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Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.
Wednesday,2015-03-04 14:10 America/Los_Angeles — zdrager
| Title | Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. |
| Publication Type | Journal Article |
| Year of Publication | 2014 |
| Authors | Sinner, 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, Dörr, 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/Institutional Authors | METASTROKE Consortium, AFGen Consortium |
| Journal | Circulation |
| Volume | 130 |
| Issue | 15 |
| Pagination | 1225-35 |
| Date Published | 2014 Oct 7 |
| ISSN | 1524-4539 |
| Keywords | Aged, 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 | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1161/CIRCULATIONAHA.114.009892 |
| Alternate Journal | Circulation |
| PubMed ID | 25124494 |
| PubMed Central ID | PMC4190011 |
| Grant List | 1R01 AG028321 / AG / NIA NIH HHS / United States 1R01 HL092577 / HL / NHLBI NIH HHS / United States 1R01AG032098-01A1 / AG / NIA NIH HHS / United States 1R01HL076784 / HL / NHLBI NIH HHS / United States 1UL-RR024989 / RR / NCRR NIH HHS / United States AG023629 / AG / NIA NIH HHS / United States CA 047988 / CA / NCI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States HHSN268200625226C / / PHS HHS / United States HHSN268200782096C / / PHS HHS / United States HHSN268200800007C / / PHS HHS / United States HHSN268201200036C / / PHS HHS / United States HL 043851 / HL / NHLBI NIH HHS / United States HL-093613 / HL / NHLBI NIH HHS / United States HL065962 / HL / NHLBI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States HL69757 / HL / NHLBI NIH HHS / United States K23 HL114724 / HL / NHLBI NIH HHS / United States K23HL114724 / HL / NHLBI NIH HHS / United States K24 HL105780 / HL / NHLBI NIH HHS / United States K24HL105780 / HL / NHLBI NIH HHS / United States N01- HC-55019 / HC / NHLBI NIH HHS / United States N01-AG-12100 / AG / NIA NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States N01AG62101 / AG / NIA NIH HHS / United States N01AG62103 / AG / NIA NIH HHS / United States N01AG62106 / AG / NIA NIH HHS / United States N01HC55222 / HC / NHLBI NIH HHS / United States N01HC85079 / HC / NHLBI NIH HHS / United States N01HC85080 / HC / NHLBI NIH HHS / United States N01HC85081 / HC / NHLBI NIH HHS / United States N01HC85082 / HC / NHLBI NIH HHS / United States N01HC85083 / HC / NHLBI NIH HHS / United States N01HC85086 / HC / NHLBI NIH HHS / United States N02-HL-6-4278 / HL / NHLBI NIH HHS / United States R01 HL 068986 / HL / NHLBI NIH HHS / United States R01 HL073410 / HL / NHLBI NIH HHS / United States R01 HL085251 / HL / NHLBI NIH HHS / United States R01 HL090620 / HL / NHLBI NIH HHS / United States R01 HL090620 / HL / NHLBI NIH HHS / United States R01 HL092577 / HL / NHLBI NIH HHS / United States R01 HL104156 / HL / NHLBI NIH HHS / United States R01 HL111314 / HL / NHLBI NIH HHS / United States R01 HL111314 / HL / NHLBI NIH HHS / United States R01HL086694 / HL / NHLBI NIH HHS / United States R01HL087641 / HL / NHLBI NIH HHS / United States R01HL092577 / HL / NHLBI NIH HHS / United States R01HL104156 / HL / NHLBI NIH HHS / United States R01HL59367 / HL / NHLBI NIH HHS / United States RC1-HL-099452 / HL / NHLBI NIH HHS / United States T32 HL007208 / HL / NHLBI NIH HHS / United States T32HL007208 / HL / NHLBI NIH HHS / United States U01-NS069208 / NS / NINDS NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States U10HL054512 / HL / NHLBI NIH HHS / United States UL1 TR000439 / TR / NCATS NIH HHS / United States UL1RR025005 / RR / NCRR NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States / / Canadian Institutes of Health Research / Canada / / Intramural NIH HHS / United States |