity and resistance to ROS-induced locomotor decline, we assessed locomotion of aged flies of the sequenced, wild-derived lines from the Drosophila melanogaster Genetics Reference Panel on standard medium and following chronic exposure to medium supplemented with 3 mM menadione sodium bisulfite (MSB). We found substantial genetic variation in sensitivity to oxidative stress with respect to locomotor phenotypes. We performed genome-wide association analyses to identify candidate genes associated with variation in sensitivity to ROS-induced decline in locomotor performance, and confirmed the effects for 13 of 16 mutations tested in these candidate genes. Candidate genes associated with variation in sensitivity to MSB-induced oxidative stress form networks of genes involved in neural development, immunity, and signal transduction. Many of these genes have human orthologs, highlighting the utility of genome-wide association in Drosophila for studying complex human disease. PMID:22715409

  5. A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

    PubMed

    McIntyre, Rebecca E; Nicod, Jérôme; Robles-Espinoza, Carla Daniela; Maciejowski, John; Cai, Na; Hill, Jennifer; Verstraten, Ruth; Iyer, Vivek; Rust, Alistair G; Balmus, Gabriel; Mott, Richard; Flint, Jonathan; Adams, David J

    2016-01-01

    In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males. PMID:27233670

  6. Insect herbivory elicits genome-wide alternative splicing responses in Nicotiana attenuata.

    PubMed

    Ling, Zhihao; Zhou, Wenwu; Baldwin, Ian T; Xu, Shuqing

    2015-10-01

    Changes in gene expression and alternative splicing (AS) are involved in many responses to abiotic and biotic stresses in eukaryotic organisms. In response to attack and oviposition by insect herbivores, plants elicit rapid changes in gene expression which are essential for the activation of plant defenses; however, the herbivory-induced changes in AS remain unstudied. Using mRNA sequencing, we performed a genome-wide analysis on tobacco hornworm (Manduca sexta) feeding-induced AS in both leaves and roots of Nicotiana attenuata. Feeding by M. sexta for 5 h reduced total AS events by 7.3% in leaves but increased them in roots by 8.0% and significantly changed AS patterns in leaves and roots of existing AS genes. Feeding by M. sexta also resulted in increased (in roots) and decreased (in leaves) transcript levels of the serine/arginine-rich (SR) proteins that are involved in the AS machinery of plants and induced changes in SR gene expression that were jasmonic acid (JA)-independent in leaves but JA-dependent in roots. Changes in AS and gene expression elicited by M. sexta feeding were regulated independently in both tissues. This study provides genome-wide evidence that insect herbivory induces changes not only in the levels of gene expression but also in their splicing, which might contribute to defense against and/or tolerance of herbivory.

  7. A powerful test of independent assortment that determines genome-wide significance quickly and accurately

    PubMed Central

    Stewart, W C L; Hager, V R

    2016-01-01

    In the analysis of DNA sequences on related individuals, most methods strive to incorporate as much information as possible, with little or no attention paid to the issue of statistical significance. For example, a modern workstation can easily handle the computations needed to perform a large-scale genome-wide inheritance-by-descent (IBD) scan, but accurate assessment of the significance of that scan is often hindered by inaccurate approximations and computationally intensive simulation. To address these issues, we developed gLOD—a test of co-segregation that, for large samples, models chromosome-specific IBD statistics as a collection of stationary Gaussian processes. With this simple model, the parametric bootstrap yields an accurate and rapid assessment of significance—the genome-wide corrected P-value. Furthermore, we show that (i) under the null hypothesis, the limiting distribution of the gLOD is the standard Gumbel distribution; (ii) our parametric bootstrap simulator is approximately 40 000 times faster than gene-dropping methods, and it is more powerful than methods that approximate the adjusted P-value; and, (iii) the gLOD has the same statistical power as the widely used maximum Kong and Cox LOD. Thus, our approach gives researchers the ability to determine quickly and accurately the significance of most large-scale IBD scans, which may contain multiple traits, thousands of families and tens of thousands of DNA sequences. PMID:27245422

  8. Genome-wide association study of drought-related resistance traits in Aegilops tauschii

    PubMed Central

    Qin, Peng; Lin, Yu; Hu, Yaodong; Liu, Kun; Mao, Shuangshuang; Li, Zhanyi; Wang, Jirui; Liu, Yaxi; Wei, Yuming; Zheng, Youliang

