Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans

CHARGE QRS Consortium

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)4350-4368
Number of pages19
JournalHuman Molecular Genetics
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2016

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Genome-Wide Association Study
African Americans
Single Nucleotide Polymorphism
Meta-Analysis
Population
Introns
Voltage-Gated Sodium Channels
Chromosomes, Human, Pair 18
Chromosomes, Human, Pair 1
Alleles
Genome
RNA
Mortality
Genes

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 journalArticle

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title = "Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans",
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.",
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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.

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