To identify genetic factors influencing cardiac conduction, we carried out a genome-wide association study of electrocardiographic time intervals in 6,543 Indian Asians. We identified association of a nonsynonymous SNP, rs6795970, in SCN10A (P = 2.8 × 10−15) with PR interval, a marker of cardiac atrioventricular conduction. Replication testing among 6,243 Indian Asians and 5,370 Europeans confirmed that rs6795970 (G>A) is associated with prolonged cardiac conduction (longer P-wave duration, PR interval and QRS duration, P = 10−5 to 10−20). SCN10A encodes NaV1.8, a sodium channel. We show that SCN10A is expressed in mouse and human heart tissue and that PR interval is shorter in Scn10a−/− mice than in wild-type mice. We also find that rs6795970 is associated with a higher risk of heart block (P < 0.05) and a lower risk of ventricular fibrillation (P = 0.01). Our findings provide new insight into the pathogenesis of cardiac conduction, heart block and ventricular fibrillation.
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We thank the participants involved in the research. The LOLIPOP study was supported by the British Heart Foundation (SP/04/002) and by the Wellcome Trust (084723/Z/08/Z). Studies in the AGNES population were supported by the Netherlands Heart Foundation (Grant 2007B202) and the Leducq Foundation (Grant 05-CVD). J.Z. was supported by a BBSRC LOLA award (BB/F000227/1). R.K. was supported by the British Heart Foundation (Grant F/99089). M.N.W. is supported by the Biotechnology and Biological Sciences Research Council grant BB/F020481/1. W.M. is funded by the National Institute for Health Research Biomedical Research Centres scheme. J.N.W. is a member of the Wellcome Trust-funded London Pain Consortium. We thank G. Turner and M. Minett for maintaining the Scn10a-null mutant mouse colony, M.W. Tanck and R. Pazoki for help in statistical analyses and S. Rothery for technical assistance.
The authors declare no competing financial interests.
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Chambers, J., Zhao, J., Terracciano, C. et al. Genetic variation in SCN10A influences cardiac conduction. Nat Genet 42, 149–152 (2010) doi:10.1038/ng.516
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