Abstract
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 ¼ 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 ¼ 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 ¼ 4.9 X 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P ¼ 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 ¼ 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4350-4368 |
| Number of pages | 19 |
| Journal | Human molecular genetics |
| Volume | 25 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2016 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. / Evans, Daniel S.; Avery, Christy L.; Nalls, Mike A. et al.
In: Human molecular genetics, Vol. 25, No. 19, 01.10.2016, p. 4350-4368.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans
AU - Evans, Daniel S.
AU - Avery, Christy L.
AU - Nalls, Mike A.
AU - Li, Guo
AU - Barnard, John
AU - Smith, Erin N.
AU - Tanaka, Toshiko
AU - Butler, Anne M.
AU - Buxbaum, Sarah G.
AU - Alonso, Alvaro
AU - Arking, Dan E.
AU - Berenson, Gerald S.
AU - Bis, Joshua C.
AU - Buyske, Steven
AU - Carty, Cara L.
AU - Chen, Wei
AU - Chung, Mina K.
AU - Cummings, Steven R.
AU - Deo, Rajat
AU - Eaton, Charles B.
AU - Fox, Ervin R.
AU - Heckbert, Susan R.
AU - Heiss, Gerardo
AU - Hindorff, Lucia A.
AU - Hsueh, Wen Chi
AU - Isaacs, Aaron
AU - Jamshidi, Yalda
AU - Kerr, Kathleen F.
AU - Liu, Felix
AU - Liu, Yongmei
AU - Lohman, Kurt K.
AU - Magnani, Jared W.
AU - Maher, Joseph F.
AU - Mehra, Reena
AU - Meng, Yan A.
AU - Musani, Solomon K.
AU - Newton-Cheh, Christopher
AU - North, Kari E.
AU - Psaty, Bruce M.
AU - Redline, Susan
AU - Rotter, Jerome I.
AU - Schnabel, Renate B.
AU - Schork, Nicholas J.
AU - Shohet, Ralph V.
AU - Singleton, Andrew B.
AU - Smith, Jonathan D.
AU - Soliman, Elsayed Z.
AU - Srinivasan, Sathanur R.
AU - Taylor, Herman A.
AU - van Wagoner, David R.
AU - Wilson, James G.
AU - Young, Taylor
AU - Zhang, Zhu Ming
AU - Zonderman, Alan B.
AU - Evans, Michele K.
AU - Ferrucci, Luigi
AU - Murray, Sarah S.
AU - Tranah, Gregory J.
AU - Whitsel, Eric A.
AU - Reiner, Alex P.
AU - Sotoodehnia, Nona
N1 - Funding Information: This work was supported by the National Institutes of Health [R01 HL088456 to N.S., R01 HL116747 to N.S., R01 HL111089 to N.S., R01 HL091244 to N.S., K99 HL098458 to C.L.A., 5T32CA009330-30 to A.M.B., R01 ES017794 to E.A.W., P20MD006899 to S.G.B., and U24AG051129 to D.S.E.], the Laughlin Family [to N.S.], and the German Research Foundation [SCHNA 1149/3-1 to R.B.S.]. As part of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Candidate gene Association Resource (CARe) project, the ARIC, JHS, MESA, and CFS studies contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard and MIT (N01-HC-65226) to create a genotype/phenotype database for wide dissemination to the biomedical research community. Atherosclerosis Risk in Communities (ARIC): The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Cleveland Family Study (CFS): Case Western Reserve University (NIH HL 46380, M01RR00080). Jackson Heart Study (JHS): The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the 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-HC-95165), 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), and University of Virginia (subcontract to R01-HL-071205). Health, Aging, and Body Composition Study (Health ABC): The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Healthy Aging in Neighbourhoods of Diversity across the Life Span Study (HANDLS): The HANDLS study was in part supported by the intramural research program of the National Institute on Aging and the National Center for Minority Health and Health Disparities, National Institutes of Health. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (contract # Z01-AG000513 and human subjects protocol # 2009-149). Data analyses for the HANDLS study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This manuscript was prepared in collaboration with investigators of the WHI, and has been reviewed and/or approved by the Women’s Health Initiative (WHI). WHI investigators are listed at https://www.whi.org/researchers/ Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Short%20List.pdf. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114, HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org/. The provision of geno-typing data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Baltimore Longitudinal Study of Aging (BLSA): The BLSA was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. Funding Information: Bogalusa Heart Study (BHS): BHS is supported by grants R01ES021724 from National Institute of Environmental Health Science and R01AG016592 from the National Institute on Aging. Analysis performed at STSI/TSRI was supported by U54 NS056883 and Scripps Genomic Medicine. The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The complete list of PAGE members can be found at http://www.pagestudy.org. Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, and general study coordination was provided by the PAGE Coordinating Center (U01HG007419). The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. Funding for the atrial tissue eQTL study was provided by NIH 5R01HL090620, NIH 5R01HL111314, Fondation Leducq CVD-07-03, European North American Atrial Fibrillation Research Alliance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © The Author 2016. Published by Oxford University Press.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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 ¼ 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 ¼ 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 ¼ 4.9 X 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P ¼ 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 ¼ 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.
AB - 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 ¼ 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 ¼ 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 ¼ 4.9 X 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P ¼ 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 ¼ 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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UR - http://www.scopus.com/inward/citedby.url?scp=85020862993&partnerID=8YFLogxK
U2 - 10.1093/HMG/DDW284
DO - 10.1093/HMG/DDW284
M3 - Article
C2 - 27577874
AN - SCOPUS:85020862993
VL - 25
SP - 4350
EP - 4368
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
ER -