    2016-01-01

    Abstract The D-genome progenitor of wheat (Triticum aestivum), Aegilops tauschii, possesses numerous genes for resistance to abiotic stresses, including drought. Therefore, information on the genetic architecture of A. tauschii can aid the development of drought-resistant wheat varieties. Here, we evaluated 13 traits in 373 A. tauschii accessions grown under normal and polyethylene glycol-simulated drought stress conditions and performed a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers. We identified 208 and 28 SNPs associated with all traits using the general linear model and mixed linear model, respectively, while both models detected 25 significant SNPs with genome-wide distribution. Public database searches revealed several candidate/flanking genes related to drought resistance that were grouped into three categories according to the type of encoded protein (enzyme, storage protein, and drought-induced protein). This study provided essential information for SNPs and genes related to drought resistance in A. tauschii and wheat, and represents a foundation for breeding drought-resistant wheat cultivars using marker-assisted selection. PMID:27560650

  9. Genome-wide characterization of microsatellites in Triticeae species: abundance, distribution and evolution

    PubMed Central

    Deng, Pingchuan; Wang, Meng; Feng, Kewei; Cui, Licao; Tong, Wei; Song, Weining; Nie, Xiaojun

    2016-01-01

    Microsatellites are an important constituent of plant genome and distributed across entire genome. In this study, genome-wide analysis of microsatellites in 8 Triticeae species and 9 model plants revealed that microsatellite characteristics were similar among the Triticeae species. Furthermore, genome-wide microsatellite markers were designed in wheat and then used to analyze the evolutionary relationship of wheat and other Triticeae species. Results displayed that Aegilops tauschii was found to be the closest species to Triticum aestivum, followed by Triticum urartu, Triticum turgidum and Aegilops speltoides, while Triticum monococcum, Aegilops sharonensis and Hordeum vulgare showed a relatively lower PCR amplification effectivity. Additionally, a significantly higher PCR amplification effectivity was found in chromosomes at the same subgenome than its homoeologous when these markers were subjected to search against different chromosomes in wheat. After a rigorous screening process, a total of 20,666 markers showed high amplification and polymorphic potential in wheat and its relatives, which were integrated with the public available wheat markers and then anchored to the genome of wheat (CS). This study not only provided the useful resource for SSR markers development in Triticeae species, but also shed light on the evolution of polyploid wheat from the perspective of microsatellites. PMID:27561724

  10. Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study

    PubMed Central

    Roberts, Chrissy h.; Franklin, Christopher S.; Makalo, Pateh; Joof, Hassan; Sarr, Isatou; Mahdi, Olaimatu S.; Sillah, Ansumana; Bah, Momodou; Payne, Felicity; Jeffreys, Anna E.; Bottomley, William; Natividad, Angels; Molina-Gonzalez, Sandra; Burr, Sarah E.; Preston, Mark; Kwiatkowski, Dominic; Rockett, Kirk A.; Clark, Taane G.; Burton, Matthew J.; Mabey, David C. W.; Bailey, Robin; Barroso, Inês; Holland, Martin J.

    2015-01-01

    Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 × 10−6 > P > 5 × 10−8). The most strongly associated SNP (rs111513399, P = 5.38 × 10−7) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling. PMID:26616738

  11. Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

    PubMed

    Gottlieb, D J; Hek, K; Chen, T-H; Watson, N F; Eiriksdottir, G; Byrne, E M; Cornelis, M; Warby, S C; Bandinelli, S; Cherkas, L; Evans, D S; Grabe, H J; Lahti, J; Li, M; Lehtimäki, T; Lumley, T; Marciante, K D; Pérusse, L; Psaty, B M; Robbins, J; Tranah, G J; Vink, J M; Wilk, J B; Stafford, J M; Bellis, C; Biffar, R; Bouchard, C; Cade, B; Curhan, G C; Eriksson, J G; Ewert, R; Ferrucci, L; Fülöp, T; Gehrman, P R; Goodloe, R; Harris, T B; Heath, A C; Hernandez, D; Hofman, A; Hottenga, J-J; Hunter, D J; Jensen, M K; Johnson, A D; Kähönen, M; Kao, L; Kraft, P; Larkin, E K; Lauderdale, D S; Luik, A I; Medici, M; Montgomery, G W; Palotie, A; Patel, S R; Pistis, G; Porcu, E; Quaye, L; Raitakari, O; Redline, S; Rimm, E B; Rotter, J I; Smith, A V; Spector, T D; Teumer, A; Uitterlinden, A G; Vohl, M-C; Widen, E; Willemsen, G; Young, T; Zhang, X; Liu, Y; Blangero, J; Boomsma, D I; Gudnason, V; Hu, F; Mangino, M; Martin, N G; O'Connor, G T; Stone, K L; Tanaka, T; Viikari, J; Gharib, S A; Punjabi, N M; Räikkönen, K; Völzke, H; Mignot, E; Tiemeier, H

