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Delineating the Genetic Component of Gene Expression in Major Depression: Transcriptome-wide Association Study of Major Depression

Research output: Contribution to journalArticle

Original languageEnglish
JournalBiological psychiatry
DOIs
E-pub ahead of print12 Sep 2020

King's Authors

Abstract

Background: Major Depression (MD) is determined by a multitude of factors including genetic risk variants that regulate gene expression. Here, we examined the genetic component of gene expression in MD by performing a Transcriptome-Wide Association Study (TWAS), inferring gene expression-trait relationships from genetic, transcriptomic, and phenotypic information. Method: Genes differentially expressed in depression were identified with the TWAS FUSION method, based on summary statistics from the largest genome-wide association analysis of MD (Ncases = 135,458, Ncontrols = 344,901) and gene expression levels from 21 tissue datasets (brain, blood, thyroid, adrenal, and pituitary glands). Follow-up analyses were performed to extensively characterize the identified associations: colocalization, conditional, and fine-mapping analyses together with functionally-enriched pathway investigations. Results: Transcriptome-wide significant differences between cases and controls were found at 94 genes, approximately half of which were novel. Of the 94 significant genes, six represented strong, colocalized, and potentially causal associations with depression. Such “high-confidence associations” include NEGR1, CTC-467M3.3, TMEM106B, LRFN5, ESR2, PROX2. Lastly, TWAS-based enrichment analysis highlighted dysregulation of gene sets for, among others, neuronal and synaptic processes. Conclusion: This study has shed further light on the genetic component of gene expression in depression by characterizing the identified associations, unraveling novel risk genes, and determining which associations are congruent with a causal model. These findings can be used as a resource for prioritizing and designing subsequent functional studies of MD.

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