Genome-wide meta-analyses identify novel loci associated with n-3 and n-6 polyunsaturated fatty acid levels in Chinese and European-ancestry populations

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

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Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes

Nicotine & Tobacco Research ◽

10.1093/ntr/ntz099 ◽

2019 ◽

Vol 22 (6) ◽

pp. 900-909 ◽

Cited By ~ 1

Author(s):

Jingchun Chen ◽

Anu Loukola ◽

Nathan A Gillespie ◽

Roseann Peterson ◽

Peilin Jia ◽

...

Keyword(s):

Cigarette Smoking ◽

Nicotine Dependence ◽

Meta Analysis ◽

Mapk Signaling ◽

European Ancestry ◽

Effective Prevention ◽

Network Analyses ◽

Chemokine Signaling ◽

Genome Wide ◽

Meta Analyses

Abstract Introduction FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Methods Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. Results We found that SORBS2 on 4q35 (p = 4.05 × 10−8), BG182718 on 11q22 (p = 1.02 × 10−8), and AA333164 on 14q21 (p = 4.11 × 10−9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. Conclusions Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. Implications Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

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Combined analysis of keratinocyte cancers identifies novel genome-wide loci

Human Molecular Genetics ◽

10.1093/hmg/ddz121 ◽

2019 ◽

Vol 28 (18) ◽

pp. 3148-3160 ◽

Cited By ~ 6

Author(s):

Upekha E Liyanage ◽

Matthew H Law ◽

Xikun Han ◽

Jiyuan An ◽

Jue-Sheng Ong ◽

...

Keyword(s):

Cell Carcinoma ◽

Association Studies ◽

Genetic Correlations ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Multiple Trait ◽

Total N ◽

Risk Variants ◽

Genome Wide ◽

Meta Analyses

Abstract The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

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Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome

Nutrients ◽

10.3390/nu12020310 ◽

2020 ◽

Vol 12 (2) ◽

pp. 310 ◽

Cited By ~ 4

Author(s):

Oscar Coltell ◽

Jose V. Sorlí ◽

Eva M. Asensio ◽

Rocío Barragán ◽

José I. González ◽

...

Keyword(s):

Metabolic Syndrome ◽

Fatty Acids ◽

Fatty Acid ◽

Association Study ◽

Genome Wide Association ◽

Omega 3 ◽

Chromosome 11 ◽

Genome Wide ◽

Omega 6 ◽

Meta Analyses

Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10−14; FADS1-rs174550, p = 5.35 × 10−14; FADS2-rs1535, p = 5.85 × 10−14; FADS1-rs174546, p = 6.72 × 10−14; FADS2-rs174546, p = 9.75 × 10−14; FADS2-rs174576, p = 1.17 × 10−13; FADS2-rs174577, p = 1.12 × 10−12, among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10−12; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10−12; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10−11). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10−8. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10−7). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA.

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O-116 Genetic association analyses identify links between pelvic prolapse (PP) and connective tissue biology, cardiovascular and reproductive health

Human Reproduction ◽

10.1093/humrep/deab126.025 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

N Pujol Gualdo ◽

K Läll ◽

M Lepamets ◽

R Arffman ◽

T Piltonen ◽

...

