Extensive sex differences in depression-linked variants functionally assayed in mouse brain [P0&P10]

Here, we selected >1000 variants from over 30 depression-associated loci using brain epigenomic data, and functionally assayed them using in vivo functional assays in the mouse brain to examine sex-by-genotype interactions. We identify extensive sex-by-allele effects in mature hippocampus, suggesting genetic risk and thus disease mechanisms may be distinct between the sexes. Unbiased informatics approaches indicated a role for nuclear hormone receptors, which was supported by . Further, comparative analysis of allelic function in the neonatal mouse brain, during a key between developmental neonates during the masculinizing testosterone surge, and in the adult hippocampus—a region of interest in depression pathology—but not at 10 days old, a older hormonally quiescent developmental stage juveniles. Our study provides novel insights into depression genetics as influenced by age, biological sex, and cell type, and provides a framework for in vivo parallel assays at a scale not previously shown possible to functionally define interactions between sex and disease variation. AAV9 MPRA library was delivered into the mouse brain in utero (embryonic day 15). Mice were screened at birth for reporter-driven red fluorescence (visible through the skull by eye by green light illumination). Brains were collected WITHOUT cerebellum for RNA extraction at postnatal day 0 (P0) (n=9 male, n=6 female) or P10 (n=7 male, 6 female). Additional grant information: 571009 - Joseph Dougherty - Simons Foundation