Shared genetic basis for brain structure, insulin resistance and inflammation in schizophrenia: a colocalization study
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Background
Psychotic disorders such as schizophrenia (SZ) are associated with structural brain changes and increased cardiometabolic disease risk, potentially linked through shared inflammatory mechanisms. However, whether these associations reflect shared genetic architecture remains unclear. We investigated genetic overlap between SZ, brain structure, insulin resistance (IR), and interleukin (IL)-6 signalling to uncover shared biological mechanisms.
Methods
We performed Bayesian multi-trait colocalization (HyPrColoc) analysis of SZ and validated markers of structural MRI (bilateral cortical thickness, grey matter volume), IR (TG:HDL-C ratio, fasting insulin), and IL-6 signalling (IL-6, IL-6R, IL-6ST), at 137 trait-associated SNPs (GWAS p < 5×10⁻⁸). in silico characterisation of candidate SNPs included protein (p)QTL gene set enrichment and developmental brain expression profiling in publicly available datasets.
Results
Primary analysis identified colocalization between SZ and at least one trait from brain structure, IR, or IL-6 signalling at 6 loci. After sensitivity analysis, the SLC39A8 missense variant rs13107325 remained colocalized across SZ, bilateral cortical thickness, TG:HDL-C, and IL-6ST (PP coloc = 0.93–0.99). SZ also colocalized with IL-6R at MHC-region variant rs2853986 (PP coloc = 0.66–0.83). Pathway analysis of rs13107325 pQTLs revealed enrichment in synaptic development, glycan processing, and glycolysis pathways. Gene set enrichment highlighted links with coronary artery disease, myocardial infarction, and arteriosclerosis. SLC39A8 expression was enriched in cerebral vascular cells and increased during foetal and early postnatal brain development.
Conclusion
We identify shared genetic architecture between SZ, brain structure, IR, and inflammation at rs13107325. These findings underscore the importance of pleiotropic genetic effects in identifying new biological targets in psychosis.
