Cross-disorder analysis of schizophrenia and 19 immune diseases reveals genetic correlation

Epidemiological studies have revealed that schizophrenia and immune diseases co-occur in the general population at higher than expected rates. Here, we evaluated whether the epidemiologic correlation between immune diseases and schizophrenia might be explained by shared genetic risk factors. We used data from a large genome-wide association study (GWAS) of schizophrenia (N=35,476 cases and 46,839 controls) 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. Next, we investigated genome-wide sharing of common variants using polygenic risk scores for immune diseases. We identified nine variants with potential pleiotropic effects, located in regions associated with both schizophrenia and autoimmune disease. Five of these variants were located outside of the human leukocyte antigen region, and mapped to genes with known roles in calcium signaling. Polygenic risk scores revealed significant genetic overlap with schizophrenia for narcolepsy (p=4.1×10−4), primary biliary cirrhosis (p=1.4×10−8), psoriasis (p=3.6×10−5), systemic lupus erythematosus (p=2.2×10−8), type 1 diabetes (p=2.0×10−6), and ulcerative colitis (p=4.3×10−4). Genetic correlation between these immune diseases and schizophrenia, estimated using cross-trait LD Score regression, ranged from 0.10 to 0.18. We also observed suggestive evidence of sex-dependent genetic correlation between schizophrenia and multiple sclerosis (interaction p=0.02), with genetic risk scores for multiple sclerosis associated with greater risk of schizophrenia among males but not females. Our findings reveal the presence of significant genetic correlation between schizophrenia and several immune diseases, which in some cases may be sex-dependent. Author Summary Immune diseases occur at different rates among patients with schizophrenia compared to the general population. While the reasons for this are unclear, shared genetic risk (genetic correlation) has been proposed as a contributing factor. Prior studies have used GWAS data to estimate the genetic correlation between schizophrenia and a handful of immune diseases, with conflicting results. Here, we performed a comprehensive cross-disorder investigation of schizophrenia and 19 immune diseases. We identified nine individual genetic variants associated with both schizophrenia and immune diseases, including four variants close to genes involved in calcium signalling (PLCL1, BANK1, EPO, PITPNM2). We demonstrated significant genome-wide genetic correlation between schizophrenia and narcolepsy, primary biliary cirrhosis, psoriasis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis. Finally, we identified a potential sex-dependent pleiotropic effect between schizophrenia and multiple sclerosis, with genetic risk scores for multiple sclerosis associated with greater risk of schizophrenia among males but not females. Our findings point to a shared genetic basis between schizophrenia and at least a subset of immune diseases. These results raise the possibility that the same genetic variants may exert their effects on neurons or immune cells to influence the development of psychiatric and immune disorders, respectively.