Genome-wide association studies (GWAS) show conceptual promise to identify novel mechanisms of major depressive disorder (MDD), but have not yet achieved this potential. One explanation is that MDD risk acts through complex expression networks, and GWAS-identified genes represent important components of these networks but in isolation are insufficient for their functional annotation. In this study, we aimed to identify and characterize the expression networks through which GWAS-identified MDD risk genes operate. We generated and characterized seeded co-expression networks of 252 MDD risk genes over 11 brain regions. We used principal component regression and Mendelian randomization to identify a relation between the networks of two such genes (FADS1 and ZKSCAN8) and suicidal ideation. These networks were primarily expressed in astrocytes, enriched for functions related to fatty acid metabolism, and could define MDD-altered astrocyte states. We then identified FGFR3 to EPHA4 signaling as a putative downstream effector of these astrocyte states on synaptic function. Finally through transcriptomic and genetic analyses, we identify PPARA as a putative therapeutic target of these mechanisms in MDD. Our study defines a tractable pathway to translate genetic findings into therapeutically actionable mechanisms.

The authors have declared no competing interest.

This work was funded through a Hope for MDD Research Foundation grant to Dr Michael Meaney.

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The data used for the analyses described in this manuscript were obtained from: the GTEx Portal or dbGaP accession number phs000424.v9.p2 or Nagy et al at GSE144136

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