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...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
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12 April 2025
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| In: |
Translational Psychiatry
Year: 2025, Jahrgang: 15, Pages: 1-10 |
| ISSN: | 2158-3188 |
| DOI: | 10.1038/s41398-025-03349-9 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41398-025-03349-9 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41398-025-03349-9 
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| Verfasserangaben: | 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 and Janita Bralten |
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| 245 | 1 | 0 | |a Local patterns of genetic sharing between neuropsychiatric and insulin resistance-related conditions |c 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 and Janita Bralten |
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| 520 | |a 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. | ||
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