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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, DS; Avery, CL; Nalls, MA; Li, G; Barnard, J; Smith, EN; Tanaka, T; Butler, AM; Buxbaum, SG; Alonso, A; et al. Evans, DS; Avery, CL; Nalls, MA; Li, G; Barnard, J; Smith, EN; Tanaka, T; Butler, AM; Buxbaum, SG; Alonso, A; Arking, DE; Berenson, GS; Bis, JC; Buyske, S; Carty, CL; Chen, W; Chung, MK; Cummings, SR; Deo, R; Eaton, CB; Fox, ER; Heckbert, SR; Heiss, G; Hindorff, LA; Hsueh, W-C; Isaacs, A; Jamshidi, Y; Kerr, KF; Liu, F; Liu, Y; Lohman, KK; Magnani, JW; Maher, JF; Mehra, R; Meng, YA; Musani, SK; Newton-Cheh, C; North, KE; Psaty, BM; Redline, S; Rotter, JI; Schnabel, RB; Schork, NJ; Shohet, RV; Singleton, AB; Smith, JD; Soliman, EZ; Srinivasan, SR; Taylor Jr, HA; Van Wagoner, DR; Wilson, JG; Young, T; Zhang, Z-M; Zonderman, AB; Evans, MK; Ferrucci, L; Murray, SS; Tranah, GJ; Whitsel, EA; Reiner, AP; CHARGE QRS Consortium; Sotoodehnia, N (2016) Fine-mapping, Novel Loci Identification, and SNP Association Transferability in a Genome-Wide Association Study of QRS Duration in African Americans. Human Molecular Genetics, 25 (19). pp. 4350-4368. ISSN 1460-2083 https://doi.org/10.1093/hmg/ddw284
SGUL Authors: Jamshidi, Yalda

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Abstract

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with QRS duration at 22 loci among those of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a 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=4x10-14) 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=1.1x10-4). 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=4.9x10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P=7.9x10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P=9.9x10-7), 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.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Evans, DS; Avery, CL; Nalls, MA; Li, G; Barnard, J; Smith, EN; Tanaka, T; Butler, AM; Buxbaum, SG; Alonso, A; et al. (2016) Fine-mapping, Novel Loci Identification, and SNP Association Transferability in a Genome-Wide Association Study of QRS Duration in African Americans. Human Molecular Genetics, 25 (19) 4350-4368. ISSN 1460-2083 is available online at: https://doi.org/10.1093/hmg/ddw284
Keywords: Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Human Molecular Genetics
ISSN: 1460-2083
Dates:
DateEvent
19 August 2016Accepted
29 August 2016Published Online
1 October 2016Published
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
R01 HL088456National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL116747National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL111089National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 HL091244National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
K99 HL098458National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
5T32CA009330-30National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01 ES017794National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
P20MD006899National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U24AG051129National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
URI: https://openaccess.sgul.ac.uk/id/eprint/108190
Publisher's version: https://doi.org/10.1093/hmg/ddw284

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