Associations of Mechanistically Partitioned Type 2 Diabetes Polygenic Risk with Psychiatric and Related Phenotypes in UK Biobank

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Background Type 2 diabetes (T2D) and psychiatric disorders frequently co-occur, but it remains unclear whether this overlap is generalised 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 (PRS) for eight mechanistic T2D clusters and tested associations with psychiatric and sleep phenotypes and chronic pain in UK Biobank (UKB). 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 non-atypical 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. Discussion The overlap between T2D and psychiatric phenotypes was heterogeneous, with the strongest evidence for adiposity PRS and atypical depression, with more selective associations across other pathways. Considering heterogeneity in both T2D biology and psychiatric presentation may help clarify shared mechanisms.

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