Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest Dan E. Arking 2. , Kyndaron Reinier 1. , Wendy Post 3 , Jonathan Jui 4 , Gina Hilton 2 , Ashley O’Connor 2 , Ronald J. Prineas 5 , Eric Boerwinkle 6 , Bruce M. Psaty 7,8 , Gordon F. Tomaselli 3 , Thomas Rea 7 , Nona Sotoodehnia 7 , David S. Siscovick 7 , Gregory L. Burke 5 , Eduardo Marban 1 , Peter M. Spooner 3 , Aravinda Chakravarti 2 * . , Sumeet S. Chugh 1 * . 1 Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 2 Center for Complex Diseases Genomics, McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 3 Division of Cardiology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 4 Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon, United States of America, 5 Department of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina, United States of America, 6 School of Public Health, University of Texas Health Science Center, Houston, Texas, United States of America, 7 Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, United States of America, 8 Group Health Research Institute, Group Health, Seattle, Washington, United States of America Abstract Background: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA. Methodology/Principal Findings: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002– 07, population ,1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p,5 6 10 28 ). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p,10 24 and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p,0.05) and blacks (p,0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p,0.01). Conclusions/Significance: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study. Citation: Arking DE, Reinier K, Post W, Jui J, Hilton G, et al. (2010) Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest. PLoS ONE 5(3): e9879. doi:10.1371/journal.pone.0009879 Editor: Florian Kronenberg, Innsbruck Medical University, Austria Received January 21, 2010; Accepted March 4, 2010; Published March 25, 2010 Copyright: ß 2010 Arking et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Donald W. Reynolds Cardiovascular Clinical Research Center at the Johns Hopkins University School of Medicine; and National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) grant R01 HL088416 (to S.S.C) and R01 HL088456 (to N.S.). S.S.C. is the Pauline and Harold Price Professor at Cedars-Sinai Medical Center, Los Angeles, California. The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. The Cardiovascular Heart Study is supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. This publication was made possible by grant number 1UL1RR025005 from the National Center for Research Resources (NCRR), a component of the NIH, and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Aravinda Chakravarti is a paid member of the Scientific Advisory Board of Affymetrix, a role that is managed by the Committee on Conflict of Interest of the Johns Hopkins University School of Medicine. * E-mail: aravinda@jhmi.edu (AC); sumeet.chugh@cshs.org (SSC) . These authors contributed equally to this work. PLoS ONE | www.plosone.org 1 March 2010 | Volume 5 | Issue 3 | e9879