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Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn\u2019s disease via altered methylation and expression of EPHB4\u2014a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg\u00a0=\u20090.12\u2009\u00b1\u20090.03, P\u2009=\u20092.49 \u00d7 10\u22124), Crohn\u2019s disease (rg\u00a0=\u20090.097\u2009\u00b1\u20090.06, P\u2009=\u20093.27 \u00d7 10\u22123), ulcerative colitis (rg\u00a0=\u20090.11\u2009\u00b1\u20090.04, P\u2009=\u20094.05 \u00d7 10\u20133), primary biliary cirrhosis (rg\u00a0=\u20090.13\u2009\u00b1\u20090.05, P\u2009=\u20093.98 \u00d7 10\u22123), psoriasis (rg\u00a0=\u20090.18\u2009\u00b1\u20090.07, P\u2009=\u20097.78 \u00d7 10\u20133) and systemic lupus erythematosus (rg\u00a0=\u20090.13\u2009\u00b1\u20090.05, P\u2009=\u20093.76 \u00d7 10\u20133). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.<\/jats:p>","DOI":"10.1093\/hmg\/ddz145","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T15:11:02Z","timestamp":1560784262000},"page":"3498-3513","source":"Crossref","is-referenced-by-count":93,"title":["Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk"],"prefix":"10.1093","volume":"28","author":[{"given":"Jennie G","family":"Pouget","sequence":"first","affiliation":[{"name":"Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada"},{"name":"Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Schizophrenia Working Group of the Psychiatric Genomics Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buhm","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Mignot","sequence":"additional","affiliation":[{"name":"Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna M","family":"Ollila","sequence":"additional","affiliation":[{"name":"Center for Sleep Sciences and Medicine, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, Palo Alto, CA, USA"},{"name":"Finnish Institute for Molecular Medicine, Helsinki, Finland"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA and Broad Institute, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Barker","sequence":"additional","affiliation":[{"name":"School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"},{"name":"St. John\u2019s Institute of Dermatology, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Spain","sequence":"additional","affiliation":[{"name":"School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"},{"name":"Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Dand","sequence":"additional","affiliation":[{"name":"School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Trembath","sequence":"additional","affiliation":[{"name":"School of Basic and Medical Biosciences, Faculty of Life Sciences and Medicine, King\u2019s College London, London, UK"},{"name":"Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Martin","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez-Neyra, Consejo Superior de Investigaciones Cient\u00edficas (IPBLN-CSIC), Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen D","family":"Mayes","sequence":"additional","affiliation":[{"name":"The University of Texas Health Science Center\u2013Houston, Houston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Bossini-Castillo","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"L\u00f3pez-Isac","sequence":"additional","affiliation":[{"name":"Institute of Parasitology and Biomedicine L\u00f3pez-Neyra, Consejo Superior de Investigaciones Cient\u00edficas (IPBLN-CSIC), Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Jin","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO, USA"},{"name":"Department of Pediatrics, University of Colorado School of Medicine, Aurora 80045, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A","family":"Santorico","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO, USA"},{"name":"Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA"},{"name":"Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Spritz","sequence":"additional","affiliation":[{"name":"Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO, USA"},{"name":"Department of Pediatrics, University of Colorado School of Medicine, Aurora 80045, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantin","family":"Polychronakos","sequence":"additional","affiliation":[{"name":"Endocrine Genetics Laboratory, Department of Pediatrics and the Child Health Program of the Research Institute, McGill University Health Centre, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Raychaudhuri","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA"},{"name":"Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA"},{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"name":"Division of Genetics, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Rheumatology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Knight","sequence":"additional","affiliation":[{"name":"Lancaster Medical School and Data Science Institute, Lancaster University, Lancaster, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"2019120404004467000_ref1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/nature13595","article-title":"Biological