Comparison of the Multivariate Genetic Architecture of Eight Major Psychiatric Disorders Across Sex

Differences in the patterning of genetic sharing and differentiation between groups may arise from differences in biological pathways, social mechanisms, phenotyping and ascertainment. We expand the Genomic Structural Equation Modeling framework to allow for testing Genomic Structural Invariance (GSI): the formal comparison of multivariate genetic architecture across groups of individuals. We apply GSI to systematically compare the autosomal multivariate genetic architecture of eight psychiatric disorders spanning three broad factors (psychotic, neurodevelopmental, and internalizing) between cisgender males and females. We find that the genetic factor structure is largely similar between males and females, permitting meaningful comparisons of associations at the level of broad factors. However, problematic alcohol use loads on psychotic disorders in males but not in females, and both problematic alcohol use and post-traumatic stress disorder load more strongly on internalizing disorders in females than in males. Despite a high between-sex genetic correlation, the neurodevelopmental disorders factor exhibited weaker genetic correlations with psychotic and internalizing factors in females compared to males. Four biobehavioral phenotypes (educational attainment, insomnia, smoking ever, and Townsend Deprivation Index) had significant albeit small sex-differentiated associations with the psychotic factor. As GWAS samples continue to grow and diversify, GSI will become increasingly valuable for studying multivariate genetic architecture across groups. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This study was supported by NIMH grant 1R01MH120219-01A1 to E.M.T-D. and M.G.N. This work would not have been possible without the enormous efforts put forth by the investigators and participants from the UK Biobank. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The data that support the findings of this study are all publicly available or can be requested for access. Specific download links for various datasets are reported in the Data Availability Statement. 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 GWAS summary statistics from this study are available for download at https://osf.io/spg7f/ Sex-stratified summary statistics used in this study come from the following sources (see Supplementary Note for complete details): Schizophrenia, Bipolar Disorder, Major Depressive Disorder(1): https://doi.org/10.1016/j.biopsych.2021.02.972 Problematic Alcohol Use(1), ADHD: https://doi.org/10.1016/j.biopsych.2020.12.024 Autism: https://doi.org/10.1038/s41588-019-0344-8 Anxiety and Major Depressive Disorder(2): http://www.nealelab.is/uk-biobank PTSD: https://doi.org/10.1016/j.biopsych.2021.09.020 Problematic Alcohol Use(2): https://doi.org/10.1176/appi.ajp.2020.20091390