• Marissa LeBlanc, Verena Zuber, Bettina Kulle Andreassen, Aree Witoelar, Lingyao Zeng, Francesco Bettella, Yunpeng Wang, Linda K McEvoy, Wesley K Thompson, Andrew J Schork, Sjur Reppe, Elizabeth Barrett-Connor, Symen Ligthart, Abbas Dehghan, Kaare M Gautvik, Christopher P Nelson, Heribert Schunkert, Nilesh J Samani, CARDIoGRAM Consortium, Paul M Ridker, Daniel I Chasman, Pål Aukrust, Srdjan Djurovic, Arnoldo Frigessi, Rahul S Desikan, Anders M Dale, and Ole A Andreassen.
• From the Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (M.L., B.K.A.); Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, and Research Support Services, Oslo University Hospital, Oslo, Norway (M.L., A.F.); NORMENT - K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.Z., A.W., F.B., Y.W., S.D., O.A.A.); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (V.Z., A.W., F.B., S.D., O.A.A.); Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway (B.K.A.); Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (L.Z., H.S.); Deutsches Zentrum für Herz-Kreislauf-Forschung, partner site Munich Heart Alliance, Munich, Germany (L.Z., H.S.); Multimodal Imaging Laboratory, University of California at San Diego, La Jolla (Y.W., L.K.M., A.J.S., R.S.D., A.M.D., O.A.A.); Department of Neurosciences, University of California, San Diego, La Jolla, (Y.W., A.M.D.); Department of Radiology, University of California, San Diego, La Jolla (L.K.M., R.S.D., A.M.D.); Department of Psychiatry, University of California, San Diego, La Jolla (W.K.T., A.M.D.); Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, (A.J.S.); Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway (S.R.); Department of Medical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway (S.R., K.M.G.); Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (S.R., K.M.G.); Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego, La Jolla (E.B.-C.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (S.L., A.D.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (C.P.N.,
• Circ. Res. 2016 Jan 8; 118 (1): 83-94.

RationaleCoronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes.ObjectiveWe aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework.Methods And ResultsUsing genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus.ConclusionsThe observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.© 2015 American Heart Association, Inc.

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