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Clinical and epidemiological studies have been unable to unravel the nature of this relationship. We obtained summary-data of genome-wide-association studies of schizophrenia (N = 130 644), heart failure (N = 977 323), coronary artery disease (N = 332 477), systolic and diastolic blood pressure (N = 757 601), heart rate variability (N = 46 952), QT interval (N = 103 331), early repolarization and dilated cardiomyopathy ECG patterns (N = 63 700). We computed genetic correlations and conducted bi-directional Mendelian randomization (MR) to assess causality. With multivariable MR, we investigated whether causal effects were mediated by smoking, body mass index, physical activity, lipid levels, or type 2 diabetes. Genetic correlations between schizophrenia and CVD were close to zero (\u22120.02\u20130.04). There was evidence that liability to schizophrenia causally increases heart failure risk. This effect remained consistent with multivariable MR. There was also evidence that liability to schizophrenia increases early repolarization pattern, largely mediated by BMI and lipids. Finally, there was evidence that liability to schizophrenia increases heart rate variability, a direction of effect contrasting clinical studies. There was weak evidence that higher systolic blood pressure increases schizophrenia risk. Our finding that liability to schizophrenia increases heart failure is consistent with the notion that schizophrenia involves a systemic dysregulation of the body with detrimental effects on the heart. To decrease cardiovascular mortality among individuals with schizophrenia, priority should lie with optimal treatment in early stages of psychosis.<\/jats:p>","DOI":"10.1093\/schbul\/sbab132","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T17:04:28Z","timestamp":1634663068000},"page":"463-473","source":"Crossref","is-referenced-by-count":78,"title":["Exploring the Relationship Between Schizophrenia and Cardiovascular Disease: A Genetic Correlation and Multivariable Mendelian Randomization Study"],"prefix":"10.1093","volume":"48","author":[{"given":"Rada R","family":"Veeneman","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jentien M","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel","family":"Abdellaoui","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5188-5775","authenticated-orcid":false,"given":"Eleanor","family":"Sanderson","sequence":"additional","affiliation":[{"name":"Integrative Epidemiology Unit, University of Bristol, Bristol, UK"},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3961-3202","authenticated-orcid":false,"given":"Robyn E","family":"Wootton","sequence":"additional","affiliation":[{"name":"Integrative Epidemiology Unit, University of Bristol, Bristol, UK"},{"name":"Nic Waals institute, Lovisenberg Diaconal Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1472-0258","authenticated-orcid":false,"given":"Rafik","family":"Tadros","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Center, Montreal Heart Institute, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"},{"name":"Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie R","family":"Bezzina","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damiaan","family":"Denys","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus R","family":"Munaf\u00f2","sequence":"additional","affiliation":[{"name":"Integrative Epidemiology Unit, University of Bristol, Bristol, UK"},{"name":"Tobacco and Alcohol Research Group, School of Psychological Science, University of Bristol, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin J H","family":"Verweij","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorien L","family":"Treur","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The 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