title: Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.
abstract: There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis. However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se. Here we empirically test the hypothesis that variation in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated with schizophrenia, we identify 6 immune candidates (DPP4, HSPD1, EGR1, CLU, ESAM, NFATC3) encoding proteins with alternative, nonimmune roles in the brain. While our findings do not refute evidence that has accumulated in support of the immune hypothesis, they suggest that genetically mediated alterations in immune function may not play a major role in schizophrenia susceptibility. Instead, there may be a role for pleiotropic effects of a small number of immune genes that also regulate brain development and plasticity. Whether immune alterations drive schizophrenia progression is an important question to be addressed by future research, especially in light of the growing interest in applying immunotherapies in schizophrenia.
authors.affiliation: jennie.pouget@mail.utoronto.ca.
authors.forename: Jennie G
authors.initials: JG
authors.lastname: Pouget
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada;
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Gonçalves
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Division of Genetics and Molecular Medicine, King's College London, London, UK;
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Spain
authors.affiliation: Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA;
authors.forename: Hilary K
authors.initials: HK
authors.lastname: Finucane
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.affiliation: Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada; Lancaster Medical School and Data Science Institute, Lancaster University, Lancaster, UK;
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D012559:Schizophrenia / Q000235:genetics* / Q000276:immunology*
keywords: autoimmune; genetic; immune; inflammation; inflammatory; schizophrenia