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

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DOI

  • Xueping Liu, 1] Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark. [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.
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  • Ron Nudel, Institute of Biological Psychiatry
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  • Wesley K Thompson, Department of Dermatology, University of California, San Diego, California; Department of Pediatrics, University of California, San Diego, California; Rady Children's Hospital, San Diego, California.
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  • Vivek Appadurai, Institute of Biological Psychiatry
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  • Andrew J Schork, Institute of Biological Psychiatry
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  • Alfonso Buil, Institute of Biological Psychiatry
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  • Simon Rasmussen, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Københavns Universitet - Graduate School of Health and Medical Sciences Faculty of Health and Medical Sciences, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
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  • Rosa L Allesøe, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
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  • Thomas Werge, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
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  • Ole Mors
  • Anders D Børglum
  • David M Hougaard, Center for Neonatal Screening
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  • Preben B Mortensen
  • Merete Nordentoft, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.
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  • Michael E Benros, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark Danish Arrhythmia Research Centre, University of Copenhagen, Copenhagen, Denmark.

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 1,383 (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 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.

OriginalsprogEngelsk
TidsskriftBrain, Behavior, and Immunity
ISSN0889-1591
DOI
StatusE-pub ahead of print - 10 jun. 2020

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Copyright © 2020. Published by Elsevier Inc.

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