Journal
CIRCULATION
Volume 130, Issue 15, Pages 1225-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.114.009892
Keywords
atrial fibrillation; epidemiology; genetics; gene expression; polymorphism; single nucleotide; zebrafish
Funding
- National Institutes of Health (NIH) [N01-AG-12100]
- NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- AFNET/KORA S4: German National Genome Research Network [NGFN 01GS0838, 01GR0803, BMBF-01EZ0874, NGFN 01GI0204, 01GR0103, NGFN-2, NGFNPlus 01GS0823, NGFNPlus 01GS0834]
- German Federal Ministry of Education and Research (BMBF) [01EZ0874]
- German Competence Network on AF (AFNET) [01 GI 0204/N]
- Leducq Foundation [07-CVD 03]
- BMBF Spitzen cluster personalized medicine m4 [01 EX1021E]
- LMU Excellence Initiative [42595-6]
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- BMBF
- State of Bavaria
- German Heart Foundation
- DZHK (German Center for Cardiovascular Research)
- BMBF (German Ministry of Education and Research)
- ARIC: National Heart, Lung, and Blood Institute (NHLBI) [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, U10HL054512]
- National Human Genome Research Institute [U01HG004402]
- NIH [HHSN268200625226C, UL1RR025005, HHSN268200782096C, K23HL114724, T32HL007208, R01HL092577, HL065962, R01HL104156, K24HL105780]
- NIH Roadmap for Medical Research
- NHLBI [RC1-HL-099452, R01 HL090620, R01 HL111314, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HL080295, HL087652, HL105756, N01-HC-25195, R01 HL 068986, R01 HL085251, R01 HL073410, HL 043851, HL69757]
- American Heart Association. BioBank Japan [09SDG2280087]
- Ministry of Education, Culture, Sports, Science, and Technology, Japan
- SENSIN Medical Research Foundation, Japan
- Danish National Research Foundation Center for Cardiac Arrhythmia
- John and Birthe Meyer Foundation
- Research Foundation of the Heart Center Rigshospitalet
- Laegernes Forsikringsforening af 1891
- Arvid Nilsson Foundation
- Director Henrik Ibsens Foundation
- Villadsen Family Foundation
- stockbroker Henry Hansen and wife Karla Hansen, born Westergaard, Grant
- Danish Heart Foundation [07-10-R60-A1815-B573-22398]
- NIH/National Center for Research Resources Clinical and Translational Scienece Award [1UL-RR024989]
- Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic
- Atrial Fibrillation Innovation Center, State of Ohio
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging (NIA) [AG023629]
- National Center for Advancing Translational Sciences, Clinical & Translational Science Institute [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]
- Affymetrix, Inc [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at the Boston University School of Medicine
- Boston Medical Center
- NIA [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- Intramural Research Program of the NIH, NIA
- Malmo city council
- Swedish Heart-Lung foundation
- Thorsten Westerstrom Foundation
- Swedish Medical Research Council
- Medical Faculty of Lund University
- Malmo University Hospital
- Albert Pahlsson Research Foundation
- Crafoord Foundation
- Region Skane
- Hulda and Conrad Mossfelt Foundation
- King Gustaf V and Queen Victoria Fund
- Lennart Hanssons Memorial Fund
- Wallenberg Foundation
- Doris Duke Charitable Foundation Clinical Scientist Development Award [2014105]
- American Heart Association Established Investigator Award [13EIA14220013]
- Heart and Stroke Foundations of Ontario
- Canadian Institutes for Health Research
- government of Ontario
- Heart and Stroke Foundation of Ontario Clinician-Scientist Award
- Bristol-Myers Squibb
- Netherlands Heart Foundation [2001 D 032]
- Seventh Framework Program of the European Commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- Erasmus Medical Center and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Netherlands Organization for Scientific Research [175.010.2005.011, 911.03.012]
- Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [050-060-810]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- research project Greifswald Approach to Individualized Medicine
- Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania [03IS2061A]
- BMBF [03ZIK012]
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- National Cancer Institute [CA 047988]
- Donald W. Reynolds Foundation
- Fondation Leducq
- Amgen
- Harris Family Foundation [HL-093613]
- Vascular Dementia Research Foundation
- National Institute of Neurological Disorders and Stroke [U01-NS069208]
- Grants-in-Aid for Scientific Research [221S0001, 26293052] Funding Source: KAKEN
- Novo Nordisk Fonden [NNF13OC0005339, NNF14OC0009819] Funding Source: researchfish
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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=6.5x10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2x10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7x10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8x10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0x10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9x10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6x10(-19)), GJA1 (P=2.66x10(-6)), and TBX5 (P=1.36x10(-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.
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