Metal health: a shared genetic basis for schizophrenia, inflammation, lipid metabolism and cortical structure

Background: In addition to core positive and negative symptoms, psychotic disorders are frequently characterised by a pattern of multimorbidity with chronic medical conditions such as cardiovascular disease, diabetes, and chronic inflammation. 40% of antipsychotic-naïve patients with first-episode psychosis exhibit dysglycaemia [1], and low-grade chronic inflammation in adolescence has been linked to increased risk of both psychosis and insulin resistance in adulthood [2]. Emerging evidence suggests that IL-6 signalling, particularly non-classical trans-signalling, may contribute to the pathogenesis of psychosis [3]. However, the extent to which this multimorbidity is driven by shared genetic mechanisms remains unclear. We therefore aimed to understand whether the genetic interplay between peripheral IL-6 signalling, metabolic biomarkers, and neuroimaging traits could provide insights into schizophrenia (SZ) aetiology and identify novel target mechanisms. Methods: We performed hypothesis prioritisation multi-trait colocalization (HyPrColoc) analysis [4] to examine genetic associations shared across SZ and 14 related traits: two cardiometabolic risk factors (triglycerides:HDL (TG:HDL) ratio and fasting insulin), three structural MRI traits (left- and right-hemispheric cortical thickness and peripheral grey matter volume), six fMRI independent component analysis (ICA) traits, and plasma levels of three IL-6 signalling proteins (IL-6, IL-6R, and IL-6ST). Bayesian HyPrColoc was applied to 232 SNPs associated (p0.4), suggesting functional changes to ZIP8 rather than reduced ZIP8 expression are associated with the co-localising traits. Conclusion: Our findings suggest that loss of ZIP8 function may increase risk for SZ, elevate IL-6ST levels, increase TG:HDL, and reduce cortical thickness. Hence, disrupted transmembrane metal ion transport may represent a shared mechanism underlying multimorbidity across SZ, metabolic disorders, and inflammation. Further Mendelian randomisation and functional assays are warranted to clarify causality. Table 1 Results from co-localization Bayesian analysis for π2=0.9999 and largest regional/alignment thresholds for co-localisation of >1 trait with SZ. π1 = 0.05 in all results presented.[Table presented]