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Pathway and network-based analysis of genome-wide association studies in multiple sclerosis

Baranzini, Sergio E.; Galwey, Nicholas W.; Wang, Joanne; Khankhanian, Pouya; Lindberg, Raija; Pelletier, Daniel; Wu, Wen; Uitdehaag, Bernard M.J.; Kappos, Ludwig; ; Polman, Chris H.; Matthews, Paul M.; Hauser, Stephen L.; Gibson, Rachel A.; Oksenberg, Jor
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
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Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets...

Genome-Wide Association Study of Circulating Estradiol, Testosterone, and Sex Hormone-Binding Globulin in Postmenopausal Women

Thompson, Deborah J.; Chanock, Stephen J.; Audley, Tina; Brown, Judith; Leyland, Jean; Folkerd, Elizabeth; Doody, Deborah; Jacobs, Kevin B.; Dowsett, Mitch; Easton, Douglas F.; Prescott, Jennifer; Kraft, Peter; Hankinson, Susan Elizabeth; Hunter, David J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses’ Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ∼1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint (eta) = -0.126; joint P = 2.09×10–16), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10–5)...

Genome-Wide Association Study in a Lebanese Cohort Confirms PHACTR1 as a Major Determinant of Coronary Artery Stenosis

Hager, Jörg; Kamatani, Yoichiro; Cazier, Jean-Baptiste; Youhanna, Sonia; Ghassibe-Sabbagh, Michella; Platt, Daniel E.; Abchee, Antoine B.; Romanos, Jihane; Khazen, Georges; Othman, Raed; Badro, Danielle A.; Haber, Marc; Salloum, Angelique K.; Douaihy, Bo
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10−5). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10−6), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10−10). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.

Multi-Locus Genome-Wide Association Analysis Supports the Role of Glutamatergic Synaptic Transmission in the Etiology of Major Depressive Disorder

Lee, Phil Hyoun; Perlis, Roy H.; Jung, Jae-Yoon; Byrne, Enda M.; Haddad, Stephen; Rueckert, Erroll; Siburian, Richie; Mayerfeld, Catherine E.; Heath, Andrew C.; Pergadia, Michele L.; Madden, Pamela A.F.; Boomsma, Dorret I.; Penninx, Brenda W.; Sklar, Pame
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN_US
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Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N=4346 cases and 4430 controls). After correction for multiple testing...

Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene

Sheppard, Keith; Berndt, Annerose; Leme, Adriana S.; Myers, Rachel A.; Gignoux, Christopher R.; Gauderman, W. James; Yang, James J.; Mathias, Rasika A.; Romieu, Isabelle; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Klanderman, Bar
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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116.12%
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04)...

Using eQTL weights to improve power for genome-wide association studies: a genetic study of childhood asthma

Li, Lin; Kabesch, Michael; Bouzigon, Emmanuelle; Demenais, Florence; Farrall, Martin; Moffatt, Miriam F.; Lin, Xihong; Liang, Liming
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
EN_US
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Increasing evidence suggests that single nucleotide polymorphisms (SNPs) associated with complex traits are more likely to be expression quantitative trait loci (eQTLs). Incorporating eQTL information hence has potential to increase power of genome-wide association studies (GWAS). In this paper, we propose using eQTL weights as prior information in SNP based association tests to improve test power while maintaining control of the family-wise error rate (FWER) or the false discovery rate (FDR). We apply the proposed methods to the analysis of a GWAS for childhood asthma consisting of 1296 unrelated individuals with German ancestry. The results confirm that eQTLs are enriched for previously reported asthma SNPs. We also find that some SNPs are insignificant using procedures without eQTL weighting, but become significant using eQTL-weighted Bonferroni or Benjamini–Hochberg procedures, while controlling the same FWER or FDR level. Some of these SNPs have been reported by independent studies in recent literature. The results suggest that the eQTL-weighted procedures provide a promising approach for improving power of GWAS. We also report the results of our methods applied to the large-scale European GABRIEL consortium data.

Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

Liu, Ching-Ti; Monda, Keri L.; Taylor, Kira C.; Lange, Leslie; Demerath, Ellen W.; Palmas, Walter; Wojczynski, Mary K.; Ellis, Jaclyn C.; Vitolins, Mara Z.; Liu, Simin; Papanicolaou, George J.; Irvin, Marguerite R.; Xue, Luting; Griffin, Paula J.; Nalls,
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2...

Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis

Bunyavanich, Supinda; Schadt, Eric E; Himes, Blanca E; Lasky-Su, Jessica; Qiu, Weiliang; Lazarus, Ross; Ziniti, John P; Cohain, Ariella; Linderman, Michael; Torgerson, Dara G; Eng, Celeste S; Pino-Yanes, Maria; Padhukasahasram, Badri; Yang, James J; Mathi
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
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Background: Allergic rhinitis is a common disease whose genetic basis is incompletely explained. We report an integrated genomic analysis of allergic rhinitis. Methods: We performed genome wide association studies (GWAS) of allergic rhinitis in 5633 ethnically diverse North American subjects. Next, we profiled gene expression in disease-relevant tissue (peripheral blood CD4+ lymphocytes) collected from subjects who had been genotyped. We then integrated the GWAS and gene expression data using expression single nucleotide (eSNP), coexpression network, and pathway approaches to identify the biologic relevance of our GWAS. Results: GWAS revealed ethnicity-specific findings, with 4 genome-wide significant loci among Latinos and 1 genome-wide significant locus in the GWAS meta-analysis across ethnic groups. To identify biologic context for these results, we constructed a coexpression network to define modules of genes with similar patterns of CD4+ gene expression (coexpression modules) that could serve as constructs of broader gene expression. 6 of the 22 GWAS loci with P-value ≤ 1x10−6 tagged one particular coexpression module (4.0-fold enrichment, P-value 0.0029), and this module also had the greatest enrichment (3.4-fold enrichment...

Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the Generation R Study

Medina-Gomez, Carolina; Felix, Janine Frédérique; Estrada, Karol; Peters, Marjoline Josephine; Herrera, Lizbeth; Kruithof, Claudia Jeanette; Duijts, Liesbeth; Hofman, Albert; van Duijn, Cornelia Marja; Uitterlinden, Andreas Gerardus; Jaddoe, Vincent Wil
Fonte: Springer Netherlands Publicador: Springer Netherlands
Tipo: Artigo de Revista Científica
EN_US
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Genome-wide association studies (GWAS) have been successful in identifying loci associated with a wide range of complex human traits and diseases. Up to now, the majority of GWAS have focused on European populations. However, the inclusion of other ethnic groups as well as admixed populations in GWAS studies is rapidly rising following the pressing need to extrapolate findings to non-European populations and to increase statistical power. In this paper, we describe the methodological steps surrounding genetic data generation, quality control, study design and analytical procedures needed to run GWAS in the multiethnic and highly admixed Generation R Study, a large prospective birth cohort in Rotterdam, the Netherlands. Furthermore, we highlight a number of practical considerations and alternatives pertinent to the quality control and analysis of admixed GWAS data. Electronic supplementary material The online version of this article (doi:10.1007/s10654-015-9998-4) contains supplementary material, which is available to authorized users.

Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

Correia, Catarina; Diekmann, Yoan; Vicente, Astrid; Pereira-Leal, José
Fonte: MDPI Publicador: MDPI
Tipo: Artigo de Revista Científica
Publicado em 29/09/2014 ENG
Relevância na Pesquisa
116.03%
Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability...

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em /02/2015 ENG
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Erratum in: Corrigendum: Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. [Nat Neurosci. 2015]; Astrid M Vicente - Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium; Disponível em texto integral em: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25599223/; Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

Correia, C.; Diekmann, Y.; Vicente, A.M.; Pereira-Leal, J.B.
Fonte: Molecular Diversity Preservation International (MDPI) Publicador: Molecular Diversity Preservation International (MDPI)
Tipo: Artigo de Revista Científica
Publicado em /09/2014 ENG
Relevância na Pesquisa
116.03%
Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability...

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function

Tang, W.; Kowgier, M.; Loth, D.W.; Soler Artigas, M.; Joubert, B.R.; Hodge, E.; Gharib, S.A.; Smith, A.V.; Ruczinski, I.; Gudnason, V.; Mathias, R.A.; Harris, T.B.; Hansel, N.N.; Launer, L.J.; Barnes, K.C.; Hansen, J.G.; Albrecht, E.; Aldrich, M.C.; Aller
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
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126.08%
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16...

