Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions
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...
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Nature Publishing Group
2025-04-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03349-9 |
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| author | Giuseppe Fanelli Barbara Franke Chiara Fabbri Josefin Werme Izel Erdogan Ward De Witte Geert Poelmans I. Hyun Ruisch Lianne Maria Reus Veerle van Gils Willemijn J. Jansen Stephanie J. B. Vos Kazi Asraful Alam Aurora Martinez Jan Haavik Theresa Wimberley Søren Dalsgaard Ábel Fóthi Csaba Barta Fernando Fernandez-Aranda Susana Jimenez-Murcia Simone Berkel Silke Matura Jordi Salas-Salvadó Martina Arenella Alessandro Serretti Nina Roth Mota Janita Bralten |
| author_facet | Giuseppe Fanelli Barbara Franke Chiara Fabbri Josefin Werme Izel Erdogan Ward De Witte Geert Poelmans I. Hyun Ruisch Lianne Maria Reus Veerle van Gils Willemijn J. Jansen Stephanie J. B. Vos Kazi Asraful Alam Aurora Martinez Jan Haavik Theresa Wimberley Søren Dalsgaard Ábel Fóthi Csaba Barta Fernando Fernandez-Aranda Susana Jimenez-Murcia Simone Berkel Silke Matura Jordi Salas-Salvadó Martina Arenella Alessandro Serretti Nina Roth Mota Janita Bralten |
| author_sort | Giuseppe Fanelli |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ca100ff09c4f4ec8b5137c22df0b6561 |
| institution | OA Journals |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
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| series | Translational Psychiatry |
| spelling | doaj-art-ca100ff09c4f4ec8b5137c22df0b65612025-08-20T02:16:59ZengNature Publishing GroupTranslational Psychiatry2158-31882025-04-0115111010.1038/s41398-025-03349-9Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditionsGiuseppe Fanelli0Barbara Franke1Chiara Fabbri2Josefin Werme3Izel Erdogan4Ward De Witte5Geert Poelmans6I. Hyun Ruisch7Lianne Maria Reus8Veerle van Gils9Willemijn J. Jansen10Stephanie J. B. Vos11Kazi Asraful Alam12Aurora Martinez13Jan Haavik14Theresa Wimberley15Søren Dalsgaard16Ábel Fóthi17Csaba Barta18Fernando Fernandez-Aranda19Susana Jimenez-Murcia20Simone Berkel21Silke Matura22Jordi Salas-Salvadó23Martina Arenella24Alessandro Serretti25Nina Roth Mota26Janita Bralten27Donders Institute for Brain, Cognition and Behaviour, Radboud UniversityDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityDepartment of Biomedical and Neuromotor Sciences, University of BolognaDepartment of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam NeuroscienceDepartment of Human Genetics, Radboud University Medical CenterDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityAlzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmcDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht UniversityDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht UniversityDepartment of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht UniversityDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenDepartment of Biomedicine, University of BergenNational Centre for Register-based Research, School of Business and Social Sciences, Aarhus UniversityNational Centre for Register-based Research, School of Business and Social Sciences, Aarhus UniversityDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis UniversityDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis UniversityClinical Psychology Department, University Hospital of BellvitgeClinical Psychology Department, University Hospital of BellvitgeInstitute of Human Genetics, Heidelberg UniversityDepartment of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University FrankfurtUniversitat Rovira i Virgili, Biochemistry and biotechnology Department, Grup Alimentació, Nutrició, Desenvolupament i Salut Mental, Unitat de Nutrició HumanaDepartment of Human Genetics, Radboud University Medical CenterDepartment of Medicine and Surgery, Kore University of EnnaDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityDonders Institute for Brain, Cognition and Behaviour, Radboud UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03349-9 |
| spellingShingle | Giuseppe Fanelli Barbara Franke Chiara Fabbri Josefin Werme Izel Erdogan Ward De Witte Geert Poelmans I. Hyun Ruisch Lianne Maria Reus Veerle van Gils Willemijn J. Jansen Stephanie J. B. Vos Kazi Asraful Alam Aurora Martinez Jan Haavik Theresa Wimberley Søren Dalsgaard Ábel Fóthi Csaba Barta Fernando Fernandez-Aranda Susana Jimenez-Murcia Simone Berkel Silke Matura Jordi Salas-Salvadó Martina Arenella Alessandro Serretti Nina Roth Mota Janita Bralten Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions Translational Psychiatry |
| title | Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |
| title_full | Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |
| title_fullStr | Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |
| title_full_unstemmed | Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |
| title_short | Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |
| title_sort | local patterns of genetic sharing between neuropsychiatric and insulin resistance related conditions |
| url | https://doi.org/10.1038/s41398-025-03349-9 |
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