Extensive sex differences in depression-linked variants functionally assayed in mouse brain [Hippocampus]

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. Overall design: n=5 replicates each of AAV9-transduced adult mouse brain tissues: male total hippocampus, female total hippocampus, male Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction, female Vglut1+ translating-ribosome affinity purification immunoprecipitated RNA fraction. Additional grant information: 571009 - Joseph Dougherty - Simons Foundation