Articles producció científica> Bioquímica i Biotecnologia

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

  • Dades identificatives

    Identificador: imarina:9452190
    Handle: https://hdl.handle.net/20.500.11797/imarina9452190
    Autors:
    Fanelli, GiuseppeFranke, BarbaraFabbri, ChiaraWerme, JosefinErdogan, IzelDe Witte, WardPoelmans, GeertRuisch, I HyunReus, Lianne Mariavan Gils, VeerleJansen, Willemijn JVos, Stephanie J BAlam, Kazi AsrafulMartinez, AuroraHaavik, JanWimberley, TheresaDalsgaard, SorenFothi, AbelBarta, CsabaFernandez-Aranda, FernandoJimenez-Murcia, SusanaBerkel, SimoneMatura, SilkeSalas-Salvado, JordiArenella, MartinaSerretti, AlessandroMota, Nina RothBralten, Janita
    Resum:
    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, 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

  • Altres:

    Autor segons l'article: Fanelli, Giuseppe; Franke, Barbara; Fabbri, Chiara; Werme, Josefin; Erdogan, Izel; De Witte, Ward; Poelmans, Geert; Ruisch, I Hyun; Reus, Lianne Maria; van Gils, Veerle; Jansen, Willemijn J; Vos, Stephanie J B; Alam, Kazi Asraful; Martinez, Aurora; Haavik, Jan; Wimberley, Theresa; Dalsgaard, Soren; Fothi, Abel; Barta, Csaba; Fernandez-Aranda, Fernando; Jimenez-Murcia, Susana; Berkel, Simone; Matura, Silke; Salas-Salvado, Jordi; Arenella, Martina; Serretti, Alessandro; Mota, Nina Roth; Bralten, Janita
    Departament: Bioquímica i Biotecnologia
    Autor/s de la URV: Salas Salvadó, Jorge
    Paraules clau: Zinc-sulfate Quantitative trait loci Phenotype Obesity Metabolic syndrome Mental disorders Management Lin Insulin resistance Humans Genome-wide association study Genetic predisposition to disease Extracellular-matrix Double-blind Disorders Diabetes mellitus, type 2 Bcl11a
    Resum: 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, 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.
    Grup de recerca: Alimentació, Nutrició, Desenvolupament i Salut Mental
    Àrees temàtiques: Saúde coletiva Psychiatry and mental health Psychiatry Psicología Nutrição Medicina ii Medicina i Linguística e literatura Interdisciplinar Engenharias iv Enfermagem Educação física Ciências biológicas ii Ciências biológicas i Cellular and molecular neuroscience Biotecnología Biological psychiatry
    Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
    Adreça de correu electrònic de l'autor: jordi.salas@urv.cat
    Identificador de l'autor: 0000-0003-2700-7459
    Data d'alta del registre: 2025-04-30
    Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
    Referència a l'article segons font original: Translational Psychiatry. 15 (1): 145-
    Referència de l'ítem segons les normes APA: Fanelli, Giuseppe; Franke, Barbara; Fabbri, Chiara; Werme, Josefin; Erdogan, Izel; De Witte, Ward; Poelmans, Geert; Ruisch, I Hyun; Reus, Lianne Maria (2025). Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions. Translational Psychiatry, 15(1), 145-. DOI: 10.1038/s41398-025-03349-9
    URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
    Entitat: Universitat Rovira i Virgili
    Any de publicació de la revista: 2025
    Tipus de publicació: Journal Publications

  • Paraules clau:

    Biological Psychiatry,Cellular and Molecular Neuroscience,Psychiatry,Psychiatry and Mental Health
    Zinc-sulfate
    Quantitative trait loci
    Phenotype
    Obesity
    Metabolic syndrome
    Mental disorders
    Management
    Lin
    Insulin resistance
    Humans
    Genome-wide association study
    Genetic predisposition to disease
    Extracellular-matrix
    Double-blind
    Disorders
    Diabetes mellitus, type 2
    Bcl11a
    Saúde coletiva
    Psychiatry and mental health
    Psychiatry
    Psicología
    Nutrição
    Medicina ii
    Medicina i
    Linguística e literatura
    Interdisciplinar
    Engenharias iv
    Enfermagem
    Educação física
    Ciências biológicas ii
    Ciências biológicas i
    Cellular and molecular neuroscience
    Biotecnología
    Biological psychiatry

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