TY - JOUR
T1 - Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions
AU - Fanelli, Giuseppe
AU - Franke, Barbara
AU - Fabbri, Chiara
AU - Werme, Josefin
AU - Erdogan, Izel
AU - De Witte, Ward
AU - Poelmans, Geert
AU - Ruisch, I Hyun
AU - Reus, Lianne Maria
AU - van Gils, Veerle
AU - Jansen, Willemijn J
AU - Vos, Stephanie J B
AU - Alam, Kazi Asraful
AU - Martinez, Aurora
AU - Haavik, Jan
AU - Wimberley, Theresa
AU - Dalsgaard, Søren
AU - Fóthi, Ábel
AU - Barta, Csaba
AU - Fernandez-Aranda, Fernando
AU - Jimenez-Murcia, Susana
AU - Berkel, Simone
AU - Matura, Silke
AU - Salas-Salvadó, Jordi
AU - Arenella, Martina
AU - Serretti, Alessandro
AU - Mota, Nina Roth
AU - Bralten, Janita
PY - 2025/4/12
Y1 - 2025/4/12
N2 - 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 | = 0.21-1, p < 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.
AB - 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 | = 0.21-1, p < 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.
KW - Humans
KW - Insulin Resistance/genetics
KW - Genome-Wide Association Study
KW - Diabetes Mellitus, Type 2/genetics
KW - Metabolic Syndrome/genetics
KW - Obesity/genetics
KW - Quantitative Trait Loci
KW - Mental Disorders/genetics
KW - Phenotype
KW - Genetic Predisposition to Disease
U2 - 10.1038/s41398-025-03349-9
DO - 10.1038/s41398-025-03349-9
M3 - Article
SN - 2158-3188
VL - 15
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 145
ER -