Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

Published

Journal Article

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

Full Text

Duke Authors

Cited Authors

  • Sinner, MF; Tucker, NR; Lunetta, KL; Ozaki, K; Smith, JG; Trompet, S; Bis, JC; Lin, H; Chung, MK; Nielsen, JB; Lubitz, SA; Krijthe, BP; Magnani, JW; Ye, J; Gollob, MH; Tsunoda, T; Müller-Nurasyid, M; Lichtner, P; Peters, A; Dolmatova, E; Kubo, M; Smith, JD; Psaty, BM; Smith, NL; Jukema, JW; Chasman, DI; Albert, CM; Ebana, Y; Furukawa, T; Macfarlane, PW; Harris, TB; Darbar, D; Dörr, M; Holst, AG; Svendsen, JH; Hofman, A; Uitterlinden, AG; Gudnason, V; Isobe, M; Malik, R; Dichgans, M; Rosand, J; Van Wagoner, DR; METASTROKE Consortium, ; AFGen Consortium, ; Benjamin, EJ; Milan, DJ; Melander, O; Heckbert, SR; Ford, I; Liu, Y; Barnard, J; Olesen, MS; Stricker, BHC; Tanaka, T; Kääb, S; Ellinor, PT

Published Date

  • October 7, 2014

Published In

Volume / Issue

  • 130 / 15

Start / End Page

  • 1225 - 1235

PubMed ID

  • 25124494

Pubmed Central ID

  • 25124494

Electronic International Standard Serial Number (EISSN)

  • 1524-4539

Digital Object Identifier (DOI)

  • 10.1161/CIRCULATIONAHA.114.009892

Language

  • eng

Conference Location

  • United States