Journal
NATURE GENETICS
Volume 42, Issue 2, Pages 149-U80Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.516
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Funding
- British Heart Foundation [SP/04/002, F/99089]
- Wellcome Trust [084723/Z/08/Z]
- Netherlands Heart Foundation [2007B202]
- Leducq Foundation [05-CVD]
- BBSRC LOLA [BB/F000227/1]
- Biotechnology and Biological Sciences Research Council [BB/F020481/1]
- National Institute for Health Research Biomedical Research Centres
- Wellcome Trust
- BBSRC [BB/F020481/1, BB/F000227/1] Funding Source: UKRI
- MRC [G0601966, G0901905, G9717869, G0801056, G0700931] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F000227/1, BB/F020481/1] Funding Source: researchfish
- Medical Research Council [G9717869, G0801056, G0801056B, G0601966, G0901905, G0700931] Funding Source: researchfish
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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 x 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 Na(V)1.8, 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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