scholarly journals Investigating the genetic architecture of eye colour in a Canadian cohort

2021 ◽  
Author(s):  
Frida Lona-Durazo ◽  
Rohit Thakur ◽  
Erola Pairo-Castineira ◽  
Karen Funderburk ◽  
Tongwu Zhang ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
European Ancestry ◽  
Chromosome 15 ◽  
Genome Wide Association Studies ◽  
Eye Colour ◽  
Causal Variants ◽  
Genome Level

The main factors that determine eye colour are the amount of melanin concentrated in iris melanocytes, as well as the shape and distribution of melanosomes. Eye colour is highly variable in populations with European ancestry, in which eye colour categories cover a continuum of low to high quantities of melanin accumulated in the iris. A few polymorphisms in the HERC2/OCA2 locus in chromosome 15 have the largest effect on eye colour in these populations, although there is evidence of other variants in the locus and across the genome also influencing eye colour. To improve our understanding of the genetic loci determining eye colour, we performed a meta-analysis of genome-wide association studies in a Canadian cohort of European ancestry (N= 5,641) and investigated putative causal variants. Our fine-mapping results indicate that there are several candidate causal signals in the HERC2/OCA2 region, whereas other significant loci in the genome likely harbour a single causal signal (TYR, TYRP1, IRF4, SLC24A4). Furthermore, a short subset of the associated eye colour regions was colocalized with the gene expression or methylation profiles of cultured melanocytes (HERC2, OCA2), and transcriptome-wide association studies highlighted the expression of two genes associated with eye colour: SLC24A4 and OCA2. Finally, genetic correlations of eye and hair colour from the same cohort suggest high pleiotropy at the genome level, but locus-level evidence hints at several differences in the genetic architecture of both traits. Overall, we provide a better picture of how polymorphisms modulate eye colour variation, particularly in the HERC2/OCA2 locus, which may be a consequence of specific molecular processes in the iris melanocytes.

scholarly journals Sexual differences in genetic architecture in UK Biobank

2020 ◽  
Author(s):  
Elena Bernabeu ◽  
Oriol Canela-Xandri ◽  
Konrad Rawlik ◽  
Andrea Talenti ◽  
James Prendergast ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Mammalian Species ◽  
Genetic Correlations ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank

ABSTRACTSex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Gene by sex interactions (GxS) are thought to account for some of this sexual dimorphism. However, the extent and basis of these interactions are poorly understood.Here we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We also found that, in some cases, sex-agnostic GWAS efforts might be missing loci of interest, and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the dimorphism observed through sex-biased eQTL and gene-level analyses.This study marks a broad examination of the genetics of sexual dimorphism. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Our results suggest the need to consider sex-stratified analyses for future studies in order to shed light into possible sex-specific molecular mechanisms.

scholarly journals Multiethnic meta-analysis identifies new loci for pulmonary function

2017 ◽  
Author(s):  
Annah B. Wyss ◽  
Tamar Sofer ◽  
Mi Kyeong Lee ◽  
Natalie Terzikhan ◽  
Jennifer N. Nguyen ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Drug Targets ◽  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Causal Variants ◽  
Multiethnic Population ◽  
Meta Analyses

AbstractNearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

scholarly journals Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

2018 ◽  
Author(s):  
Caroline M. Nievergelt ◽  
Adam X. Maihofer ◽  
Torsten Klengel ◽  
Elizabeth G. Atkinson ◽  
Chia-Yen Chen ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Association Studies ◽  
Meta Analysis ◽  
African Ancestry ◽  
Genetic Correlations ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Post Traumatic Stress ◽  
Genome Wide

AbstractPost-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

scholarly journals Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

2021 ◽  
Author(s):  
Rachel L Kember ◽  
Rachel A. Vickers-Smith ◽  
Heng Xu ◽  
Sylvanus Toikumo ◽  
Maria Niarchou ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Opioid Use Disorder ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Opioid Use ◽  
Opioid Prescription ◽  
Genome Wide ◽  
The Cross

Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10-10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rg's) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.

scholarly journals Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects on brain

2021 ◽  
Author(s):  
Rachel Kember ◽  
Rachel Vickers-Smith ◽  
Heng Xu ◽  
Sylvanus Toikumo ◽  
Maria Niarchou ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Opioid Use Disorder ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Opioid Use ◽  
Opioid Prescription ◽  
Genome Wide ◽  
The Cross

Abstract Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide significant (GWS) loci, with replicated findings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classification of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription fills. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10−10), and a recently reported exonic variant in FURIN, we identified intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-specific analyses identified an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identified a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identified 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Significant genetic correlations (rg’s) were identified for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most significantly enriched cell type group was the central nervous system with gene-expression enrichment identified in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identified 14 loci for OUD, including 12 novel loci, some of which were ancestry specific. These findings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic.

scholarly journals A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shenping Zhou ◽  
Rongrong Ding ◽  
Fanming Meng ◽  
Xingwang Wang ◽  
Zhanwei Zhuang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Average Daily Gain ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

Trans-Ethnic Meta-Analysis of Interactions Between Genetics and Early-Life Socioeconomic Context on Memory Performance and Decline in Older Americans

2021 ◽  
Author(s):  
Jessica D Faul ◽  
Minjung Kho ◽  
Wei Zhao ◽  
Kalee E Rumfelt ◽  
Miao Yu ◽  
...  
Keyword(s):  
Parental Education ◽  
Association Studies ◽  
Memory Performance ◽  
Meta Analysis ◽  
African Ancestry ◽  
Later Life ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Multiple Testing Correction ◽  
Socioeconomic Context

