We validate key properties of Genomic SEM with a series of simulations and illustrate the flexibility and utility of Genomic SEM with analyses of real data. These include a joint analysis of GWAS summary statistics from five genetically correlated psychiatric case-control traits: schizophrenia, bipolar disorder, major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety. We model their joint genetic architecture using a general factor of psychopathology (p), for which we identify 27 independent SNPs not previously identified in the univariate GWASs, 5 of which can be validated based on separate GWASs. Polygenic scores derived using this p-factor consistently outperform polygenic scores derived from GWASs of the individual traits in out-of-sample prediction of psychiatric symptoms. Other demonstrations include a multivariate GWAS of neuroticism items, an exploratory factor analysis of anthropometric traits, and a simultaneous analysis of the unique genetic associations between schizophrenia, bipolar disorder, and educational attainment.
