MON-722 Cross-Species Glucocorticoid-Sensitive Posterior Dentate Gyrus Gene Network: Developing a Polygenic Score Associated to Susceptibility to Depression After Early Life Adversity Exposure in Humans
Authors: Arcego Danusa Mar , O’Toole Nick , Buschdorf Jan-Paul , Rayan Nirmala Arul , Barth Barbara , Pokhvisneva Irina , Wang Zihan , Patel Sachin , Filho Euclides José de Mendonça , de Lima Randriely Merscher Sobreira , Dalmaz Carla , Silveira Patricia Pelufo , Meaney Michael Joseph 
Published: May 2020

Abstract
Exposure to stress during the life-course has consistently been associated with neuropsychological disorders, but the precise role of stress released glucocorticoids remains unclear in this context. We aimed at using hippocampal gene expression data from macaques to identify clusters of genes sensible to glucocorticoid exposure and create a biologically relevant polygenic score to investigate emotional disorders in a child and adult humans exposed to early adversity. RNA-sequencing data from the posterior dentate gyrus (pDG) of adult Macaca fascicularis females treated with Betamethasone (glucocorticoid) or saline injections for 8 consecutive days were analyzed from two cohorts: Singapore (reference) and Vietnam (replication) with N=12/each. Weighted gene co-expression network analysis (WGCNA) was used to identify clusters (modules) of co-expressed genes associated with betamethasone. In Singaporean animals, genes were clustered in 52 modules, in which 5 were associated with betamethasone. Two modules were preserved in a replication dataset (Vietnam) and in data from female rats treated with corticosterone for 6 weeks, being the black module (557 genes, P=0.01, r=0.7) the one having the highest correlation with glucocorticoid exposure. Gene ontology analysis (FDR&lt;0.05, Metacore®) revealed that this module is associated with transcription processes. The SNPs derived from genes within the module were used to calculate an expression-based polygenic risk score (ePRS) in the human samples, weighing each SNP by the slope of the association between genotype and gene expression (GTex). Linear regression analysis showed a significant interaction between ePRS and early adversity on the Dominique - major depressive disorder domain (β=1304; P=0.003; N=65) in girls aged 6 years (MAVAN), in which a higher ePRS was associated with more symptoms as the adversity scores increases (simple slope analysis,P=0.004). A comparable interaction between the ePRS and postnatal adversity was also observed in adult women (UK Biobank), in which there was an increased risk for early depression onset (β= -424.3, P=0.04; N=13899). In the adult cohort, whole brain gray matter volume was also associated with differences in the expression of the genes that composed the ePRS-black network (main ePRS effect, β=1865776, P=0.03, N=10902). Glucocorticoid exposure affects a specific group of genes in pDG of adult female macaques and rats, influencing transcriptional processes. Variations in the expression of this gene network sensible to glucocorticoids were associated with susceptibility for the development of depression in girls and adult women exposed to early life adversity. These show the importance of glucocorticoids on the development of depressive symptoms. The gene network affected by glucocorticoids can guide future pharmacological or mechanistic studies in other samples or species.