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide ◽

Meta Analyses ◽

Personalized Risk

Abstract Study question Can genome-wide association analysis unravel the biological underpinnings of PP and facilitate personalized risk assessment via genetic risk scores construction? Summary answer We unravel novel links with urogenital development and vascular health in PP and present polygenic risk score as a tool to stratify PP risk. What is known already Prolapse is characterized by a descent of the pelvic organs into the vaginal cavity. PP affects around 40% of women after menopause and is the main indication for major gynecological surgery, having an important health, social and economic burden. Although the etiology and biological mechanisms underlying PP remain poorly understood, prior studies suggest genetic factors might play a role. Recently, a genome-wide association study (GWAS) identified seven genome-wide significant loci, located in or near genes involved in connective tissue metabolism and estrogen exposure in the etiology of PP. Study design, size, duration We conducted a three-stage case-control genome-wide association study. Firstly, in the discovery phase, we meta-analyzed Icelandic, UK Biobank and the FinnGen R3 datasets, comprising a total of 20118 cases and 427426 controls of European ancestry. For replication we used an independent dataset from Estonian Biobank (7968 cases and 118895 controls). Finally, we conducted a joint meta-analysis, containing 28086 cases and 546321 controls, which is the largest GWAS of PP to date. Participants/materials, setting, methods We performed functional annotation on genetic variants unraveled by GWAS and integrated these with expression quantitative trait loci and chromatin interaction data. In addition, we looked at enrichment of association signal on gene-set, tissue and cell type level and analyzed associations with other phenotypes both on genetic and phenotypic level. Colocalisation analyses were conducted to help pinpoint causal genes. We further constructed polygenic risk scores to explore options for personalized risk assessment and prevention. Main results and the role of chance In the discovery phase, we identified 18 genetic loci and 20 genetic variants significantly associated with POP (p < 5 × 10−8) and 75% of the variants show nominal significance association (p < 0.05) in the replication. Notably, the joint meta-analyses detected 20 genetic loci significantly associated with POP, from which 13 loci were novel. Novel genetic variants are located in or near genes involved in gestational duration and preterm birth (rs2687728 p = 2.19x10-9, EEFSEC), cardiovascular health and pregnancy success (rs1247943 p = 5.83x10-18, KLF13), endometriosis (rs12325192 p = 3.72x10-18, CRISPLD2), urogenital tract development (rs7126322, p = 4.35x10-15, WT1 and rs42400, p = 4.8x10-10, ADAMTS16) and regulation of the oxytocin receptor (rs2267372, p = 4.49x10-13, MAFF). Further analyses demonstrated that POP GWAS signals colocalise with several eQTLS (including EEFSEC, MAFF, KLF13, etc.), providing further evidence for mapping associated genes. Tissue and cell enrichment analyses underlined the role of the urogenital system, muscle cells, myocytes and adipocytes (p < 0.00001, FDR<0.05). Furthermore, genetic correlation analyses supported a shared genetic background with gastrointestinal disorders, joint and musculoskeletal disorders and cardiovascular disease. Polygenic risk scores analyses included a total of 125551 people in the target dataset, with 5379 prevalent patients and 2517 incident patients. Analyzing the best GRS as a quintile showed association with incident disease (Harrell c-statistic= 0.603, SD = 0.006). Limitations, reasons for caution This GWAS meta-analyses focused on European ancestry populations, which challenges the generalizability of GWAS findings to non-European populations. Moreover, this study included women with PP from population-based biobanks identified using the ICD-10 code N81, which limits analyses considering different disease stages and severity. Wider implications of the findings Our study provides genetic evidence to improve the current understanding of PP pathogenesis and serves as basis for further functional studies. Moreover, we provide a genetic tool for personalized risk stratification, which could help prevent PP development and improve the quality of a vast quantity of women. Trial registration number not applicable

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Genome-wide association study of the plasma triglyceride response to an n-3 polyunsaturated fatty acid supplementation

The Journal of Lipid Research ◽

10.1194/jlr.m045898 ◽

2014 ◽

Vol 55 (7) ◽

pp. 1245-1253 ◽

Cited By ~ 26

Author(s):

Iwona Rudkowska ◽

Frédéric Guénard ◽

Pierre Julien ◽

Patrick Couture ◽

Simone Lemieux ◽

...

Keyword(s):

Fatty Acid ◽

Association Study ◽

Polyunsaturated Fatty Acid ◽

Genome Wide Association Study ◽

Plasma Triglyceride ◽

Genome Wide Association ◽

Fatty Acid Supplementation ◽

Acid Supplementation ◽

Genome Wide

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The genome-wide supported CACNA1C gene polymorphisms and the risk of schizophrenia: an updated meta-analysis

10.21203/rs.2.24453/v2 ◽

2020 ◽

Author(s):

Yongping Liu ◽

Xue Wu ◽

Xi Xia ◽

Jun Yao ◽

Bao-jie Wang

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

European Ancestry ◽

Bias Analysis ◽

Influence Model ◽

Asian Populations ◽

Model Study ◽

Genome Wide ◽

Meta Analyses ◽

European Populations

Abstract Background: The CACNA1C gene was defined as a risk gene for schizophrenia in a large genome-wide association study of European ancestry performed by the Psychiatric Genomics Consortium. Previous meta-analyses focused on the association between the CACNA1C gene rs1006737 and schizophrenia. The present study focused on whether there was a racial difference in the effect of the CACNA1C gene rs1006737 on schizophrenia. rs2007044 and rs4765905 were analyzed for their effect on the risk of schizophrenia. Methods: Pooled, subgroup, sensitivity, and publication bias analysis were conducted.Results: A total of 18 studies met the inclusion criteria, including fourteen rs1006737 studies (15,213 cases, 19,412 controls), three rs2007044 studies (6,007 cases, 6,518 controls), and two rs4765905 studies (2,435 cases, 2,639 controls). An allele model study also related rs2007044 and rs4765905 to schizophrenia. The overall meta-analysis for rs1006737, which included the allele contrast, dominant, recessive, codominance, and complete overdominance models, showed significant differences between rs1006737 and schizophrenia. However, the race-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in European populations. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asian populations. Conclusions: Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asian and European populations demonstrated both similarities and differences between the two populations.

