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Circulation DOI:10.1161/CIRCULATIONAHA.114.009892

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

Publication TypeJournal Article
Year of Publication2014
AuthorsSinner, MF, Tucker, NR, Lunetta, KL, Ozaki, K, J Smith, G, Trompet, S, Bis, JC, Lin, H, Chung, MK, Nielsen, JB, Lubitz, SA, Krijthe, BP, Magnani, JW, Ye, J, Gollob, MH, Tsunoda, T, Müller-Nurasyid, M, Lichtner, P, Peters, A, Dolmatova, E, Kubo, M, Smith, JD, Psaty, BM, Smith, NL, J Jukema, W, Chasman, DI, Albert, CM, Ebana, Y, Furukawa, T, Macfarlane, PW, Harris, TB, Darbar, D, Dorr, M, Holst, AG, Svendsen, JH, Hofman, A, Uitterlinden, AG, Gudnason, V, Isobe, M, Malik, R, Dichgans, M, Rosand, J, Van Wagoner, DR, Benjamin, EJ, Milan, DJ, Melander, O, Heckbert, SR, Ford, I, Liu, Y, Barnard, J, Olesen, MS, Stricker, BHC, Tanaka, T, Kääb, S, Ellinor, PT
Corporate AuthorsMETASTROKE Consortium, AFGen Consortium
JournalCirculation
Volume130
Issue15
Pages1225-35
Date Published2014 Oct 07
ISSN1524-4539
KeywordsAged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins
Abstract

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

URLhttp://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=25124494
DOI10.1161/CIRCULATIONAHA.114.009892
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25124494?dopt=Abstract

Alternate JournalCirculation
PubMed ID25124494
PubMed Central IDPMC4190011
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
K23HL114724 / HL / NHLBI NIH HHS / United States
R01HL104156 / HL / NHLBI NIH HHS / United States
UL1 RR024989 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
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N01AG12100 / AG / NIA NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
K24 HL105780 / HL / NHLBI NIH HHS / United States
R01HL092577 / HL / NHLBI NIH HHS / United States
AHA_09FTF2190028 / AHA / None / None
R01HL59367 / HL / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01 AG062101 / AG / NIA NIH HHS / United States
1R01 AG028321 / AG / NIA NIH HHS / United States
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HL 043851 / HL / NHLBI NIH HHS / United States
HL69757 / HL / NHLBI NIH HHS / United States
R01 HL104156 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 HL068986 / HL / NHLBI NIH HHS / United States
R01 HL043851 / HL / NHLBI NIH HHS / United States
K24HL105780 / HL / NHLBI NIH HHS / United States
1UL-RR024989 / RR / NCRR NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
HL-093613 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
R01 HL085251 / HL / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
HL065962 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01-NS069208 / NS / NINDS NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
RC1 HL099452 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
R01 HL076784 / HL / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01 AG062106 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
R01 HL 068986 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL090620 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
CA 047988 / CA / NCI NIH HHS / United States
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T32 HL007208 / HL / NHLBI NIH HHS / United States
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P30 DK063491 / DK / NIDDK NIH HHS / United States
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1R01 HL092577 / HL / NHLBI NIH HHS / United States
/ / Intramural NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01HL087641 / HL / NHLBI NIH HHS / United States
U01 NS069208 / NS / NINDS NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01 AG062103 / AG / NIA NIH HHS / United States
RC1-HL-099452 / HL / NHLBI NIH HHS / United States
R21 HL093613 / HL / NHLBI NIH HHS / United States
R01 HL111314 / HL / NHLBI NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
1R01HL076784 / HL / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
R01 CA047988 / CA / NCI NIH HHS / United States
N01- HC-55019 / HC / NHLBI NIH HHS / United States
HHSN268200800007C / / PHS HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
U19 HL069757 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
T32HL007208 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268200782096C / / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
U10HL054512 / HL / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 AG028321 / AG / NIA NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
R01 HL073410 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
AG023629 / AG / NIA NIH HHS / United States
U01 HL069757 / HL / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
U10 HL054512 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States