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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10 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

ASJC Scopus subject areas

  • General


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