Comparison of the multivariate genetic architecture of eight major psychiatric disorders across sex

Differences in the patterning of genetic sharing between groups of individuals may arise from biological pathways, social mechanisms, phenotyping and ascertainment. We expand genomic structural equation modeling to allow for testing genomic structural invariance (GSI), that is, the formal comparison of multivariate genetic architecture across groups. We apply GSI to compare the autosomal multivariate genetic architecture of eight psychiatric disorders spanning three factors (psychotic, neurodevelopmental and internalizing) between cisgender males and females. We find that the genetic factor structure is largely similar across sex, permitting meaningful comparisons of associations at the level of the factors. However, in females, problematic alcohol use and posttraumatic stress disorder loaded more strongly on the internalizing factor, while the neurodevelopmental disorder factor exhibited weaker genetic correlations with the other factors. Four phenotypes (educational attainment, insomnia, smoking and deprivation) showed significant, albeit small, sex-differentiated associations with the psychotic factor. As genome-wide association study samples grow and diversify, GSI will become increasingly valuable for comparing multivariate genetic architecture across groups.