期刊
HUMAN MOLECULAR GENETICS
卷 25, 期 19, 页码 4350-4368出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw284
关键词
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资金
- National Institutes of Health [R01 HL088456, R01 HL116747, R01 HL111089, R01 HL091244, K99 HL098458, 5T32CA009330-30, R01 ES017794, HHSN268200625226C, UL1RR025005, P20MD006899, U24AG051129, HHSN268200782096C]
- Laughlin Family
- German Research Foundation [SCHNA 1149/3-1]
- National Heart, Lung, and Blood Institute (NHLBI)sponsored Candidate gene Association Resource (CARe) project
- ARIC
- JHS
- MESA
- CFS
- Broad Institute of Harvard
- MIT [N01-HC-65226]
- Atherosclerosis Risk in Communities (ARIC):National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- NIH Roadmap for Medical Research
- Cleveland Family Study (CFS): Case Western Reserve University [NIH HL 46380, M01RR00080]
- Jackson Heart Study (JHS) from the National Heart, Lung, and Blood Institute [HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C]
- National Institute on Minority Health and Health Disparities
- Multi-Ethnic Study of Atherosclerosis (MESA): University of Washington [N01-HC-95159]
- Regents of the University of California [N01-HC-95160]
- Columbia University [N01-HC-95161]
- Johns Hopkins University [N01-HC-95162, N01-HC-95168]
- University of Minnesota [N01-HC95163]
- Northwestern University [N01-HC-95164]
- Wake Forest University [N01-HC95165]
- University of Vermont [N01-HC-95166]
- New England Medical Center [N01-HC-95167]
- Harbor-UCLA Research and Education Institute [N01-HC-95169]
- Cedars-Sinai Medical Center [R01-HL-071205]
- University of Virginia [R01-HL-071205]
- Health, Aging, and Body Composition Study (Health ABC): NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- Center for Inherited Disease Research (CIDR)
- Intramural Research Program of the NIH, National Institute on Aging
- Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): intramural research program of the National Institute on Aging
- National Center for Minority Health and Health Disparities, National Institutes of Health
- National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]
- Women's Health Initiative (WHI): National Heart, Lung, and Blood Institute
- U.S. Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
- NHLBI [N02-HL-64278]
- Cardiovascular Health Study (CHS):NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114, HL085251]
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute on Aging (NIA) [AG023629]
- National Center for Advancing Translational Sciences
- CTSI [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- Baltimore Longitudinal Study of Aging (BLSA): Intramural Research Program of the NIH
- National Institute on Aging
- MedStar Research Institute
- Bogalusa Heart Study (BHS): National Institute of Environmental Health Science [R01ES021724]
- National Institute on Aging [R01AG016592]
- STSI/TSRI [U54 NS056883]
- Scripps Genomic Medicine
- National Human Genome Research Institute (NHGRI) [U01HG007416, U01HG007417, U01HG007397, U01HG007376, U01HG007419]
- PAGE Coordinating Center [U01HG007419]
- NIH [5R01HL090620, 5R01HL111314]
- Fondation Leducq [CVD-07-03]
- European North American Atrial Fibrillation Research Alliance
The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 x 10(-14)) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 x 10(-4)). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 x 10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 x 10(-9)). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 x 10(-7)), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
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