Polygenic scores of subcortical brain volumes as possible modulators of treatment response in depression

Abstract

A significant proportion of patients with major depressive disorder (MDD) do not experience remission after one or more pharmacological treatments. Research has explored brain structural measures, particularly the hippocampus, as potential predictors of treatment response in MDD, as well as genetic factors.This study investigated the association of polygenic scores (PGSs) for seven subcortical brain volumes (including the hippocampus, nucleus accumbens, amygdala, and caudate nucleus) with treatment non-response and non-remission in MDD.Patients with MDD were recruited in the context of five clinical studies, including a total of 3,637 individuals. PGSs were estimated using a Bayesian framework and continuous shrinkage priors (PRS-CS-auto) after standard genotype quality control and imputation. Logistic regressions were performed between PGSs and non-response or non-remission in each sample, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, using a random-effect model.Caudate volume PGS was nominally associated with non-remission (OR=1.09, 95% CI=1.01–1.19, p=0.036). Leave-one-out sensitivity analyses suggested a possible association with the amygdala and thalamus PGSs. However, no association was significant after multiple testing correction.These results, although preliminary, suggest a possible link between caudate volume PGS and lack of symptom remission. Methodological improvements in PGSs estimation and statistical power may enhance their predictive performance and provide a contribution to precision psychiatry.