Author:
Sinner Moritz F.,Tucker Nathan R.,Lunetta Kathryn L.,Ozaki Kouichi,Smith J. Gustav,Trompet Stella,Bis Joshua C.,Lin Honghuang,Chung Mina K.,Nielsen Jonas B.,Lubitz Steven A.,Krijthe Bouwe P.,Magnani Jared W.,Ye Jiangchuan,Gollob Michael H.,Tsunoda Tatsuhiko,Müller-Nurasyid Martina,Lichtner Peter,Peters Annette,Dolmatova Elena,Kubo Michiaki,Smith Jonathan D.,Psaty Bruce M.,Smith Nicholas L.,Jukema J. Wouter,Chasman Daniel I.,Albert Christine M.,Ebana Yusuke,Furukawa Tetsushi,Macfarlane Peter W.,Harris Tamara B.,Darbar Dawood,Dörr Marcus,Holst Anders G.,Svendsen Jesper H.,Hofman Albert,Uitterlinden Andre G.,Gudnason Vilmundur,Isobe Mitsuaki,Malik Rainer,Dichgans Martin,Rosand Jonathan,Van Wagoner David R.,Benjamin Emelia J.,Milan David J.,Melander Olle,Heckbert Susan R.,Ford Ian,Liu Yongmei,Barnard John,Olesen Morten S.,Stricker Bruno H.C.,Tanaka Toshihiro,Kääb Stefan,Ellinor Patrick T.
Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine