Pervasive pleiotropy between psychiatric disorders and immune disorders revealed by integrative analysis of multiple GWAS.
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 x 10(-285), and schizophrenia-Crohn's disease with MHC region excluded (p = 1.1 x 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.
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.|Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.
Qian
Q
Wang
VA CT Healthcare Center, West Haven, CT, USA.|Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.|Department of Mathematics, Hong Kong Baptist University, Hong Kong, Hong Kong SAR.
Can
C
Yang
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|VA CT Healthcare Center, West Haven, CT, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale School of Medicine, West Haven, CT, USA.
Joel
J
Gelernter
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. hongyu.zhao@yale.edu.|Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA. hongyu.zhao@yale.edu.|Department of Genetics, Yale School of Medicine, West Haven, CT, USA. hongyu.zhao@yale.edu.|VA Cooperative Studies Program Coordinating Center, West Haven, CT, USA. hongyu.zhao@yale.edu.
Hongyu
H
Zhao
D001172:Arthritis, Rheumatoid / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics; D018511:Systems Integration
D009419:Nerve Tissue Proteins