Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.

Journal Article (Journal Article)

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4 ) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

Full Text

Duke Authors

Cited Authors

  • Miles, AE; Dos Santos, FC; Byrne, EM; Renteria, ME; McIntosh, AM; Adams, MJ; Pistis, G; Castelao, E; Preisig, M; Baune, BT; Schubert, KO; Lewis, CM; Jones, LA; Jones, I; Uher, R; Smoller, JW; Perlis, RH; Levinson, DF; Potash, JB; Weissman, MM; Shi, J; Lewis, G; Penninx, BWJH; Boomsma, DI; Hamilton, SP; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, ; Sibille, E; Hariri, AR; Nikolova, YS

Published Date

  • December 2021

Published In

Volume / Issue

  • 46 / 13

Start / End Page

  • 2304 - 2311

PubMed ID

  • 34588609

Pubmed Central ID

  • PMC8580972

Electronic International Standard Serial Number (EISSN)

  • 1740-634X

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/s41386-021-01189-x


  • eng