    2015-10-01

    Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

  12. Development and application of a novel genome-wide SNP array reveals domestication history in soybean.

    PubMed

    Wang, Jiao; Chu, Shanshan; Zhang, Huairen; Zhu, Ying; Cheng, Hao; Yu, Deyue

    2016-02-09

    Domestication of soybeans occurred under the intense human-directed selections aimed at developing high-yielding lines. Tracing the domestication history and identifying the genes underlying soybean domestication require further exploration. Here, we developed a high-throughput NJAU 355 K SoySNP array and used this array to study the genetic variation patterns in 367 soybean accessions, including 105 wild soybeans and 262 cultivated soybeans. The population genetic analysis suggests that cultivated soybeans have tended to originate from northern and central China, from where they spread to other regions, accompanied with a gradual increase in seed weight. Genome-wide scanning for evidence of artificial selection revealed signs of selective sweeps involving genes controlling domestication-related agronomic traits including seed weight. To further identify genomic regions related to seed weight, a genome-wide association study (GWAS) was conducted across multiple environments in wild and cultivated soybeans. As a result, a strong linkage disequilibrium region on chromosome 20 was found to be significantly correlated with seed weight in cultivated soybeans. Collectively, these findings should provide an important basis for genomic-enabled breeding and advance the study of functional genomics in soybean.

  13. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects

    PubMed Central

    Ramachandran, Dhanya; Zeng, Zhen; Locke, Adam E.; Mulle, Jennifer G.; Bean, Lora J.H.; Rosser, Tracie C.; Dooley, Kenneth J.; Cua, Clifford L.; Capone, George T.; Reeves, Roger H.; Maslen, Cheryl L.; Cutler, David J.; Feingold, Eleanor; Sherman, Stephanie L.; Zwick, Michael E.

    2015-01-01

    The goal of this study was to identify the contribution of common genetic variants to Down syndrome−associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome−associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population. PMID:26194203

  14. Genome-Wide High-Resolution Mapping by Recurrent Intermating Using Arabidopsis Thaliana as a Model

    PubMed Central

    Liu, S. C.; Kowalski, S. P.; Lan, T. H.; Feldmann, K. A.; Paterson, A. H.

    1996-01-01

    We demonstrate a method for developing populations suitable for genome-wide high-resolution genetic linkage mapping, by recurrent intermating among F(2) individuals derived from crosses between homozygous parents. Comparison of intermated progenies to F(2) and ``recombinant inbred'' (RI) populations from the same pedigree corroborate theoretical expectations that progenies intermated for four generations harbor about threefold more information for estimating recombination fraction between closely linked markers than either RI-selfed or F(2) individuals (which are, in fact, equivalent in this regard). Although intermated populations are heterozygous, homozygous ``intermated recombinant inbred'' (IRI) populations can readily be generated, combining additional information afforded by intermating with the permanence of RI populations. Intermated populations permit fine-mapping of genetic markers throughout a genome, helping to bridge the gap between genetic map resolution and the DNA-carrying capacity of modern cloning vectors, thus facilitating merger of genetic and physical maps. Intermating can also facilitate high-resolution mapping of genes and QTLs, accelerating map-based cloning. Finally, intermated populations will facilitate investigation of other fundamental genetic questions requiring a genome-wide high-resolution analysis, such as comparative mapping of distantly related species, and the genetic basis of heterosis. PMID:8770602

  15. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese.