Moving into a new era of periodontal genetic studies: relevance of large case-control samples using severe phenotypes for genome-wide association studies

Vaithilingam, R.D.; Safii, S.H.; Baharuddin, N.A.; Ng, C.C.; Cheong, S.C.; Bartold, P.M.; Schaefer, A.S.; Loos, B.G.
Fonte: John Wiley Publicador: John Wiley
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
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Studies to elucidate the role of genetics as a risk factor for periodontal disease have gone through various phases. In the majority of cases, the initial 'hypothesis-dependent' candidate-gene polymorphism studies did not report valid genetic risk loci. Following a large-scale replication study, these initially positive results are believed to be caused by type 1 errors. However, susceptibility genes, such as CDKN2BAS (Cyclin Dependend KiNase 2B AntiSense RNA; alias ANRIL [ANtisense Rna In the Ink locus]), glycosyltransferase 6 domain containing 1 (GLT6D1) and cyclooxygenase 2 (COX2), have been reported as conclusive risk loci of periodontitis. The search for genetic risk factors accelerated with the advent of 'hypothesis-free' genome-wide association studies (GWAS). However, despite many different GWAS being performed for almost all human diseases, only three GWAS on periodontitis have been published - one reported genome-wide association of GLT6D1 with aggressive periodontitis (a severe phenotype of periodontitis), whereas the remaining two, which were performed on patients with chronic periodontitis, were not able to find significant associations. This review discusses the problems faced and the lessons learned from the search for genetic risk variants of periodontitis. Current and future strategies for identifying genetic variance in periodontitis...

Using Family-Based Imputation in Genome-Wide Association Studies with Large Complex Pedigrees: The Framingham Heart Study

Chen, Ming-Huei; Huang, Jie; Chen, Wei-Min; Larson, Martin G.; Fox, Caroline; Vasan, Ramachandran S.; Seshadri, Sudha; O'Donnell, Christopher Joseph; Yang, Qiong
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with ≥60% SNP- and ≥50% person-specific imputation certainty. In summary...

Genome-Wide Association Study of Retinopathy in Individuals Without Diabetes

Jensen, Richard A.; Sim, Xueling; Li, Xiaohui; Cotch, Mary Frances; Ikram, M. Kamran; Holliday, Elizabeth G.; Eiriksdottir, Gudny; Harris, Tamara B.; Jonasson, Fridbert; Klein, Barbara E. K.; Launer, Lenore J.; Smith, Albert Vernon; Boerwinkle, Eric; Cheu
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
116.07%
Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), \(p = 6.6×10^{-9}\). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%)...

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

Chasman, Daniel I.; Fuchsberger, Christian; Pattaro, Cristian; Teumer, Alexander; Böger, Carsten A.; Endlich, Karlhans; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Clau
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
116.02%
In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4–2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance...

easyGWAS: An Integrated Computational Framework for Advanced Genome-Wide Association Studies

Grimm, Dominik Gerhard
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
EN
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126.11%
Recent advances in sequencing technologies have made it possible for the first time to sequence and analyse the genomes of whole populations of individuals in both a cost-effective manner and in a reasonable amount of time. One of the primary applications of this data is to better understand and investigate the genetic basis of common traits or diseases. For this purpose, genome-wide association studies (GWASs) are often used to find loci that are associated with a phenotype of interest. However, conducting GWASs is a challenging endeavour: first, different types of hidden confounding factors, such as population structure, environmental or technical influences, could lead to spurious associations. Second, it has been shown in several studies that associated loci often fail to explain much of the phenotypic variability — a phenomenon referred to as the problem of missing heritability. Many tools have been developed to partly address these challenges. The large diversity of these tools, however, have led to a highly fragmented and confusing landscape of tools. In addition, most of these tools do not share a common data format and do not provide straightforward solutions to visualise and annotate their results. In this thesis...

Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

Correia, Catarina; Diekmann, Yoan; Vicente, Astrid; Pereira-Leal, José
Fonte: MDPI AG Publicador: MDPI AG
Tipo: Artigo de Revista Científica
Publicado em 29/09/2014 ENG
Relevância na Pesquisa
116.03%
Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability...

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex-hormone-related phenotypes

Ruth, Katherine S.; Campbell, Purdey J.; Chew, Shelby; Lim, Ee Mun; Hadlow, Narelle; Stuckey, Bronwyn G. A.; Brown, Suzanne J.; Feenstra, Bjarke; Joseph, John; Surdulescu, Gabriela L.; Zheng, Hou Feng; Richards, J. Brent; Murray, Anna; Spector, Tim D.; Wi
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Article; published version
EN
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This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ejhg.2015.102; Genetic factors contribute strongly to sex-hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2,913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardized for age, sex, BMI, stage of menstrual cycle, and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex-hormone binding globulin and t 47 estosterone. Eight independent genetic variants reached genome-wide significance (p<5?10^-8)...