Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk

Pouget, Jennie G and Han, Buhm and Wu, Yang and Mignot, Emmanuel and Ollila, Hanna M and Barker, Jonathan and Spain, Sarah and Dand, Nick and Trembath, Richard and Martin, Javier and Mayes, Maureen D and Bossini-Castillo, Lara and López-Isac, Elena and Jin, Ying and Santorico, Stephanie A and Spritz, Richard A and Hakonarson, Hakon and Polychronakos, Constantin and Raychaudhuri, Soumya and Knight, Jo and Schizophrenia Working Group of the Psychiatric Genomics Consorti (2019) Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk. Human Molecular Genetics, 28 (20). pp. 3498-3513. ISSN 0964-6906

Abstract

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. 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's disease via altered methylation and expression of EPHB4-a 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 = 0.12 ± 0.03, P = 2.49 × 10-4), Crohn's disease (rg = 0.097 ± 0.06, P = 3.27 × 10-3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10-3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10-3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10-3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10-3). 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.