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Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.

TitleCommon genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.
Publication TypeJournal Article
Year of Publication2013
AuthorsDeo R, Nalls MA, Avery CL, Smith JG, Evans DS, Keller MF, Butler AM, Buxbaum SG, Li G, P Quibrera M, Smith EN, Tanaka T, Akylbekova EL, Alonso A, Arking DE, Benjamin EJ, Berenson GS, Bis JC, Chen LYee, Chen W, Cummings SR, Ellinor PT, Evans MK, Ferrucci L, Fox ER, Heckbert SR, Heiss G, Hsueh WC, Kerr KF, Limacher MC, Liu Y, Lubitz SA, Magnani JW, Mehra R, Marcus GM, Murray SS, Newman AB, Njajou O, North KE, Paltoo DN, Psaty BM, Redline SS, Reiner AP, Robinson JG, Rotter JI, Samdarshi TE, Schnabel RB, Schork NJ, Singleton AB, Siscovick D, Soliman EZ, Sotoodehnia N, Srinivasan SR, Taylor HA, Trevisan M, Zhang Z-M, Zonderman AB, Newton-Cheh C
Secondary AuthorsWhitsel EA
JournalHeart Rhythm
Volume10
Issue3
Pagination401-8
Date Published2013 Mar
ISSN1556-3871
KeywordsAdult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States
Abstract

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

DOI10.1016/j.hrthm.2012.11.014
Alternate JournalHeart Rhythm
PubMed ID23183192
PubMed Central IDPMC3718037
Grant ListR00 HL098458 / HL / NHLBI NIH HHS / United States
32105-6 / / PHS HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
1-R01-ES017794 / ES / NIEHS NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
M01RR00080 / RR / NCRR NIH HHS / United States
HL085251 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
42107-26 / / PHS HHS / United States
32115 / / PHS HHS / United States
R00HL098458 / HL / NHLBI NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
N01-WH-2-2110 / WH / WHI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
32100-2 / / PHS HHS / United States
24152 / / PHS HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
N01HC-55222 / HC / NHLBI NIH HHS / United States
HL 46380 / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
42129-32 / / PHS HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
P20 MD006899 / MD / NIMHD NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC95163 / HC / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
K23DK089118 / DK / NIDDK NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
32118-32119 / / PHS HHS / United States
K23 DK089118 / DK / NIDDK NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
R01-HL-071205 / HL / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
32108-9 / / PHS HHS / United States
N01-HC-95171 / HC / NHLBI NIH HHS / United States
UL1RR025774 / RR / NCRR NIH HHS / United States
N01HC-15103 / HC / NHLBI NIH HHS / United States
HD-062783 / HD / NICHD NIH HHS / United States
N01-HC-95172 / HC / NHLBI NIH HHS / United States
AG-16592 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268200782096C / / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01AG62106 / AG / NIA NIH HHS / United States
32122 / / PHS HHS / United States
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AG-023629 / AG / NIA NIH HHS / United States
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44221 / / PHS HHS / United States
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32111-13 / / PHS HHS / United States
N01-HC-95170 / HC / NHLBI NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States