Transcriptomic Similarity Informs Neuromorphic Deviations in Depression Biotypes.

BACKGROUND:Major depressive disorder (MDD) is complicated by population heterogeneity, motivating the investigation of biotypes through imaging-derived phenotypes. However, neuromorphic heterogeneity in MDD remains unclear, and how the correlated gene expression (CGE) connectome constrains these neuromorphic anomalies in MDD biotypes has not yet been studied. METHODS:Here, we related cortical thickness deviations in MDD biotypes to a pattern of CGE connectome. Cortical thickness was estimated from 3-dimensional T1-weighted magnetic resonance images in 2 independent cohorts (discovery cohort: N = 425; replication cohort: N = 217). The transcriptional activity was measured according to Allen Human Brain Atlas. A density peak-based clustering algorithm was used to identify MDD biotypes. RESULTS:We found that patients with MDD were clustered into 2 replicated biotypes based on single-patient regional deviations from healthy control participants across 2 datasets. Biotype 1 mainly exhibited cortical thinning across the brain, whereas biotype 2 mainly showed cortical thickening in the brain. Using brainwide gene expression data, we found that deviations of transcriptionally connected neighbors predicted regional deviation for both biotypes. Furthermore, putative CGE-informed epicenters of biotype 1 were concentrated on the cognitive control circuit, whereas biotype 2 epicenters were located in the social perception circuit. The patterns of epicenter likelihood were separately associated with depression- and anxiety-response maps, suggesting that epicenters of MDD biotypes may be associated with clinical efficacies. CONCLUSIONS:Our findings linked the CGE connectome and neuromorphic deviations to identify distinct epicenters in MDD biotypes, providing insight into how microscale gene expressions informed MDD biotypes.