Abstract
Although some existing epidemiological observations and molecular experiments suggested that brain disorders in the realm of psychiatry may be influenced by immune dysregulation, the degree of genetic overlap between psychiatric disorders and immune disorders has not been well established. We investigated this issue by integrative analysis of genome-wide association studies of 18 complex human traits/diseases (five psychiatric disorders, seven immune disorders, and others) and multiple genome-wide annotation resources (central nervous system genes, immune-related expression-quantitative trait loci (eQTL) and DNase I hypertensive sites from 98 cell lines). We detected pleiotropy in 24 of the 35 psychiatric-immune disorder pairs. The strongest pleiotropy was observed for schizophrenia-rheumatoid arthritis with MHC region included in the analysis (\(p=3.9\times 10^{-285}\)), and schizophrenia-Crohn’s disease with MHC region excluded (\(p=1.1\times 10^{-36}\)). Significant enrichment (>1.4 fold) of immune-related eQTL was observed in four psychiatric disorders. Genomic regions responsible for pleiotropy between psychiatric disorders and immune disorders were detected. The MHC region on chromosome 6 appears to be the most important with other regions, such as cytoband 1p13.2, also playing significant roles in pleiotropy. We also found that most alleles shared between schizophrenia and Crohn’s disease have the same effect direction, with similar trend found for other disorder pairs, such as bipolar-Crohn’s disease. Our results offer a novel bird’s-eye view of the genetic relationship and demonstrate strong evidence for pervasive pleiotropy between psychiatric disorders and immune disorders. Our findings might open new routes for prevention and treatment strategies for these disorders based on a new appreciation of the importance of immunological mechanisms in mediating risk of many psychiatric diseases.
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This study was supported by grants RC2 DA028909, R01 DA12690, R01 DA12849, R01 DA18432, R01 AA11330, R01 AA017535, P50 AA12870, R01 GM59507, and R01 DA030976 from National Institutes of Health, grant No. 61501389 from National Science Funding of China, grant No. 22302815 from the Hong Kong Research Grant Council, and grant FRG2/14-15/069 from Hong Kong Baptist University.
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Q. Wang and C. Yang contributed equally to this work.
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Wang, Q., Yang, C., Gelernter, J. et al. Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS. Hum Genet 134, 1195–1209 (2015). https://doi.org/10.1007/s00439-015-1596-8
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DOI: https://doi.org/10.1007/s00439-015-1596-8