Genetic factors underlying the bidirectional relationship between autoimmune and mental disorders – findings from a Danish population-based study

Background Previous studies have indicated the bidirectionality between autoimmune and mental disorders. However, genetic studies underpinning the co-occurrence of the two disorders have been lacking. In this study, we examined the potential genetic contribution to the association between autoimmune and mental disorders. Methods We used diagnostic information for patients with seven autoimmune diseases and six mental disorders from the Danish population-based case-cohort sample (iPSYCH2012). We explored the epidemiological association using survival analysis and modelled the effect of polygenic risk scores (PRSs) on two diseases. The genetic factors were investigated using GWAS and HLA imputation data based on iPSYCH cohort. Results Among 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1,383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two diseases ( P =2.67×10 -7 , OR=1.38, 95%CI=1.22-1.56), with an overall bidirectional association wherein individuals with autoimmune diseases had an increased risk of subsequent mental disorders (HR=1.13, 95%CI: 1.07-1.21, P =7.95×10 -5 ) and vice versa (HR=1.27, 95%CI=1.16-1.39, P =8.77×10 -15 ). Though PRSs were significantly correlated with both types of diagnosis, PRSs had little effect on the bidirectional relationship. Importantly, we for the first time observed 12 human leukocyte antigen (HLA) loci and 20 HLA alleles strongly associated with overall autoimmune diseases, but we did not find significant evidence of their associations with overall mental disorders. Conclusions Our findings confirm the overall comorbidity and bidirectionality between autoimmune and mental disorders and discover HLA genes which are significantly associated with overall autoimmune diseases, but not with overall mental disorders.