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Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.

TitleTargeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.
Publication TypeJournal Article
Year of Publication2014
AuthorsLin H, Sinner MF, Brody JA, Arking DE, Lunetta KL, Rienstra M, Lubitz SA, Magnani JW, Sotoodehnia N, McKnight B, McManus DD, Boerwinkle E, Psaty BM, Rotter JI, Bis JC, Gibbs RA, Muzny D, Kovar CL, Morrison AC, Gupta M, Folsom AR, Kääb S, Heckbert SR, Alonso A, Ellinor PT
Secondary AuthorsBenjamin EJ
Corporate AuthorsCHARGE Atrial Fibrillation Working Group
JournalHeart Rhythm
Volume11
Issue3
Pagination452-7
Date Published2014 Mar
ISSN1556-3871
KeywordsAged, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6
Abstract

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

DOI10.1016/j.hrthm.2013.11.012
Alternate JournalHeart Rhythm
PubMed ID24239840
PubMed Central IDPMC3943920
Grant ListN02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R21 DA027021 / DA / NIDA NIH HHS / United States
1R01HL104156 / HL / NHLBI NIH HHS / United States
1RC1HL099452 / HL / NHLBI NIH HHS / United States
5RC2HL102419 / HL / NHLBI NIH HHS / United States
1RC1HL101056 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
HHSN2682011000010C / / PHS HHS / United States
R01 HL104156 / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
UL1 TR000161 / TR / NCATS NIH HHS / United States
RC1 HL099452 / HL / NHLBI NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
1K24HL105780 / HL / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
HHSN2682011000012C / / PHS HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
6R01-NS 17950 / NS / NINDS NIH HHS / United States
N01HC-15103 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
1R01HL102214 / HL / NHLBI NIH HHS / United States
N01-HC25195 / HC / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
AG-023629 / AG / NIA NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
1R01HL092577 / HL / NHLBI NIH HHS / United States
5R21DA027021 / DA / NIDA NIH HHS / United States
HHSN2682011000011C / / PHS HHS / United States