A Novel Polygenic Risk Score Indexing Somatostatin-Expressing Inhibitory Neurons Predicts Somatostatin-Expressing Cell Proportions and Severity of Symptoms in Late-Life Depression

Postmortem studies suggest that somatostatin-expressing (SST+) neurons are selectively vulnerable in aging and depression. We developed a novel polygenic risk score (PRS) as an in-vivo index of inter-individual variability of SST-related function and evaluated its association with late-life depression (LLD)-related phenotypes. We identified genes co-expressed with SST and their corresponding cis- expression quantitative trait loci (cis-eQTL) in dorsolateral prefrontal cortical (dlPFC) tissue. We aggregated these variants into multiple PRSs (SST-PRSs), testing each as a predictor of SST+ cell proportion estimated from bulk postmortem tissue RNASeq data. The SST-PRS most predictive of SST+ cell proportion was computed in a cohort of older adults (393 with LLD; 416 never-depressed) and tested as a predictor of depressive symptoms (Montgomery-Åsberg Depression Rating Scale, MADRS), and cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status, RBANS; Delis-Kaplan Executive Function System, DKEFS). To assess generalizability, we sought to replicate LLD-specific associations in a subset of older-adult UK Biobank participants (≥60 years old) with a history of recurrent depression. SST-PRS was associated with reduced dlPFC SST+ neuron proportion (R=0.5; p=1.783x10 -4 ) but not with LLD diagnosis (p=0.39). Among individuals with LLD, SST-PRS was associated with higher MADRS scores regardless of sex (t(369)=2.267, p=0.024) and lower RBANS language scores in males only (t(120)=-3.077, p=0.003; interaction p=0.002). In the UK Biobank, SST-PRS was modestly associated with lower Symbol Digit Substitution scores (p=0.044) and higher depressive symptoms (p=0.07) in males. SST-PRS may serve as a novel biomarker of SST+ neuron pathology and of depressive and cognitive symptom burden in LLD