Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.
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Author
Docherty, Anna RMoscati, Arden
Bigdeli, Tim B
Edwards, Alexis C
Peterson, Roseann E
Adkins, Daniel E
Anderson, John S
Flint, Jonathan
Kendler, Kenneth S
Bacanu, Silviu-Alin
Journal title
Psychological medicineDate Published
2019-04-02Publication Volume
50Publication Issue
5Publication Begin page
793Publication End page
798
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The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets.Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status.
Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD.
Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.
Citation
Docherty AR, Moscati A, Bigdeli TB, Edwards AC, Peterson RE, Adkins DE, Anderson JS, Flint J, Kendler KS, Bacanu SA. Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE. Psychol Med. 2020 Apr;50(5):793-798. doi: 10.1017/S0033291719000618. Epub 2019 Apr 2. PMID: 30935430; PMCID: PMC6774907.DOI
10.1017/S0033291719000618ae974a485f413a2113503eed53cd6c53
10.1017/S0033291719000618
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