Shared genetic and molecular architecture between insulin resistance and cognitive performance

Insulin signalling contributes to neurodevelopment and brain function, and insulin resistance (IR)-related traits are associated with cognitive performance. However, the genetic architecture shared across specific cognitive domains and IR-related phenotypes remains insufficiently defined. We analysed large-scale genome-wide association study summary statistics for 11 IR-related traits (N=53,334-933,970) and 10 cognitive measures (N=28,156-436,853) to quantify global and local genetic correlations, fine-map shared association signals, and annotate implicated genes and drug-gene interactions. Pairwise global and local genetic correlations were estimated, and shared high-confidence variants were prioritised using the multivariate Sum of Single Effects model. Positional and expression quantitative trait locus mapping was performed, and implicated genes were examined through functional annotation, tissue enrichment, and drug-gene interaction analyses. Low-to-moderate genetic correlations were observed between six IR-related traits and seven cognitive measures (|rg|=0.08-0.34), with predominantly opposite directions, except for correlations involving visual declarative short-term memory. Local genetic correlations showed mixed effect directions across most trait pairs, and multivariate fine-mapping prioritised 696 shared likely causal variants with high posterior support. Gene annotation indicated enrichment in several pathways, including immune-related, signal transduction, neurogenesis, neurotransmitter metabolism, receptor regulation, and lipid and cholesterol metabolism regulation. Implicated genes were expressed across various brain regions and showed prior associations with neuropsychiatric and cardiometabolic conditions. Several drug-gene interactions were identified, involving immunomodulatory and anti-inflammatory compounds. These findings indicate widespread heterogeneous genetic overlap between IR-related traits, particularly body mass index and waist-to-hip ratio, and cognitive measures of general intelligence, processing speed, and short-term visual declarative memory. The findings prioritise apolipoprotein-related lipid transport and inflammatory and oxidative stress pathways as candidate mechanisms linking cognitive, cardiometabolic, and neuropsychiatric phenotypes.