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bioRxiv · 10.1101/2025.07.23.666268

Shared genetic basis for brain structure, insulin resistance and inflammation in schizophrenia: a colocalization study

Couch, A. C. M.·Perry, B. I.·Palmer, E. R.·Rogers, J.·Upthegrove, R.
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Abstract

Schizophrenia (SZ) is accompanied by structural brain alterations and elevated cardiometabolic risk, potentially linked through shared immune-metabolic mechanisms. To test for shared genetic underpinnings, we performed multi-trait colocalization across SZ, structural MRI measures (bilateral cortical thickness, grey matter volume), insulin resistance markers (TG:HDL-C ratio, fasting insulin adjusted for BMI), and IL-6 signalling traits (IL-6, IL-6R, IL-6ST) at 185 genome-wide significant loci. Colocalization was detected at 53 loci, including a robust cluster at the SLC39A8 missense variant rs13107325 linking SZ with cortical structure, peripheral IL-6ST, and TG:HDL-C (PPcoloc = 0.73-0.99). A secondary, lower-confidence colocalization signal at FGF21 (PPcoloc = 0.6) further implicated metabolic- behavioural coupling as a convergent pathway. Downstream analyses of rs13107325 pQTLs indicated enrichment in synaptic development and cardiometabolic pathways. Together, these findings identify rs13107325 as a shared causal variant bridging neurodevelopment, immunity, and metabolism, and highlight metal-ion transport and FGF21 signalling as potential therapeutic entry points to address the intertwined psychiatric and metabolic burden of SZ.

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Couch, A. C. M., Perry, B. I., Palmer, E. R., Rogers, J., Upthegrove, R.. 2025-07-24. Shared genetic basis for brain structure, insulin resistance and inflammation in schizophrenia: a colocalization study. https://doi.org/10.1101/2025.07.23.666268

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