In order to identify gene sets and categories in which shared and unique genetic signal for multiple disorders is disproportionally localized, we developed and validated both a multivariate extension of S-LDSC and Stratified Genomic SEM. In line with prior findings linking SCZ and BIP to excitatory hippocampal CA142,43 and CA344,45 neurons and GABAergic neurons46,47, we observe that the intersection between PI genes and genes expressed in both excitatory and GABAergic neurons explained an outsized proportion of the genetic variance in the Psychotic disorders factor. These results converge with considerable evidence from prior univariate work in indicating shared risk pathways for SCZ and BIP. Enrichment of variance unique to MDD, rather than shared across internalizing disorders, in excitatory dentate gyrus (DG) neurons is consistent with prior findings on the anti-depressive effects of DG stimulation in mouse models48 and the observation that anti-depressants increase neurogenesis in this region49.
