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Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.

TitleGenome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy.
Publication TypeJournal Article
Year of Publication2018
AuthorsNapier MD, Franceschini N, Gondalia R, Stewart JD, Méndez-Giráldez R, Sitlani CM, Seyerle AA, Highland HM, Li Y, Wilhelmsen KC, Yan S, Duan Q, Roach J, Yao J, Guo X, Taylor KD, Heckbert SR, Rotter JI, North KE, Reiner AP, Zhang Z-M, Tinker LF, Liao D, Laurie CC, Gogarten SM, Lin HJ, Brody JA, Bartz TM, Psaty BM, Sotoodehnia N, Soliman EZ, Avery CL
Secondary AuthorsWhitsel EA
JournalSci Rep
Volume8
Issue1
Pagination5675
Date Published2018 04 04
ISSN2045-2322
KeywordsAged, Atrial Premature Complexes, Bayes Theorem, Clinical Trials as Topic, Cohort Studies, Electrocardiography, Female, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Tachycardia, Supraventricular, Ventricular Premature Complexes
Abstract

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10) and multi-trait analysis (P = 2.9 × 10) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

DOI10.1038/s41598-018-23843-z
Alternate JournalSci Rep
PubMed ID29618737
PubMed Central IDPMC5884864
Grant ListP30 ES010126 / ES / NIEHS NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R21 HL123677 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States