Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions

作者：Giuseppe Fanelli, Barbara Franke, Chiara Fabbri, Josefin Werme, Izel Erdogan, Ward De Witte, Geert Poelmans, I. Hyun Ruisch, Lianne M. Reus, Veerle van Gils, Willemijn J. Jansen, Stephanie J. B. Vos, Kazi Asraful Alam, Aurora Martı́nez, Jan Haavik, Theresa Wimberley, Søren Dalsgaard, Ábel Fóthi, Csaba Barta, Fernando Fernández‐Aranda, Susana Jiménez‐Múrcia, Simone Berkel, Silke Matura, Jordi Salas‐Salvadó, Martina Arenella, Alessandro Serretti, Nina Roth Mota, Janita Bralten · 发表于：Translational Psychiatry · 年份：2025 · DOI：10.1038/s41398-025-03349-9 · 被引用次数：16 · 研究领域：Genetic Associations and Epidemiology、Epigenetics and DNA Methylation、Diabetes Treatment and Management

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 (|r g | = 0.21–1, p FDR < 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....