    PubMed

    Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

    2015-05-13

    Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

  16. Genome-Wide Microsatellite Characterization and Marker Development in the Sequenced Brassica Crop Species

    PubMed Central

    Shi, Jiaqin; Huang, Shunmou; Zhan, Jiepeng; Yu, Jingyin; Wang, Xinfa; Hua, Wei; Liu, Shengyi; Liu, Guihua; Wang, Hanzhong

    2014-01-01

    Although much research has been conducted, the pattern of microsatellite distribution has remained ambiguous, and the development/utilization of microsatellite markers has still been limited/inefficient in Brassica, due to the lack of genome sequences. In view of this, we conducted genome-wide microsatellite characterization and marker development in three recently sequenced Brassica crops: Brassica rapa, Brassica oleracea and Brassica napus. The analysed microsatellite characteristics of these Brassica species were highly similar or almost identical, which suggests that the pattern of microsatellite distribution is likely conservative in Brassica. The genomic distribution of microsatellites was highly non-uniform and positively or negatively correlated with genes or transposable elements, respectively. Of the total of 115 869, 185 662 and 356 522 simple sequence repeat (SSR) markers developed with high frequencies (408.2, 343.8 and 356.2 per Mb or one every 2.45, 2.91 and 2.81 kb, respectively), most represented new SSR markers, the majority had determined physical positions, and a large number were genic or putative single-locus SSR markers. We also constructed a comprehensive database for the newly developed SSR markers, which was integrated with public Brassica SSR markers and annotated genome components. The genome-wide SSR markers developed in this study provide a useful tool to extend the annotated genome resources of sequenced Brassica species to genetic study/breeding in different Brassica species. PMID:24130371

  17. Genome-Wide Analysis of Acute Endurance Exercise-Induced Translational Regulation in Mouse Skeletal Muscle

    PubMed Central

    Sako, Hiroaki; Yada, Koichi; Suzuki, Katsuhiko

    2016-01-01

    Exercise dynamically changes skeletal muscle protein synthesis to respond and adapt to the external and internal stimuli. Many studies have focused on overall protein synthesis to understand how exercise regulates the muscular adaptation. However, despite the probability that each gene transcript may have its own unique translational characteristics and would be differentially regulated at translational level, little attention has been paid to how exercise affects translational regulation of individual genes at a genome-wide scale. Here, we conducted a genome-wide translational analysis using ribosome profiling to investigate the effect of a single bout of treadmill running (20 m/min for 60 min) on mouse gastrocnemius. Global translational profiles largely differed from those in transcription even at a basal resting condition as well as immediately after exercise. As for individual gene, Slc25a25 (Solute carrier family 25, member 25), localized in mitochondrial inner membrane and maintaining ATP homeostasis and endurance performance, showed significant up-regulation at translational level. However, multiple regression analysis suggests that Slc25a25 protein degradation may also have a role in mediating Slc25a25 protein abundance in the basal and early stages after acute endurance exercise. PMID:26845575

  18. Neuregulin-1 and schizophrenia in the genome-wide association study era.

    PubMed

    Mostaid, Md Shaki; Lloyd, David; Liberg, Benny; Sundram, Suresh; Pereira, Avril; Pantelis, Christos; Karl, Tim; Weickert, Cynthia Shannon; Everall, Ian P; Bousman, Chad A

    2016-09-01

    Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1's relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1's role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia. PMID:27283360

  19. A genome-wide association study identifies multiple loci for variation in human ear morphology.

    PubMed

    Adhikari, Kaustubh; Reales, Guillermo; Smith, Andrew J P; Konka, Esra; Palmen, Jutta; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Calderón, Rosario; Rosique, Javier; Cheeseman, Michael; Bhutta, Mahmood F; Humphries, Steve E; Gonzalez-José, Rolando; Headon, Denis; Balding, David; Ruiz-Linares, Andrés

    2015-01-01

    Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1. PMID:26105758

  20. Quantifying the heritability of glioma using genome-wide complex trait analysis

    PubMed Central

    Kinnersley, Ben; Mitchell, Jonathan S.; Gousias, Konstantinos; Schramm, Johannes; Idbaih, Ahmed; Labussière, Marianne; Marie, Yannick; Rahimian, Amithys; Wichmann, H.-Erich; Schreiber, Stefan; Hoang-Xuan, Khe; Delattre, Jean-Yves; Nöthen, Markus M.; Mokhtari, Karima; Lathrop, Mark; Bondy, Melissa; Simon, Matthias; Sanson, Marc; Houlston, Richard S.

