Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE
Anna Docherty, Arden Moscati, T Bernard Bigdeli, Alexis C Edwards, Roseann Peterson, Daniel E Adkins, John S Anderson, Jonathan Flint, Kenneth S Kendler, Silviu-Alin Bacanu. (2019). “Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.” Psychological Medicine, (In press). https://doi.org/10.1017/S0033291719000618
Background
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.
Methods
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.
Results
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.
Conclusions
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.