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Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

ABSTRACT: The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P?=?4?×?10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P?=?1.1?×?10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P?=?4.9?×?10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P?=?7.9?×?10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P?=?9.9?×?10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

SUBMITTER: Evans DS

PROVIDER: S-EPMC5291202 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

Evans Daniel S DS Avery Christy L CL Nalls Mike A MA Li Guo G Barnard John J Smith Erin N EN Tanaka Toshiko T Butler Anne M AM Buxbaum Sarah G SG Alonso Alvaro A Arking Dan E DE Berenson Gerald S GS Bis Joshua C JC Buyske Steven S Carty Cara L CL Chen Wei W Chung Mina K MK Cummings Steven R SR Deo Rajat R Eaton Charles B CB Fox Ervin R ER Heckbert Susan R SR Heiss Gerardo G Hindorff Lucia A LA Hsueh Wen-Chi WC Isaacs Aaron A Jamshidi Yalda Y Kerr Kathleen F KF Liu Felix F Liu Yongmei Y Lohman Kurt K KK Magnani Jared W JW Maher Joseph F JF Mehra Reena R Meng Yan A YA Musani Solomon K SK Newton-Cheh Christopher C North Kari E KE Psaty Bruce M BM Redline Susan S Rotter Jerome I JI Schnabel Renate B RB Schork Nicholas J NJ Shohet Ralph V RV Singleton Andrew B AB Smith Jonathan D JD Soliman Elsayed Z EZ Srinivasan Sathanur R SR Taylor Herman A HA Van Wagoner David R DR Wilson James G JG Young Taylor T Zhang Zhu-Ming ZM Zonderman Alan B AB Evans Michele K MK Ferrucci Luigi L Murray Sarah S SS Tranah Gregory J GJ Whitsel Eric A EA Reiner Alex P AP Sotoodehnia Nona N

Human molecular genetics 20160829 19

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten ...[more]

PMID: 27577874

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Project description:The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P?1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P?1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple populations, that novel signals exist in African Americans, and that the SNPs identified as strong candidates for functional evaluation implicate gene regulatory dysfunction in QT prolongation.

Dataset Information

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

Publications

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

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