Sex significantly impacts the function of major depression-linked variants in vivo

Sex significantly impacts the function of major depression-linked variants in vivo. Bernard Mulvey, Din Selmanovic, Joseph D. Dougherty. bioRxiv, Nov 4 2021. https://www.biorxiv.org/content/10.1101/2021.11.01.466849v1.full.pdf

Abstract: Genome-wide association studies have discovered blocks of common variants—likely transcriptional-regulatory—associated with major depressive disorder (MDD), though the 15 functional subset and their biological impacts remain unknown. Likewise, why depression occurs in females more frequently than males is unclear. We therefore tested the hypothesis that risk-associated functional variants interact with sex and produce greater impact in female brains. We  developed methods to directly measure regulatory variant activity and sex interactions using  massively parallel reporter assays (MPRAs) in the mouse brain in vivo, in a cell type-specific  20 manner. We measured activity of >1,000 variants from >30 MDD loci, identifying extensive sex by-allele effects in mature hippocampal neurons and suggesting sex-differentiated impacts of  genetic risk may underlie sex bias in disease. Unbiased informatics approaches indicated that  functional MDD variants recurrently disrupt sex hormone receptor binding sequences. We  confirmed this with MPRAs in neonatal brains, comparing brains undergoing the masculinizing  25 hormone surge to hormonally-quiescent juveniles. Our study provides novel insights into the  influence of age, biological sex, and cell type on regulatory-variant function, and provides a  framework for in vivo parallel assays to functionally define interactions between organismal variables like sex and regulatory variation.

One-Sentence Summary: Massively parallel assays in vivo identified extensive functional and 30 sex-interacting common variants in depression risk loci.