Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions 2025 Bralten et al

Abstract

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a major 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 (|rg| = 0.21–1, pFDR < 0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer’s disease, bipolar disorder, and Tourette’s syndrome.

Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs.

Overall, our findings highlight the complex genetic architecture of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

Open access

 

"Input datasets

We leveraged publicly available summary statistics from the largest genome-wide association studies (GWASs) on the three most prevalent IR-related conditions, namely obesity, MetS, and T2DM (n = 244,890–933,970), and nine neuropsychiatric disorders, including AD, ADHD, AN, autism spectrum disorder (ASD), BD, MDD, OCD, schizophrenia, and Tourette’s syndrome (TS) (n = 9,725–933,970). These neuropsychiatric disorders were chosen because they are the best genetically characterised by the Psychiatric Genomics Consortium [24]."