Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions.

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|r Local genetic correlations found even in the absence of global correlations.Both positive and negative local correlations found for IR-neuropsychiatric pairs.Enrichment for immune, and insulin signalling pathways, among others.Pinpointed shared likely causal variants within 10 genomic regions.Identified therapeutic targets, e.g., SLC39A8 and HLA-DRB1, for drug repurposing.