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PgmNr 66: Genetic studies in the eMERGE network and UK Biobank offer new insights into pleiotropy across cardiovascular diseases and central nervous system disorders.

Authors:
X. Zhang 1,2; Y. Veturi 2; A. Verma 2; T.G. Drivas 2; W.K. Chung 3; D. Crosslin 4; J.C. Denny 5; D. Fasel 6; H. Hakonarson 7; S. Hebbring 8; G.P. Jarvik 4; I. Kullo 9; E.B. Larson 10; S.A. Pendergrass 11; L. Rasmussen-Torvik 12; D. Schaid 13; P. Sleiman 7; J.W. Smoller 14; I.B. Stanaway 4; W. Wei 15; C. Weng 16; M.D. Ritchie 2

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Affiliations:
1) Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 2) Department of Genetics and Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 3) Department of Pediatrics, Columbia University, New York, NY; 4) Departments of Medicine and Genomic Sciences, University of Washington School of Medicine, Seattle, WA; 5) Department of Medicine, Vanderbilt University, Nashville, TN; 6) Department of Biomedical Informatics, Columbia University, New York, NY; 7) Center for Applied Genomics, Children's Hospital of Philadelphia, PA; 8) Center for Human Genetics, Marshfield Clinic, Marshfield, WI; 9) Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; 10) Kaiser Permanente Washington Health Research Institute, Seattle, WA; 11) Biomedical and Translational Informatics Institute, Geisinger Health System, Danville, PA; 12) Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; 13) Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Rochester, MN; 14) Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA; 15) Department of Biomedical Informatics in School of Medicine, Vanderbilt University, Nashville, TN; 16) Department of Biomedical Informatics, Columbia University, New York, NY


Cardiovascular diseases and central nervous system disorders (such as coronary artery disease, heart failure, Alzheimer’s disease and multiple sclerosis) have a significant impact on mortality rate worldwide and frequently co-occur in patients. Improving disease treatment would benefit from knowledge of the relationship between multiple diseases in these categories. The contribution of pleiotropy to these conditions remains largely unknown given that previous studies generally focused on single diseases for genetic variant discovery. Here we use Phenome-wide association studies (PheWAS) and multi-trait joint association studies to identify pleiotropic genetic variants. A comprehensive set of phenotypes was curated for eMERGE network and UK Biobank using International Classification of Diseases codes from the electronic health records. After quality control in the eMERGE network, we used 61 cardiovascular diseases and 28 central nervous system disorders in 43,015 European-ancestry adults and 7 million SNPs. We performed PheWAS and multi-trait joint analyses (via MultiPhen) for these 89 diseases using all SNPs. Both methods were able to identify previously known disease-associated SNPs, such as Alzheimer’s disease (rs429358) and coronary artery disease (rs1333049). Among 565 Bonferroni significant (α=0.05) SNPs identified by the PheWAS, 359 were Bonferroni significant in multi-trait joint analyses. We conducted replication studies using 294,753 European-ancestry adult samples from UK Biobank. 82 SNPs had a significant association in both PheWAS and MultiPhen; these SNPs were mapped to HLA, LPA, CDKN2B-AS1, NECTIN2, TOMM40, APOE and APOC1 regions. Since the rejection of the null hypothesis for multi-trait joint analysis fails to provide exact associated diseases, we further performed a formal statistical test for pleiotropy using sequential multivariate analyses. We characterized novel SNPs that showed significance across cardiovascular diseases and central nervous system disorders. For instance, rs56131196 (downstream APOC1), which has been previously shown to be associated with Alzheimer’s disease, has implicated its potential pleiotropic influence on dementia, abdominal aortic aneurysm, and ischemic heart disease in eMERGE network and UK Biobank. Our research discovered novel pleiotropy across cardiovascular diseases and central nervous system disorders, which have the potential for assisting in disease prevention and drug repositioning in future research.