    2015-01-01

    Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20–31%, P = 1.15 × 10−17) for all forms of glioma - 26% (95% CI: 17–35%, P = 1.05 × 10−8) for glioblastoma multiforme (GBM) and 25% (95% CI: 17–32%, P = 1.26 × 10−10) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified. PMID:26625949

  1. Genome-wide alterations of the DNA replication program during tumor progression

    NASA Astrophysics Data System (ADS)

    Arneodo, A.; Goldar, A.; Argoul, F.; Hyrien, O.; Audit, B.

    2016-08-01

    Oncogenic stress is a major driving force in the early stages of cancer development. Recent experimental findings reveal that, in precancerous lesions and cancers, activated oncogenes may induce stalling and dissociation of DNA replication forks resulting in DNA damage. Replication timing is emerging as an important epigenetic feature that recapitulates several genomic, epigenetic and functional specificities of even closely related cell types. There is increasing evidence that chromosome rearrangements, the hallmark of many cancer genomes, are intimately associated with the DNA replication program and that epigenetic replication timing changes often precede chromosomic rearrangements. The recent development of a novel methodology to map replication fork polarity using deep sequencing of Okazaki fragments has provided new and complementary genome-wide replication profiling data. We review the results of a wavelet-based multi-scale analysis of genomic and epigenetic data including replication profiles along human chromosomes. These results provide new insight into the spatio-temporal replication program and its dynamics during differentiation. Here our goal is to bring to cancer research, the experimental protocols and computational methodologies for replication program profiling, and also the modeling of the spatio-temporal replication program. To illustrate our purpose, we report very preliminary results obtained for the chronic myelogeneous leukemia, the archetype model of cancer. Finally, we discuss promising perspectives on using genome-wide DNA replication profiling as a novel efficient tool for cancer diagnosis, prognosis and personalized treatment.

  2. Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma

    PubMed Central

    Chahal, Harvind S.; Lin, Yuan; Ransohoff, Katherine J.; Hinds, David A.; Wu, Wenting; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.

    2016-01-01

    Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7–11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10−8) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma. PMID:27424798

  3. A genome-wide association study of periodontitis in a Japanese population.

    PubMed

    Shimizu, S; Momozawa, Y; Takahashi, A; Nagasawa, T; Ashikawa, K; Terada, Y; Izumi, Y; Kobayashi, H; Tsuji, M; Kubo, M; Furuichi, Y

    2015-04-01

    Periodontitis is a multifactorial disease in which bacterial, lifestyle, and genetic factors are involved. Although previous genetic association studies identified several susceptibility genes for periodontitis in European populations, there is little information for Asian populations. Here, we conducted a genome-wide association study and a replication study consisting of 2,760 Japanese periodontitis patients and 15,158 Japanese controls. Although single-nucleotide polymorphisms that surpassed a stringent genome-wide significance threshold (P < 5 × 10(-8)) were not identified, we found 2 suggestive loci for periodontitis: KCNQ5 on chromosome 6q13 (rs9446777, P = 4.83 × 10(-6), odds ratio = 0.82) and GPR141-NME8 at chromosome 7p14.1 (rs2392510, P = 4.17 × 10(-6), odds ratio = 0.87). A stratified analysis indicated that the GPR141-NME8 locus had a strong genetic effect on the susceptibility to generalized periodontitis in Japanese individuals with a history of smoking. In conclusion, this study identified 2 suggestive loci for periodontitis in a Japanese population. This study should contribute to a further understanding of genetic factors for enhanced susceptibility to periodontitis.

  4. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes.

    PubMed

    Vacic, Vladimir; Ozelius, Laurie J; Clark, Lorraine N; Bar-Shira, Anat; Gana-Weisz, Mali; Gurevich, Tanya; Gusev, Alexander; Kedmi, Merav; Kenny, Eimear E; Liu, Xinmin; Mejia-Santana, Helen; Mirelman, Anat; Raymond, Deborah; Saunders-Pullman, Rachel; Desnick, Robert J; Atzmon, Gil; Burns, Edward R; Ostrer, Harry; Hakonarson, Hakon; Bergman, Aviv; Barzilai, Nir; Darvasi, Ariel; Peter, Inga; Guha, Saurav; Lencz, Todd; Giladi, Nir; Marder, Karen; Pe'er, Itsik; Bressman, Susan B; Orr-Urtreger, Avi

