Association between antidiabetic drug targets and psychiatric disorders.

Abstract

Psychiatric disorders present a significant global health burden with limited effective medications. Observing the widespread comorbidities between diabetes and psychiatric disorders, we explored the potential of repurposing antidiabetic drug targets for psychiatric treatments. We identified 32 target genes of 60 antidiabetics and performed Mendelian randomization analyses using expression and protein quantitative trait loci data from brain tissues alongside summary data for seven psychiatric disorders. Additionally, we conducted colocalization analyses, replication analyses in blood and at the single-cell level, single-cell gene annotation, developmental trajectory analysis, and various functional assessments. We found that elevated GANC expression in the putamen basal ganglia, nucleus accumbens basal ganglia, cortex, and whole blood was associated with a reduced risk of bipolar disorder (OR, 0.532-0.877; P, 4.04 × 10^-5 to 1.45 × 10^-7), implying that antagonism of GANC by the antidiabetic drug miglitol could increase bipolar risk. Conversely, increased ABCC8 expression in the cortex, cerebellum, cerebellar hemisphere, and VIP- and LAMP5-expressing inhibitory neurons was linked to a higher risk of schizophrenia (OR, 1.054-1.119; P, 1.46 × 10^-3 to 4.42 × 10^-5), suggesting that ABCC8 inhibition by sulfonylureas or glinides may lower the risk of schizophrenia. Colocalization analysis further confirmed the above associations. GANC and ABCC8 displayed specific developmental trajectories, and functional analyses revealed that they affected psychiatric risk through pathways related to potassium ion channels, insulin secretion, and glucose metabolism. Our findings highlight GANC and ABCC8 as potential targets, suggesting caution in miglitol use for bipolar disorder and the potential repurposing of sulfonylureas and glinides for schizophrenia.