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Multiethnic Genome-wide Association Study of Subclinical Atherosclerosis in Individuals with Type 2 Diabetes

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003258 ◽

2021 ◽

Author(s):

Yingchang Lu ◽

Latchezar Dimitrov ◽

Shyh-Huei Chen ◽

Lawrence F. Bielak ◽

Joshua C. Bis ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coronary Artery ◽

Subclinical Atherosclerosis ◽

Genome Wide Association ◽

European Ancestry ◽

Potential Candidate ◽

Cvd Risk ◽

Genome Wide ◽

Meta Analyses

Background - Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease (CVD). Type 2 diabetes (T2D) is an independent CVD risk factor that accelerates atherosclerosis. Methods - We performed meta-analyses of genome-wide association studies (GWAS) in up to 2,500 T2D individuals of European ancestry (EA) and 1,590 T2D individuals of African ancestry (AA) with or without exclusion of prevalent CVD, for CAC measured by cardiac computed tomography, and 3,608 EA and 838 AA with T2D for cIMT measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Results - We replicated two loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B ) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1 ) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P =2.0×10 -8 in EA. No additional loci were identified with the meta-analyses of EA and AA. The expression QTL analysis with nearby expressed genes derived from arterial wall and metabolic tissues from GTEx pinpoints POSTN , encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations ( P <3.1×10 -4 ) for three previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). Conclusions - Our results provide potential biological mechanisms that could link CAC and cIMT to increased CVD risk in individuals with T2D.

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Abstract 048: Association Analyses of up to ∼263,000 Individuals Provide New Insights into the Biology and Genetic Architecture of the Extremes of Anthropometric Traits

Circulation ◽

10.1161/circ.125.suppl_10.a048 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

Erik Ingelsson ◽

Reedik Mägi ◽

Stefan Gustafsson ◽

Andrea Ganna ◽

Eleanor Wheeler ◽

...

Keyword(s):

General Population ◽

Genetic Architecture ◽

Class Ii ◽

Overweight And Obesity ◽

European Ancestry ◽

Continuous Measure ◽

Phenotypic Variance ◽

Obesity Class ◽

Genome Wide ◽

Meta Analyses

Anthropometric traits have a strong genetic component with heritability estimates between 40–70% for body mass index (BMI) and ∼80% for height; however, established loci only account for a small fraction (1–10%) of the phenotypic variance of these complex traits. It has been hypothesized that the extremes of the distributions of these traits are enriched for genetic loci and may have a distinct genetic architecture compared to the general population. To explore the genetic contribution of the extremes (defined as the upper and lower 5th percentile) of BMI, height, and waist-hip ratio [WHR] adjusted for BMI and clinical classes of obesity (including overweight and obesity classes I, II, and III), we conducted meta-analyses of ∼2.8 million SNPs from 49 genome-wide association studies of European ancestry totaling from 4,774 cases and 5,481 controls (extreme WHR) to 93,015 cases and 65,840 controls (overweight) for these traits. The most promising loci from each meta-analysis (P<5 x 10 −6 ) were taken forward for replication into up to 65,332 cases and 39,294 controls. In meta-analyses of the combined stages, we observed genome-wide significant associations (P<5 x 10 −8 ) for 191 loci (extreme BMI, height and WHR: 10, 96 and 2 loci, respectively; overweight and obesity classes I, II, and III: 25, 33, 24 and 1 loci, respectively). Out of these 191 loci, we identified 9 novel loci that have not been previously associated with anthropometric traits when studying the whole distributions (P<5 x 10 −8 ), including three loci for extreme height ( ZNF36, H6PD , RSRC1 ), three for obesity class II ( OLFM4 , HS6ST3 , AK5/ZZZ3 ), two for obesity class I ( GNAI3/MIR197/GNAT2, HNF4G ), and two for overweight ( RPTOR, HNF4G ). Several loci for obesity were located near genes expressed primarily in the brain (e.g. CACNA1D, AK5 ), suggesting a neuronal influence, whereas the loci for overweight were near genes involved in other processes, such as mTOR signaling (e.g. RPTOR ). All of the novel loci discovered for the extremes and obesity classes were nominally associated with the trait as a continuous measure in the general population (N = 123,865) but at a lesser significance level (P range: 0.003 – 1.4x10 −5 ). A polygenetic risk score including all independent SNPs associated with BMI (at different P-value thresholds) revealed that significantly more of the variance was explained for the extremes of BMI and obesity class II, than for BMI as a continuous measure in the population (variance explained, 20%, 10% and 5%, respectively), suggesting a greater genetic influence on the extremes. Investigations are underway to evaluate haplotypes and additional signals at known BMI and height loci in the extreme samples to explore allelic heterogeneity. In conclusion, this study identifies additional loci and provides novel insights into the genetic architecture of the extremes of anthropometric traits.

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The Trans-Ancestral Genomic Architecture of Glycaemic Traits

10.1101/2020.07.23.217646 ◽

2020 ◽

Author(s):

Ji Chen ◽

Cassandra N. Spracklen ◽

Gaëlle Marenne ◽

Arushi Varshney ◽

Laura J Corbin ◽

...

Keyword(s):

Association Studies ◽

Glycated Haemoglobin ◽

European Ancestry ◽

Cardiometabolic Health ◽

Genomic Feature ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Credible Sets ◽

Meta Analyses ◽

Glycaemic Traits

AbstractGlycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P<5×10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

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