    2014-09-01

    The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts. PMID:24842889

  5. A powerful test of independent assortment that determines genome-wide significance quickly and accurately.

    PubMed

    Stewart, W C L; Hager, V R

    2016-08-01

    In the analysis of DNA sequences on related individuals, most methods strive to incorporate as much information as possible, with little or no attention paid to the issue of statistical significance. For example, a modern workstation can easily handle the computations needed to perform a large-scale genome-wide inheritance-by-descent (IBD) scan, but accurate assessment of the significance of that scan is often hindered by inaccurate approximations and computationally intensive simulation. To address these issues, we developed gLOD-a test of co-segregation that, for large samples, models chromosome-specific IBD statistics as a collection of stationary Gaussian processes. With this simple model, the parametric bootstrap yields an accurate and rapid assessment of significance-the genome-wide corrected P-value. Furthermore, we show that (i) under the null hypothesis, the limiting distribution of the gLOD is the standard Gumbel distribution; (ii) our parametric bootstrap simulator is approximately 40 000 times faster than gene-dropping methods, and it is more powerful than methods that approximate the adjusted P-value; and, (iii) the gLOD has the same statistical power as the widely used maximum Kong and Cox LOD. Thus, our approach gives researchers the ability to determine quickly and accurately the significance of most large-scale IBD scans, which may contain multiple traits, thousands of families and tens of thousands of DNA sequences.

  6. Genome-wide association study of antipsychotic-induced QTc interval prolongation.

    PubMed

    Aberg, K; Adkins, D E; Liu, Y; McClay, J L; Bukszár, J; Jia, P; Zhao, Z; Perkins, D; Stroup, T S; Lieberman, J A; Sullivan, P F; van den Oord, E J C G

    2012-04-01

    QT prolongation is associated with increased risk of cardiac arrhythmias. Identifying the genetic variants that mediate antipsychotic-induced prolongation may help to minimize this risk, which might prevent the removal of efficacious drugs from the market. We performed candidate gene analysis and five drug-specific genome-wide association studies (GWASs) with 492K single-nucleotide polymorphisms to search for genetic variation mediating antipsychotic-induced QT prolongation in 738 schizophrenia patients from the Clinical Antipsychotic Trial of Intervention Effectiveness study. Our candidate gene study suggests the involvement of NOS1AP and NUBPL (P-values=1.45 × 10(-05) and 2.66 × 10(-13), respectively). Furthermore, our top GWAS hit achieving genome-wide significance, defined as a Q-value <0.10 (P-value=1.54 × 10(-7), Q-value=0.07), located in SLC22A23, mediated the effects of quetiapine on prolongation. SLC22A23 belongs to a family of organic ion transporters that shuttle a variety of compounds, including drugs, environmental toxins and endogenous metabolites, across the cell membrane. This gene is expressed in the heart and is integral in mouse heart development. The genes mediating antipsychotic-induced QT prolongation partially overlap with the genes affecting normal QT interval variation. However, some genes may also be unique for drug-induced prolongation. This study demonstrates the potential of GWAS to discover genes and pathways that mediate antipsychotic-induced QT prolongation.

  7. Genome-Wide Identification of Susceptibility Alleles for Viral Infections through a Population Genetics Approach

    PubMed Central

    Fumagalli, Matteo; Pozzoli, Uberto; Cagliani, Rachele; Comi, Giacomo P.; Bresolin, Nereo

    2010-01-01

    Viruses have exerted a constant and potent selective pressure on human genes throughout evolution. We utilized the marks left by selection on allele frequency to identify viral infection-associated allelic variants. Virus diversity (the number of different viruses in a geographic region) was used to measure virus-driven selective pressure. Results showed an excess of variants correlated with virus diversity in genes involved in immune response and in the biosynthesis of glycan structures functioning as viral receptors; a significantly higher than expected number of variants was also seen in genes encoding proteins that directly interact with viral components. Genome-wide analyses identified 441 variants significantly associated with virus-diversity; these are more frequently located within gene regions than expected, and they map to 139 human genes. Analysis of functional relationships among genes subjected to virus-driven selective pressure identified a complex network enriched in viral products-interacting proteins. The novel approach to the study of infectious disease epidemiology presented herein may represent an alternative to classic genome-wide association studies and provides a large set of candidate susceptibility variants for viral infections. PMID:20174570

