Gene-gene Interaction Analyses for Atrial Fibrillation

Honghuang Lin, Martina Mueller-Nurasyid, Albert V. Smith, Dan E. Arking, John Barnard, Traci M. Bartz, Kathryn L. Lunetta, Kurt Lohman, Marcus E. Kleber, Steven A. Lubitz, Bastiaan Geelhoed, Stella Trompet, Maartje N. Niemeijer, Tim Kacprowski, Daniel I. Chasman, Derek Klarin, Moritz F. Sinner, Melanie Waldenberger, Thomas Meitinger, Tamara B. HarrisLenore J. Launer, Elsayed Z. Soliman, Lin Y. Chen, Jonathan D. Smith, David R. Van Wagoner, Jerome I. Rotter, Bruce M. Psaty, Zhijun Xie, Audrey E. Hendricks, Jingzhong Ding, Graciela E. Delgado, Niek Verweij, Pim Van Der Harst, Peter W. Macfarlane, Ian Ford, Albert Hofman, André Uitterlinden, Jan Heeringa, Oscar H. Franco, Jan A. Kors, Stefan Weiss, Henry Völzke, Lynda M. Rose, Pradeep Natarajan, Sekar Kathiresan, Stefan Kääb, Vilmundur Gudnason, Alvaro Alonso, Mina K. Chung, Susan R. Heckbert, Emelia J. Benjamin, Yongmei Liu, Winfried März, Michiel Rienstra, J. Wouter Jukema, Bruno H. Stricker, Marcus Dörr, Christine M. Albert, Patrick T. Ellinor

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9 Scopus citations


Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27-1.65, P = 4.3 × 10-8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10-7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.

Original languageEnglish (US)
Article number35371
JournalScientific reports
StatePublished - Nov 8 2016

Bibliographical note

Funding Information:
The study was supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN), the German National Competence network on atrial fibrillation (AFNET), the Leducq Foundation (07-CVD 03), the D.W. Reynolds Foundation Clinical Cardiovascular Research Center at Johns Hopkins University, and the Bioinformatics for the Functional Analysis of Mammalian Genomes program (BFAM) by grants to Stefan K??b (01GS0499, 01GI0204, 01GS0838). The KORA study was initiated and financed by the Helmholtz Zentrum M?nchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universit?t, as part of LMUinnovativ. Dr. Sinner is supported by the German Heart Foundation. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, R01HL086694, and R01HL111314; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Dr. Alonso is supported by grant 16EIA26410001 from the American Heart Association. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. This CHS research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268200800007C, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL103612, HL105756, HL120393 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also The Cleveland Clinic AF study was supported by NIH grants to Drs. Chung, Barnard, Smith, and Van Wagoner (R01HL090620, R01HL111314), an NIH/NCRR CTSA grant (1ULRR024989), Heart and Vascular Institute Philanthropic grant, Department of Cardiovascular Medicine, Cleveland Clinic (Chung), and a Leducq Fondation grant 07-CVD-03 (Van Wagoner). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195; HHSN268201500001I). This project also was supported by NIH grants to Drs. Ellinor, Benjamin, and Lunetta (1RO1HL092577) and Benjamin and Ellinor (1R01HL128914). LURIC was supported by the 7th Framework Program (AtheroRemo, grant agreement number 201668 and RiskyCAD, grant agreement number 305739) of the EU. The PREVEND study is supported by the Dutch Kidney Foundation (grant E0.13), the National Institutes of Health (grant 2R01LM010098), The Netherlands organization for health research and development (NWOGroot grant 175.010.2007.006, ZonMw grant 90.700.441), and the Dutch Inter University Cardiology Institute Netherlands (ICIN), and the Netherlands Heart Foundation (grant NHS2010B280). Dr. M. Rienstra is supported by a grant from the Netherlands Organization for Scientific Research (Veni grant 016.136.055). There are no relations with industry. The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI-MED)' funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the 'Center of Knowledge Interchange' program of the Siemens AG and the Cach? Campus program of the InterSystems GmbH. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is supported by the Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for Scientific Research (NWO); the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE) the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sport; the European Commission (DG XII); and the Municipality of Rotterdam. Dr. Ellinor is supported by grants from the National Institutes of Health (HL104156, HL105780, HL065962). Dr. Ellinor is also supported by an Established Investigator Award from the American Heart Association (13EIA14220013) and by support from the Fondation Leducq (14CVD01). Dr. Lubitz is supported by NIH grants K23HL114724, and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105.

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