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Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.
Tuesday,2012-11-06 12:25 America/Los_Angeles — eenright
| Title | Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. |
| Publication Type | Journal Article |
| Year of Publication | 2010 |
| Authors | Sotoodehnia, N, Isaacs, A, de Bakker, PIW, Dörr, M, Newton-Cheh, C, Nolte, IM, van der Harst, P, Müller, M, Eijgelsheim, M, Alonso, A, Hicks, AA, Padmanabhan, S, Hayward, C, Smith, AVernon, Polasek, O, Giovannone, S, Fu, J, Magnani, JW, Marciante, KD, Pfeufer, A, Gharib, SA, Teumer, A, Li, M, Bis, JC, Rivadeneira, F, Aspelund, T, Köttgen, A, Johnson, T, Rice, K, Sie, MPS, Wang, YA, Klopp, N, Fuchsberger, C, Wild, SH, Leach, IMateo, Estrada, K, Völker, U, Wright, AF, Asselbergs, FW, Qu, J, Chakravarti, A, Sinner, MF, Kors, JA, Petersmann, A, Harris, TB, Soliman, EZ, Munroe, PB, Psaty, BM, Oostra, BA, Cupples, AL, Perz, S, de Boer, RA, Uitterlinden, AG, Völzke, H, Spector, TD, Liu, F-Y, Boerwinkle, E, Dominiczak, AF, Rotter, JI, van Herpen, G, Levy, D, Wichmann, H-E, van Gilst, WH, Witteman, JCM, Kroemer, HK, Kao, LWH, Heckbert, SR, Meitinger, T, Hofman, A, Campbell, H, Folsom, AR, van Veldhuisen, DJ, Schwienbacher, C, O'Donnell, CJ, Volpato, CBeu, Caulfield, MJ, Connell, JM, Launer, L, Lu, X, Franke, L, Fehrmann, RSN, Meerman, Gte, Groen, HJM, Weersma, RK, van den Berg, LH, Wijmenga, C, Ophoff, RA, Navis, G, Rudan, I, Snieder, H, Wilson, JF, Pramstaller, PP, Siscovick, DS, Wang, TJ, Gudnason, V, van Duijn, CM, Felix, SB, Fishman, GI, Jamshidi, Y, Stricker, BHCh, Samani, NJ, Kääb, S, Arking, DE |
| Journal | Nat Genet |
| Volume | 42 |
| Issue | 12 |
| Pagination | 1068-76 |
| Date Published | 2010 Dec |
| ISSN | 1546-1718 |
| Keywords | Animals, Animals, Newborn, Chromosomes, Human, Computational Biology, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Heart Conduction System, Humans, Mice, Mice, Transgenic, Models, Animal, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium Channels |
| Abstract | <p>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 genome-wide 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 × 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.</p> |
| DOI | 10.1038/ng.716 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 21076409 |
| PubMed Central ID | PMC3338195 |
| Grant List | M01-RR00425 / RR / NCRR NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States R01HL64757 / HL / NHLBI NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States CZB/4/710 / / Chief Scientist Office / United Kingdom G9521010 / / Medical Research Council / United Kingdom G0400874 / / Medical Research Council / United Kingdom HL80025 / HL / NHLBI NIH HHS / United States N01-HC-85085 / HC / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States U01 HL080295 / HL / NHLBI NIH HHS / United States RG/07/005/23633 / / British Heart Foundation / United Kingdom G20234 / / Biotechnology and Biological Sciences Research Council / United Kingdom N01-HC-55022 / HC / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States K23HL80025 / HL / NHLBI NIH HHS / United States MC_U127561128 / / Medical Research Council / United Kingdom N01-HC-55016 / HC / NHLBI NIH HHS / United States G9521010D / / Medical Research Council / United Kingdom NS058980 / NS / NINDS NIH HHS / United States / / Department of Health / United Kingdom HHSN268200625226C / / PHS HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01 HL088456 / HL / NHLBI NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States R01 HL088456-04 / HL / NHLBI NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States / / Intramural NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States L30 HL097675 / HL / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States 06/094 / / British Heart Foundation / United Kingdom SP/08/005/25115 / / British Heart Foundation / United Kingdom N01-HC-85083 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States R01 HL082727 / HL / NHLBI NIH HHS / United States PG/02/128 / / British Heart Foundation / United Kingdom N01-AG-12100 / AG / NIA NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States R01 HL087652 / HL / NHLBI NIH HHS / United States / / Chief Scientist Office / United Kingdom N01-HC-55018 / HC / NHLBI NIH HHS / United States 076113/B/04/Z / / Wellcome Trust / United Kingdom N01-HC-85084 / HC / NHLBI NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States |