Abstract Background Later-life cognitive function is influenced by genetics as well as early- and later-life socioeconomic context. However, few studies have examined the interaction between genetics and early childhood factors. Methods Using gene-based tests (interaction sequence kernel association test [iSKAT]/iSKAT optimal unified test), we examined whether common and/or rare exonic variants in 39 gene regions previously associated with cognitive performance, dementia, and related traits had an interaction with childhood socioeconomic context (parental education and financial strain) on memory performance or decline in European ancestry (EA, N = 10 468) and African ancestry (AA, N = 2 252) participants from the Health and Retirement Study. Results Of the 39 genes, 22 in EA and 19 in AA had nominally significant interactions with at least one childhood socioeconomic measure on memory performance and/or decline; however, all but one (father’s education by solute carrier family 24 member 4 [SLC24A4] in AA) were not significant after multiple testing correction (false discovery rate [FDR] < .05). In trans-ethnic meta-analysis, 2 genes interacted with childhood socioeconomic context (FDR < .05): mother’s education by membrane-spanning 4-domains A4A (MS4A4A) on memory performance, and father’s education by SLC24A4 on memory decline. Both interactions remained significant (p < .05) after adjusting for respondent’s own educational attainment, apolipoprotein-ε4 allele (APOE ε4) status, lifestyle factors, body mass index, and comorbidities. For both interactions in EA and AA, the genetic effect was stronger in participants with low parental education. Conclusions Examination of common and rare variants in genes discovered through genome-wide association studies shows that childhood context may interact with key gene regions to jointly impact later-life memory function and decline. Genetic effects may be more salient for those with lower childhood socioeconomic status.

scholarly journals GWAS of Depression Phenotypes in the Million Veteran Program and Meta-analysis in More than 1.2 Million Participants Yields 178 Independent Risk Loci

2020 ◽  
Author(s):  
Daniel F Levey ◽  
Murray B Stein ◽  
Frank R Wendt ◽  
Gita A Pathak ◽  
Hang Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Meta Analysis ◽  
African Ancestry ◽  
Genetic Correlations ◽  
Brain Regions ◽  
Self Report ◽  
European Ancestry ◽  
Causal Variants ◽  
Using Data ◽  
Genomic Risk

We report a large meta-analysis of depression using data from the Million Veteran Program (MVP), 23andMe Inc., UK Biobank, and FinnGen; including individuals of European ancestry (n=1,154,267; 340,591 cases) and African ancestry (n=59,600; 25,843 cases). We identified 223 and 233 independent SNPs associated with depression in European ancestry and transancestral analysis, respectively. Genetic correlations within the MVP cohort across electronic health records diagnosis, survey self-report of diagnosis, and a 2-item depression screen exceeded 0.81. Using transcriptome-wide association study (TWAS) we found significant associations for gene expression in several brain regions, including hypothalamus (NEGR1, p=3.19x10-25) and nucleus accumbens (DRD2, p=1.87x10-20). 178 genomic risk loci were fine-mapped to find likely causal variants. We identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our TWAS, including TRAF3. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

scholarly journals Genome-Wide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy

2020 ◽  
Author(s):  
Katherina C. Chua ◽  
Chenling Xiong ◽  
Carol Ho ◽  
Taisei Mushiroda ◽  
Chen Jiang ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Regulatory Elements ◽  
Hazard Ratio ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Sensory Peripheral Neuropathy ◽  
Genome Wide ◽  
Microtubule Targeting Agents

AbstractMicrotubule targeting agents (MTAs) are anticancer therapies commonly prescribed for breast cancer and other solid tumors. Sensory peripheral neuropathy (PN) is the major dose-limiting toxicity for MTAs and can limit clinical efficacy. The current pharmacogenomic study aimed to identify genetic variations that explain patient susceptibility and drive mechanisms underlying development of MTA-induced PN. A meta-analysis of genome-wide association studies (GWAS) from two clinical cohorts treated with MTAs (CALGB 40502 and CALGB 40101) was conducted using a Cox regression model with cumulative dose to first instance of grade 2 or higher PN. Summary statistics from a GWAS of European subjects (n = 469) in CALGB 40502 that estimated cause-specific risk of PN were meta-analyzed with those from a previously published GWAS of European ancestry (n = 855) from CALGB 40101 that estimated the risk of PN. Novel single nucleotide polymorphisms in an enhancer region downstream of sphingosine-1-phosphate receptor 1 (S1PR1 encoding S1PR1; e.g., rs74497159, βCALGB40101 per allele log hazard ratio (95% CI) = 0.591 (0.254 - 0.928), βCALGB40502 per allele log hazard ratio (95% CI) = 0.693 (0.334 - 1.053); PMETA = 3.62×10−7) were the most highly ranked associations based on P-values with risk of developing grade 2 and higher PN. In silico functional analysis identified multiple regulatory elements and potential enhancer activity for S1PR1 within this genomic region. Inhibition of S1PR1 function in iPSC-derived human sensory neurons shows partial protection against paclitaxel-induced neurite damage. These pharmacogenetic findings further support ongoing clinical evaluations to target S1PR1 as a therapeutic strategy for prevention and/or treatment of MTA-induced neuropathy.

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