Biol Psychiatry Glob Open Sci. 2026 Aug 28;6(6):100817. doi: 10.1016/j.bpsgos.2026.100817. eCollection 2026 Nov.
ABSTRACT
BACKGROUND: Type 2 diabetes (T2D) and psychiatric disorders frequently co-occur; however, it remains unclear whether this overlap is generalized or defined by particular T2D mechanisms and psychiatric phenotypes. We investigated whether genetically defined T2D pathways show distinct associations with psychiatric and related phenotypes.
METHODS: We calculated polygenic risk scores (PRSs) for 8 mechanistic T2D clusters and tested associations with psychiatric and sleep phenotypes and chronic pain in the UK Biobank. The study included 408,063 White British participants (54.1% female) and 50,214 non-overlapping White European participants (56.2% female). Models incorporated demographic, socioeconomic, lifestyle, anthropometric, and medication factors, with false discovery rate (FDR) correction across all tests.
RESULTS: Adiposity PRS showed the broadest associations. Body-fat distribution PRS was associated with atypical major depressive disorder across all models, whereas obesity-mediated insulin-resistance PRS was associated only in the minimally adjusted model. Neither PRS was associated with nonatypical depression after FDR correction. Body-fat PRS was associated with generalized anxiety disorder, mood instability, long sleep duration, and chronic pain in all models. Associations for the other pathways were more selective and were concentrated in sleep duration and chronotype; metabolic-syndrome PRS was consistently associated with neuroticism. Cross-sample support was strongest for the association between obesity-mediated insulin-resistance PRS and morning chronotype.
CONCLUSIONS: The overlap between T2D and psychiatric phenotypes was heterogeneous, with the strongest evidence for adiposity PRS and atypical depression and with more selective associations across other pathways. Considering heterogeneity in both T2D biology and psychiatric presentation may help clarify shared mechanisms.
PMID:42891141 | PMC:PMC13673341 | DOI:10.1016/j.bpsgos.2026.100817