Journal
NATURE GENETICS
Volume 42, Issue 12, Pages 1068-U62Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.716
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Funding
- Chief Scientist Office [CZB/4/710] Funding Source: researchfish
- Medical Research Council [G9521010, MC_U127561128, G0400874] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [G20234] Funding Source: Medline
- British Heart Foundation [SP/08/005/25115, PG/02/128, 06/094, RG/07/005/23633] Funding Source: Medline
- Intramural NIH HHS Funding Source: Medline
- Medical Research Council [G9521010D, G9521010, MC_U127561128, G0400874] Funding Source: Medline
- NCRR NIH HHS [M01-RR00425, UL1RR025005] Funding Source: Medline
- NHGRI NIH HHS [U01HG004402] Funding Source: Medline
- NHLBI NIH HHS [R01HL087641, N01 HC-15103, N01-HC-55022, R01HL086694, N01-HC-55018, N01-HC-45133, N01-HC-85079, N01-HC-85081, N01-HC-55019, R01 HL087652, N01-HC-25195, L30 HL097675, N01 HC-55222, N01-HC-35129, N01-HC-85084, U01 HL080295, N01-HC-85080, N01-HC-55020, N01-HC-75150, N01-HC-85083, R01HL59367, N01-HC-85085, HL80025, N01-HC-55015, N01-HC-55021, N01-HC-85086, R01 HL088456, R01HL64757, R01 HL088456-04, N01-HC-85082, N01-HC-55016, N02-HL-6-4278, K23HL80025, R01 HL082727] Funding Source: Medline
- NIA NIH HHS [N01-AG-12100] Funding Source: Medline
- NIDDK NIH HHS [DK063491] Funding Source: Medline
- NINDS NIH HHS [NS058980] Funding Source: Medline
- PHS HHS [HHSN268200625226C] Funding Source: Medline
- Wellcome Trust [076113/B/04/Z] Funding Source: Medline
- Department of Health Funding Source: Medline
- Chief Scientist Office [CZB/4/710] Funding Source: Medline
- MRC [MC_U127561128, G0400874, G9521010] Funding Source: UKRI
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The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
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