Importance: Autoimmune and autoinflammatory diseases have been linked to psychiatric disorders in the phenotypic and genetic literature. However, a comprehensive model that investigates the association between a broad range of psychiatric disorders and immune-mediated disease in a multivariate framework is lacking. Objective: This study aims to establish a factor structure based on the genetic correlations of immune-mediated diseases and investigate their genetic relationships with clusters of psychiatric disorders. Design, Setting, and Participants: We utilized Genomic Structural Equation Modeling (Genomic SEM) to establish a factor structure of 11 immune-mediated diseases. Genetic correlations between these immune factors were examined with five established factors across 13 psychiatric disorders representing compulsive, schizophrenia/bipolar, neurodevelopmental, internalizing, and substance use disorders. We included GWAS summary statistics of individuals of European ancestry with sample sizes from 1,223 cases for Addison's disease to 170,756 cases for major depressive disorder. Main Outcomes and Measures: Genetic correlations between psychiatric and immune-mediated disease factors and traits to determine genetic overlap. We develop and validate a new heterogeneity metric, QFactor, that quantifies the degree to which factor correlations are driven by more specific pairwise associations. We also estimate residual genetic correlations between pairs of psychiatric disorders and immune-mediated diseases. Results: A four-factor model of immune-mediated diseases fit the data well and described a continuum from autoimmune to autoinflammatory diseases. The four factors reflected autoimmune, celiac, mixed pattern, and autoinflammatory diseases. Analyses revealed seven significant factor correlations between the immune and psychiatric factors, including autoimmune and mixed pattern diseases with the internalizing and substance use factors, and autoinflammatory diseases with the compulsive, schizophrenia/bipolar, and internalizing factors. Additionally, we find evidence of divergence in associations within factors as indicated by QFactor. This is further supported by 14 significant residual genetic correlations between individual psychiatric disorders and immune-mediated diseases. Conclusion and Relevance: Our results revealed genetic links between clusters of immune-mediated diseases and psychiatric disorders. Current analyses indicate that previously described relationships between specific psychiatric disorders and immune-mediated diseases often capture broader pathways of risk sharing indexed by our genomic factors, yet are more specific than a general association across all psychiatric disorders and immune-mediated diseases.

The authors have declared no competing interest.

SB, ADG, JML, LSS are supported by NIMH Grant R01MH120219. ADG is supported by NIA Grant RF1AG073593. SB is supported by the Shurl and Kay Curci Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data used in this study came from publically available sources. Summary statistics for data from the Psychiatric Genomics Consortium (PGC) can be downloaded or requested here: https://www.med.unc.edu/pgc/download-results/; Summary statistics for the Anxiety phenotype can be downloaded here: https://drive.google.com/drive/folders/1fguHvz7l2G45sbMI9h_veQun4aXNTy1v; Summary statistics for Celiac Disease: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90014001-GCST90015000/GCST90014442/; Summary statistics for Systemic Lupus Erythematosus: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST003001-GCST004000/GCST003156/; Summary statistics for Diabetes Type 1: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90014001-GCST90015000/GCST90014023/; Summary statistics for Rheumatoid Arthritis: http://plaza.umin.ac.jp/~yokada/datasource/software.htm; Summary statistics for Crohn's Disease: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004132/; Summary statistics for Ulcerative colitis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST004001-GCST005000/GCST004133/; Summary statistics for Juvenile idiopathic arthritis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90010001-GCST90011000/GCST90010715/harmonised/; Summary statistics for Addison's Disease: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90011001-GCST90012000/GCST90011871/harmonised/; Summary statistics for Myasthenia gravis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90093001-GCST90094000/GCST90093061/; Summary statistics for Psoriasis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90019001-GCST90020000/GCST90019016/; Summary statistics for Psoriatic arthritis: http://ftp.ebi.ac.uk/pub/databases/gwas/summary_statistics/GCST90243001-GCST90244000/GCST90243956/; Links to the LD-scores, reference panel data, and the code used to produce the current results can all be found at: https://github.com/GenomicSEM/GenomicSEM/wiki