  8. Genome-wide association study of leukotriene modifier response in asthma.

    PubMed

    Dahlin, A; Litonjua, A; Irvin, C G; Peters, S P; Lima, J J; Kubo, M; Tamari, M; Tantisira, K G

    2016-04-01

    Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene-environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV1) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10(-08)); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV1 following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10(-07)). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs. PMID:26031901

  9. Genome-wide association study for feedlot average daily gain in Nellore cattle (Bos indicus).

    PubMed

    Santana, M H A; Utsunomiya, Y T; Neves, H H R; Gomes, R C; Garcia, J F; Fukumasu, H; Silva, S L; Leme, P R; Coutinho, L L; Eler, J P; Ferraz, J B S

    2014-06-01

    The genome-wide association study (GWAS) results are presented for average daily gain (ADG) in Nellore cattle. Phenotype of 720 male Bos indicus animals with information of ADG in feedlots and 354,147 single-nucleotide polymorphisms (SNPs) obtained from a database added by information from Illumina Bovine HD (777,962 SNPs) and Illumina BovineSNP50 (54,609) by imputation were used. After quality control and imputation, 290,620 SNPs remained in the association analysis, using R package Genome-wide Rapid Association using Mixed Model and Regression method GRAMMAR-Gamma. A genomic region with six significant SNPs, at Bonferroni-corrected significance, was found on chromosome 3. The most significant SNP (rs42518459, BTA3: 85849977, p = 9.49 × 10(-8)) explained 5.62% of the phenotypic variance and had the allele substitution effect of -0.269 kg/day. Important genes such as PDE4B, LEPR, CYP2J2 and FGGY are located near this region, which is overlapped by 12 quantitative trait locus (QTLs) described for several production traits. Other regions with markers with suggestive effects were identified in BTA6 and BTA10. This study showed regions with major effects on ADG in Bos indicus in feedlots. This information may be useful to increase the efficiency of selecting this trait and to understand the physiological processes involved in its regulation.

  10. Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas

    PubMed Central

    Deitz, Kevin C.; Athrey, Giridhar A.; Jawara, Musa; Overgaard, Hans J.; Matias, Abrahan; Slotman, Michel A.

    2016-01-01

    Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq) from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression. PMID:27466271

  11. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

    PubMed Central

    Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter HL; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

    2016-01-01

    Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. DOI: http://dx.doi.org/10.7554/eLife.10557.001 PMID:27162171

  12. Genome-Wide DNA Methylation in Mixed Ancestry Individuals with Diabetes and Prediabetes from South Africa

    PubMed Central

    Pheiffer, Carmen; Humphries, Stephen E.; Gamieldien, Junaid; Erasmus, Rajiv T.

    2016-01-01

    Aims. To conduct a genome-wide DNA methylation in individuals with type 2 diabetes, individuals with prediabetes, and control mixed ancestry individuals from South Africa. Methods. We used peripheral blood to perform genome-wide DNA methylation analysis in 3 individuals with screen detected diabetes, 3 individuals with prediabetes, and 3 individuals with normoglycaemia from the Bellville South Community, Cape Town, South Africa, who were age-, gender-, body mass index-, and duration of residency-matched. Methylated DNA immunoprecipitation (MeDIP) was performed by Arraystar Inc. (Rockville, MD, USA). Results. Hypermethylated DMRs were 1160 (81.97%) and 124 (43.20%), respectively, in individuals with diabetes and prediabetes when both were compared to subjects with normoglycaemia. Our data shows that genes related to the immune system, signal transduction, glucose transport, and pancreas development have altered DNA methylation in subjects with prediabetes and diabetes. Pathway analysis based on the functional analysis mapping of genes to KEGG pathways suggested that the linoleic acid metabolism and arachidonic acid metabolism pathways are hypomethylated in prediabetes and diabetes. Conclusions. Our study suggests that epigenetic changes are likely to be an early process that occurs before the onset of overt diabetes. Detailed analysis of DMRs that shows gradual methylation differences from control versus prediabetes to prediabetes versus diabetes in a larger sample size is required to confirm these findings. PMID:27555869

  13. Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects.

    PubMed

    Ramachandran, Dhanya; Zeng, Zhen; Locke, Adam E; Mulle, Jennifer G; Bean, Lora J H; Rosser, Tracie C; Dooley, Kenneth J; Cua, Clifford L; Capone, George T; Reeves, Roger H; Maslen, Cheryl L; Cutler, David J; Feingold, Eleanor; Sherman, Stephanie L; Zwick, Michael E

    2015-07-20

    The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared with the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this increased risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background by using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio >2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population.