insights from 108 schizophrenia-associated genetic loci","volume":"511","author":"Schizophrenia Working Group of the Psychiatric Genomics 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Psychiatry"},{"key":"2019120404004467000_ref5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1176\/appi.ajp.2013.13010086","article-title":"A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis","volume":"171","author":"Benros","year":"2014","journal-title":"Am. J. Psychiatry"},{"key":"2019120404004467000_ref6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1176\/appi.ajp.163.3.521","article-title":"Association of schizophrenia and autoimmune diseases: linkage of Danish national registers","volume":"163","author":"Eaton","year":"2006","journal-title":"Am. J. Psychiatry"},{"key":"2019120404004467000_ref7","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1111\/j.1399-5618.2010.00853.x","article-title":"Autoimmune diseases, bipolar disorder, and non-affective psychosis","volume":"12","author":"Eaton","year":"2010","journal-title":"Bipolar Disord."},{"key":"2019120404004467000_ref8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/ajmg.b.32282","article-title":"The relationship between schizophrenia and rheumatoid arthritis revisited: genetic and epidemiological analyses","volume":"168B","author":"Euesden","year":"2015","journal-title":"Am. J. Med. Genet. B. Neuropsychiatr. Genet."},{"key":"2019120404004467000_ref9","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature16549","article-title":"Schizophrenia risk from complex variation of complement component 4","volume":"530","author":"Sekar","year":"2016","journal-title":"Nature"},{"key":"2019120404004467000_ref10","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1002\/art.39589","article-title":"Effects of complement C4 gene copy number variations, size dichotomy, and C4A deficiency on genetic risk and clinical presentation of systemic lupus erythematosus in East Asian populations","volume":"68","author":"Yih Chen","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"2019120404004467000_ref11","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1093\/schbul\/sbw059","article-title":"Genome-wide association studies suggest limited immune gene enrichment in schizophrenia compared to 5 autoimmune diseases","volume":"42","author":"Pouget","year":"2016","journal-title":"Schizophr. Bull."},{"key":"2019120404004467000_ref12","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/S0140-6736(12)62129-1","article-title":"Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis","volume":"381","author":"Cross-Disorder Group of the Psychiatric Genomics Consortium","year":"2013","journal-title":"Lancet"},{"key":"2019120404004467000_ref13","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/ng.2711","article-title":"Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs","volume":"45","author":"Cross-Disorder Group of the Psychiatric Genomics Consortium","year":"2013","journal-title":"Nat. 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Genet."},{"key":"2019120404004467000_ref18","doi-asserted-by":"crossref","first-page":"eaap8757","DOI":"10.1126\/science.aap8757","article-title":"Analysis of shared heritability in common disorders of the brain","volume":"360","author":"Brainstorm Consortium","year":"2018","journal-title":"Science"},{"key":"2019120404004467000_ref19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.tig.2012.10.010","article-title":"The many faces of pleiotropy","volume":"29","author":"Paaby","year":"2013","journal-title":"Trends Genet."},{"key":"2019120404004467000_ref20","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/ng.3572","article-title":"A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases","volume":"48","author":"Han","year":"2016","journal-title":"Nat. Genet."},{"key":"2019120404004467000_ref21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s00439-017-1854-z","article-title":"The ubiquity of pleiotropy in human disease","volume":"137","author":"Chesmore","year":"2018","journal-title":"Hum. Genet."},{"key":"2019120404004467000_ref22","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"2019120404004467000_ref23","article-title":"The landscape of pervasive horizontal pleiotropy in human genetic variation is driven by extreme polygenicity of human traits and diseases","author":"Jordan","year":"2018","journal-title":"bio Rxiv"},{"key":"2019120404004467000_ref24","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1126\/science.aad6469","article-title":"Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap","volume":"359","author":"Gandal","year":"2018","journal-title":"Science"},{"key":"2019120404004467000_ref25","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.schres.2014.09.004","article-title":"Genetic liability for schizophrenia predicts risk of immune disorders","volume":"159","author":"Stringer","year":"2014","journal-title":"Schizophr. 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