| Title: | A novel polygenic risk score indexing somatostatin-expressing (SST+) inhibitory neurons predicts SST+ cell proportions and severity of symptoms in late-life depression |
| Journal: | Biological Psychiatry Global Open Science |
| Published: | 1 Jan 2026 |
| DOI: | https://doi.org/10.1016/j.bpsgos.2025.100685 |
| URL: | http://dx.doi.org/10.1016/j.bpsgos.2025.100685 |
Publication 16927
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Abstract
Background 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. Methods 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. Results 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. Conclusions SST-PRS may serve as a novel biomarker of SST+ neuron pathology and of depressive and cognitive symptom burden in LLD</p>
11 Authors
- Fernanda C. Dos Santos
- Xiaolin Zhou
- Kevan P. Clifford
- Alex Gonzalez Segura
- Ayesha S. Syeda
- Daniel Felsky
- Eric J. Lenze
- Benoit H. Mulsant
- Shreejoy Tripathy
- Etienne Sibille
- Yuliya S. Nikolova
1 Application
| Application ID | Title |
|---|---|
| 61530 | Multimodal subtyping of mental illness across the adult lifespan through integration of multi-scale whole-person phenotypes |
Enabling scientific discoveries that improve human health