In the current application, we are interested in enrichment of genetic signal shared across subclusters of disorders and disorder-specific signal, as indexed by a factor model that allows the estimates of factor variances and disorder-specific uniquenesses, respectively, to vary across annotations, while holding all factor loadings invariant across annotations. We use a two-step model-fitting procedure to estimate the enrichment ratio in order to directly obtain an estimate of its SE. In Step 1, we estimate the factor loadings needed to scale the total genome-wide variances of the factors to 1.0. This is achieved by fitting a model to the genome-wide S-LDSC matrix in which unit variance identification is used. In Step 2, the loading estimates from the prior Step 1 model are fixed and the factor variance is freely estimated separately in each annotation using the S0,c matrices. Thus, the estimated factor variances in Step 2 are scaled proportionally relative to the genome-wide factor variance (i.e., the numerator of the enrichment ratio). This estimate and its SE are subsequently divided by the proportion of SNPs in the corresponding annotation (i.e.,
