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 = 4 × 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 × 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 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 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 × 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 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
Cite this
Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans. / CHARGE QRS Consortium.
In: Human Molecular Genetics, Vol. 25, No. 19, 01.10.2016, p. 4350-4368.Research output: Contribution to journal › Article
}
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 - CHARGE QRS Consortium
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
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.
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 = 4 × 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 × 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 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 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 × 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 = 4 × 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 × 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 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 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 × 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.
UR - http://www.scopus.com/inward/record.url?scp=85020862993&partnerID=8YFLogxK
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 -