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Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.

ABSTRACT: BACKGROUND:The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. METHODS AND RESULTS:We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ?2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (? range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (?: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)). CONCLUSIONS:This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

SUBMITTER: Butler AM

PROVIDER: S-EPMC3560365 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.

Butler Anne M AM Yin Xiaoyan X Evans Daniel S DS Nalls Michael A MA Smith Erin N EN Tanaka Toshiko T Li Guo G Buxbaum Sarah G SG Whitsel Eric A EA Alonso Alvaro A Arking Dan E DE Benjamin Emelia J EJ Berenson Gerald S GS Bis Josh C JC Chen Wei W Deo Rajat R Ellinor Patrick T PT Heckbert Susan R SR Heiss Gerardo G Hsueh Wen-Chi WC Keating Brendan J BJ Kerr Kathleen F KF Li Yun Y Limacher Marian C MC Liu Yongmei Y Lubitz Steven A SA Marciante Kristin D KD Mehra Reena R Meng Yan A YA Newman Anne B AB Newton-Cheh Christopher C North Kari E KE Palmer Cameron D CD Psaty Bruce M BM Quibrera P Miguel PM Redline Susan S Reiner Alex P AP Rotter Jerome I JI Schnabel Renate B RB Schork Nicholas J NJ Singleton Andrew B AB Smith J Gustav JG Soliman Elsayed Z EZ Srinivasan Sathanur R SR Zhang Zhu-ming ZM Zonderman Alan B AB Ferrucci Luigi L Murray Sarah S SS Evans Michele K MK Sotoodehnia Nona N Magnani Jared W JW Avery Christy L CL

Circulation. Cardiovascular genetics 20121108 6

<h4>Background</h4>The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.<h4>Methods and results</h4>We present resu ...[more]

PMID: 23139255

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Project description:The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n?=?6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10??) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta ?=?5.1 msec per minor allele, 95% CI ?=?4.1-6.1, p?=?3 x 10?²³). This SNP was also associated with PR interval (beta?=?2.4 msec per minor allele, 95% CI?=?1.8-3.0, p?=?3 x 10?¹?) in individuals of European ancestry (n?=?14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p?=?0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

Project description:BACKGROUND & AIMS:The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS:We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS:We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS:We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Dataset Information

Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.

Publications

Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts.

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