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

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.

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

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 ◽  
Model Study ◽  
Genome Wide ◽  
Meta Analyses ◽  
Allele Contrast ◽  
Allele Model

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 an ancestral 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 ancestral-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in Europeans. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asians. Conclusions: Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asians and Europeans demonstrated both similarities and differences between the two ancestors.

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

2020 ◽  
Author(s):  
Yongping Liu ◽  
Xue Wu ◽  
Xi Xia ◽  
Jun Yao ◽  
Bao-jie Wang
Keyword(s):  
Subgroup Analysis ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Recessive Model ◽  
Contrast Model ◽  
Influence Model ◽  
Genome Wide ◽  
Meta Analyses ◽  
Allele Contrast ◽  
European Populations

Abstract Background: The CACNA1C gene was defined as the risk gene for schizophrenia in a large GWAS of European ancestory by Psychiatric Genomics Consortium. Previous meta-analyses have focused on the association between CACNA1C gene rs1006737 and schizophrenia. However, the present study focused on whether there was a racial difference in the effect of CACNA1C gene rs1006737 on schizophrenia. In addition, rs2007044 and rs4765905 were used to analyzed the risk of schizophrenia.Methods: The pooled analysis, subgroup analysis, sensitivity analysis and publication bias were conducted.Results: A total of 18 studies met the inclusion criteria, 14 for rs1006737 (15,213 cases and 19,412 controls), 3 for rs2007044 (6007 cases and 6,518 controls), and 2 for rs4765905 (2,435 cases and 2,639 controls). Rs2007044 and rs4765905 were also related to schizophrenia in the only conducted allele model. For rs1006737, the allele contrast model, dominant model, recessive model, codominance models, and complete overdominance model were performed, and the overall meta-analysis showed significant differences between rs1006737 and schizophrenia. However, race-based subgroup analysis of rs1006737 and found that the genotypes GG and GG+GA were only protective factors for schizophrenia in European populations, while the GA genotype of rs1006737 only reduced the risk of schizophrenia in Asian populations.Conclusions: Rs1006737, rs2007044 and rs4765905 of CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model of rs1006737 on schizophrenia in Asian and European populations have both similarities and differences.

Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
James S Floyd ◽  
Colleen Sitlani ◽  
Christy L Avery ◽  
Eric A Whitsel ◽  
Leslie Lange ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Qt Interval ◽  
Association Studies ◽  
Meta Analysis ◽  
Small Sample ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Meta Analyses

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.

scholarly journals Identification of type 2 diabetes loci in 433,540 East Asian individuals

2019 ◽  
Author(s):  
Cassandra N Spracklen ◽  
Momoko Horikoshi ◽  
Young Jin Kim ◽  
Kuang Lin ◽  
Fiona Bragg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Association Studies ◽  
Meta Analysis ◽  
East Asian ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
European Populations

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

scholarly journals Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes

2019 ◽  
Vol 22 (6) ◽  
pp. 900-909 ◽  
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.

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

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 &lt; 5 × 10−8) and 75% of the variants show nominal significance association (p &lt; 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 &lt; 0.00001, FDR&lt;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

scholarly journals Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity

2022 ◽  
Vol 12 ◽  
Author(s):  
Li-Juan Qiu ◽  
Kang-Jia Yin ◽  
Gui-Xia Pan ◽  
Jing Ni ◽  
Bin Wang
Keyword(s):  
Severe Asthma ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Severe Disease ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide ◽  
Inverse Variance ◽  
Increased Risk

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity.Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted.Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses.Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

Abstract 152: Genome-wide Association Study of Early-Onset Ischemic Stroke Identifies Novel Locus on Chromosome 12 Near BCL7A/MLXIP

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Thomas Jaworek ◽  
Steven J Kittner ◽  
Christina Jern ◽  
Frank Erik de Leeuw ◽  
Martin Dichgans ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Ischemic Stroke ◽  
Effect Size ◽  
Early Onset ◽  
Drug Targets ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Subtype Specificity ◽  
Genome Wide

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p< 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.

Abstract 15402: A Multi-ethnic Genome Wide Association Study of Aortic Stenosis in the Million Veteran Program Identifies Several Novel Loci

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Aeron M Small ◽  
Gina Peloso ◽  
Jayashri Aragam ◽  
JASON LINEFSKY ◽  
Ashley Galloway ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Association Study ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
High Morbidity ◽  
Genetic Loci ◽  
Genome Wide

Introduction: Valvular aortic stenosis (AS) is common with high morbidity and mortality in the absence of surgical intervention, but no current medical therapies are known to prevent or slow disease progression. Previous genetic studies have identified several genetic loci associated with prevalent AS, including LPA and PALMD , although most evidence is limited to populations of European ancestry. Methods: We performed a trans-ethnic genome-wide association study (GWAS) of prevalent AS in the Veterans Administration Million Veteran Program (MVP). Cases were identified by a combination of diagnostic billing and surgical codes and validated by association to the known LPA variant (rs10455872). GWAS was run separately for White, Black, and Hispanic individuals, controlling for age, sex, and six principal components, and combined using fixed effects meta-analysis. Results were limited to variants with a minor allele frequency greater than 1% in the trans-ancestry analysis. Lead independent genome wide significant loci were annotated by nearest gene. Results: 300,182 White, 80,744 Black, and 32,069 Hispanic participants were available for analysis. Of these, there were 12,385 (4.1%) White, 1,444 (1.8%) Black, and 611 (1.9%) Hispanic AS cases. Trans-ethnic analyses identified 10 independent genome wide significant (GWS, p≤5x10 -8 ) loci, replicating 6 known AS genetic loci ( ALPL, PALMD, TEX41, LPA, IL6, FADS1 ), and identifying 4 novel genetic loci ( CEP85L, CELSR2, NCK1, SLMAP ), of which 2 were present at nominal significance in Hispanic ( CELS2R ) or Black ( SLMAP ) individuals. Ethnicity-specific analyses additionally identified 9 novel GWS loci in White individuals, and 3 novel GWS loci in Hispanic individuals. Newly identified loci supported known biological pathways in AS including lipid/metabolic, inflammatory, and calcification, but also implicated new pathways such as those pertaining to QT interval ( SLC35F1 ) and the Brugada Syndrome ( SLMAP ). Conclusions: In this large trans-ethnic GWAS for AS we replicate previously identified genetic loci for AS, and identified several novel loci both in trans-ethnic and in ethnic-specific analyses. These loci implicate known and novel biological mechanisms for future prevention and treatment of AS.

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