Gene-gene Interaction Analyses for Atrial Fibrillation

• Authors: Honghuang Lin, National Heart Lung and Blood Institute; Martina Mueller-Nurasyid, German Research Center for Environmental Health; Albert V. Smith, University of Iceland; Dan E. Arking, Johns Hopkins University; John Barnard, Cleveland Clinic Foundation; Traci M. Bartz, University of Washington; Kathryn L. Lunetta, National Heart Lung and Blood Institute; Kurt Lohman, Wake Forest University; Marcus E. Kleber, Heidelberg University; Steven A. Lubitz, Harvard University; Bastiaan Geelhoed, University of Groningen; Stella Trompet, Leiden University; Maartje N. Niemeijer, University Medical Center Rotterdam; Tim Kacprowski, University Medicine and Ernst-Moritz-Arndt University Greifswald; Daniel I. Chasman, Brigham and Women’s Hospital; Derek Klarin, Massachusetts General Hospital; Moritz F. Sinner, Ludwig-Maximilians-University Munich; Melanie Waldenberger, Heidelberg University; Thomas Meitinger, Technische Universität München; Tamara B. Harris, National Institute on Aging; Lenore J. Launer, National Institute on Aging; Elsayed Z. Soliman, Wake Forest University; Lin Y. Chen, University of Minnesota; Jonathan D. Smith, Cleveland Clinic Foundation; David R. Van Wagoner, Cleveland Clinic Foundation; Jerome I. Rotter, University of California Los Angeles; Bruce M. Psaty, University of Washington; Zhijun Xie, Boston University; Audrey E. Hendricks, National Heart Lung and Blood Institute; Jingzhong Ding, Wake Forest University; Graciela E. Delgado, Heidelberg University; Niek Verweij, University of Groningen; Pim van der Harst, University of Groningen; Peter W. Macfarlane, University of Glasgow; Ian Ford, University of Glasgow; Albert Hofman, University Medical Center Rotterdam; André Uitterlinden, University Medical Center Rotterdam; Jan Heeringa, University Medical Center Rotterdam; Oscar H. Franco, University Medical Center Rotterdam; Jan A. Kors, University Medical Center Rotterdam; Stefan Weiss, University Medicine and Ernst-Moritz-Arndt University Greifswald; Henry Volzke, University Medicine Greifswald; Lynda M. Rose, Brigham & Womens Hosp; Pradeep Natarajan, Harvard University; Sekar Kathiresan, Harvard University; Stefan Kaab, Ludwig Maximilians University Munich; Vilmundur Gudnason, University of Iceland; Alvaro Alonso, Emory University; Mina K. Chung, Cleveland Clinic Foundation; Susan R. Heckbert, Group Health Cooperative; Emelia J. Benjamin, National Heart Lung and Blood Institute; Yongmei Liu, Wake Forest University; Winfried Marz, University of Heidelberg; Michiel Rienstra, University of Groningen; J. Wouter Jukema, Leiden University; Bruno H. Stricker, University Medical Center Rotterdam; Marcus Dorr, University Medicine Greifswald; Christine M. Albert, Brigham and Women’s Hospital; Patrick T. Ellinor, Harvard University
• Journal Title: Scientific Reports
• Volume: Volume 6
• Publisher: Nature Publishing Group: Open Access Journals - Option C | 2016-11-08, Pages 35371-35371
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/srep35371
• Subjects: Biology, Genetics; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; PROTEIN-INTERACTION MAPS; FAMILIAL AGGREGATION; MISSING HERITABILITY; BREAST-CANCER; ASSOCIATION; RISK; VARIANTS; DISEASE; SUSCEPTIBILITY; METAANALYSIS

Abstract

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.