  14. Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis

    PubMed Central

    Shen, Jing; Wang, Shuang; Siegel, Abby B.; Remotti, Helen; Wang, Qiao; Sirosh, Iryna; Santella, Regina M.

    2015-01-01

    Background. Previous studies, including ours, have examined the regulation of microRNAs (miRNAs) by DNA methylation, but whether this regulation occurs at a genome-wide level in hepatocellular carcinoma (HCC) is unclear. Subjects/Methods. Using a two-phase study design, we conducted genome-wide screening for DNA methylation and miRNA expression to explore the potential role of methylation alterations in miRNAs regulation. Results. We found that expressions of 25 miRNAs were statistically significantly different between tumor and nontumor tissues and perfectly differentiated HCC tumor from nontumor. Six miRNAs were overexpressed, and 19 were repressed in tumors. Among 133 miRNAs with inverse correlations between methylation and expression, 8 miRNAs (6%) showed statistically significant differences in expression between tumor and nontumor tissues. Six miRNAs were validated in 56 additional paired HCC tissues, and significant inverse correlations were observed for miR-125b and miR-199a, which is consistent with the inactive chromatin pattern found in HepG2 cells. Conclusion. These data suggest that the expressions of miR-125b and miR-199a are dramatically regulated by DNA hypermethylation that plays a key role in hepatocarcinogenesis. PMID:25861255

  15. The genetics of loneliness: linking evolutionary theory to genome-wide genetics, epigenetics, and social science.

    PubMed

    Goossens, Luc; van Roekel, Eeske; Verhagen, Maaike; Cacioppo, John T; Cacioppo, Stephanie; Maes, Marlies; Boomsma, Dorret I

    2015-03-01

    As a complex trait, loneliness is likely to be influenced by the interplay of numerous genetic and environmental factors. Studies in behavioral genetics indicate that loneliness has a sizable degree of heritability. Candidate-gene and gene-expression studies have pointed to several genes related to neurotransmitters and the immune system. The notion that these genes are related to loneliness is compatible with the basic tenets of the evolutionary theory of loneliness. Research on gene-environment interactions indicates that social-environmental factors (e.g., low social support) may have a more pronounced effect and lead to higher levels of loneliness if individuals carry the sensitive variant of these candidate genes. Currently, there is no extant research on loneliness based on genome-wide association studies, gene-environment-interaction studies, or studies in epigenetics. Such studies would allow researchers to identify networks of genes that contribute to loneliness. The contribution of genetics to loneliness research will become stronger when genome-wide genetics and epigenetics are integrated and used along with well-established methods in psychology to analyze the complex process of gene-environment interplay.

  16. Quality control and conduct of genome-wide association meta-analyses.

    PubMed

    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C; Wood, Andrew R; Locke, Adam E; Mägi, Reedik; Ferreira, Teresa; Fall, Tove; Graff, Mariaelisa; Justice, Anne E; Luan, Jian'an; Gustafsson, Stefan; Randall, Joshua C; Vedantam, Sailaja; Workalemahu, Tsegaselassie; Kilpeläinen, Tuomas O; Scherag, André; Esko, Tonu; Kutalik, Zoltán; Heid, Iris M; Loos, Ruth J F

    2014-05-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete. PMID:24762786

  17. Genome-wide association study of behavioral disinhibition in a selected adolescent sample

    PubMed Central

    Derringer, Jaime; Corley, Robin P.; Haberstick, Brett C.; Young, Susan E.; Demmitt, Brittany; Howrigan, Daniel P.; Kirkpatrick, Robert M.; Iacono, William G.; McGue, Matt; Keller, Matthew; Brown, Sandra; Tapert, Susan; Hopfer, Christian J.; Stallings, Michael C.; Crowley, Thomas J.; Rhee, Soo Hyun; Krauter, Ken; Hewitt, John K.; McQueen, Matthew B.

    2015-01-01

    Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3% of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p=0.06). Gene-based tests identified seven genes associated with BD (p≤2.0×10−6). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD. PMID:25637581

  18. Genome-wide association study identifies 74 loci associated with educational attainment.

    PubMed

    Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

    2016-05-26

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy