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

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<sub>g</sub>| = 0.21-1, p<sub>FDR</sub> < 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.

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Publication Details

Journal
Translational Psychiatry
Published
2025-04-12
DOI
https://doi.org/10.1038/s41398-025-03349-9
Citations
8
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
14.54

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article

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

Kazi Asraful Alam, Martina Arenella, Aurora Martı́nez, Fernando Fernández‐Aranda et al.
8 citations
Translational Psychiatry
Genetic Associations and Epidemiology
14.54
article

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

Kazi Asraful Alam, Martina Arenella, Aurora Martı́nez, Fernando Fernández‐Aranda, I. Hyun Ruisch, Jordi Salas‐Salvadó, Søren Dalsgaard, Nina Roth Mota, Giuseppe Fanelli, Izel Erdogan, Chiara Fabbri, Josefin Werme, Barbara Franke, Lianne M. Reus, Susana Jiménez‐Múrcia, Simone Berkel, Silke Matura, Jan Haavik, Csaba Barta, Alessandro Serretti, Stephanie J. B. Vos, Ábel Fóthi, Willemijn J. Jansen, Veerle van Gils, Janita Bralten, Geert Poelmans, Ward De Witte, Theresa Wimberley
article en
8 citations

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 (|r<sub>g</sub>| = 0.21-1, p<sub>FDR</sub> < 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.

Translational PsychiatryVol. 15(1)
Semmelweis University (HU), Goethe University Frankfurt (DE), University of Copenhagen (DK), Radboud University Nijmegen (NL), University of California, Los Angeles (US), King's College London (GB), Aarhus University (DK), Heidelberg University (DE), Università degli Studi di Enna Kore (IT), Haukeland University Hospital (NO), Mental Health Services (DK), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), Radboud University Medical Center (NL), Maastricht University (NL), Institut d'Investigació Biomédica de Bellvitge (ES), Oasi Maria SS (IT), Institut de Recerca Biomèdica Catalunya Sud (ES), Institute of Biochemistry (HU), Amsterdam Neuroscience (NL), Radboud Institute for Molecular Life Sciences (NL), Centro de Investigación Biomédica en Red (ES), Lundbeck Foundation (DK), Amsterdam University Medical Centers (NL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Bergen (NO), Universitat Rovira i Virgili (ES), Universitat de Barcelona (ES), Vrije Universiteit Amsterdam (NL), University of Bologna (IT)
Centres de Recerca de Catalunya, European Commission, ZonMw, Generalitat de Catalunya, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Institució Catalana de Recerca i Estudis Avançats, National Institutes of Health, National Institute of Mental Health
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