Xueping Liu1, Ron Nudel2, Wesley K Thompson3, Vivek Appadurai2, Andrew J Schork2, Alfonso Buil2, Simon Rasmussen4, Rosa L Allesøe4, Thomas Werge5, Ole Mors6, Anders D Børglum7, David M Hougaard8, Preben B Mortensen9, Merete Nordentoft10, Michael E Benros11. 1. CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark. 2. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. 3. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark; Department of Family Medicine and Public Health, Division of Biostatistics, University of California, San Diego, CA, USA. 4. Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 6. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 7. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Department of Biomedicine, Aarhus University and Centre for Integrative Sequencing, iSEQ, Aarhus, Denmark; Aarhus Genome Center, Aarhus, Denmark. 8. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 9. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; National Center for Register-Based Research, Aarhus University, Aarhus, Denmark. 10. CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 11. CORE-Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark; Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: Michael.Eriksen.Benros@regionh.dk.
Abstract
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 and investigated the genetic basis of overall autoimmune disease. METHODS: We used diagnostic information from 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 autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort. RESULTS: Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (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). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00-1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10-36, OR = 1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10-8, OR = 10.65, 95%CI = 3.21-35.36). CONCLUSIONS: Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.
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 and investigated the genetic basis of overall autoimmune disease. METHODS: We used diagnostic information from 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 autoimmune and mental diseases. Genetic factors were investigated using GWAS and imputed HLA alleles in the iPSYCH cohort. RESULTS: Of 64,039 individuals, a total of 43,902 (68.6%) were diagnosed with mental disorders and 1383 (2.2%) with autoimmune diseases. There was a significant comorbidity between the two disease classes (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). Adding PRSs to these adjustment models did not have an impact on the associations. PRSs for autoimmune diseases were only slightly associated with increased risk of mental disorders (HR = 1.01, 95%CI: 1.00-1.02, p = 0.038), whereas PRSs for mental disorders were not associated with autoimmune diseases overall. Our GWAS highlighted 12 loci on chromosome 6 (minimum P = 2.74 × 10-36, OR = 1.80, 95% CI: 1.64-1.96), which were implicated in gene regulation through bioinformatic functional analyses, thereby identifying new candidate genes for overall autoimmune disease. Moreover, we observed 20 human leukocyte antigen (HLA) alleles strongly associated, either positively or negatively, with overall autoimmune disease, but we did not find significant evidence of their associations with overall mental disorders. A GWAS of a comorbid diagnosis of an autoimmune disease and a mental disorder identified a genome-wide significant locus on chromosome 7 as well (P = 1.43 × 10-8, OR = 10.65, 95%CI = 3.21-35.36). CONCLUSIONS: Our findings confirm the overall comorbidity and bidirectionality between autoimmune diseases and mental disorders and identify HLA genes which are significantly associated with overall autoimmune disease. Additionally, we identified several new candidate genes for overall autoimmune disease and ranked them based on their association with the investigated diseases.
Authors: Ron Nudel; Rosa Lundbye Allesøe; Wesley K Thompson; Thomas Werge; Simon Rasmussen; Michael E Benros Journal: J Transl Med Date: 2021-05-31 Impact factor: 5.531
Authors: Yunpeng Wang; Ron Nudel; Michael E Benros; Kristin Skogstrand; Simon Fishilevich; Doron Lancet; Jiangming Sun; David M Hougaard; Ole A Andreassen; Preben Bo Mortensen; Alfonso Buil; Thomas F Hansen; Wesley K Thompson; Thomas Werge Journal: PLoS Genet Date: 2020-11-23 Impact factor: 5.917