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

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

doi:10.1101/2024.03.07.24303921

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

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-ArandaSusana Jimenez-Murcia, Simone Berkel, Silke Matura, Jordi Salas-Salvadó, Martina Arenella, Alessandro Serretti, Nina Roth Mota, Janita Bralten

National Centre for Register-based Research

Research output: Working paper/Preprint › Preprint

Abstract

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex 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 underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

Original language	English
DOIs	https://doi.org/10.1101/2024.03.07.24303921
Publication status	Published - 8 Mar 2024

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10.1101/2024.03.07.24303921Licence: CC BY-NC-ND

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Fanelli, G., Franke, B., Fabbri, C., Werme, J., Erdogan, I., De Witte, W., Poelmans, G., Ruisch, I. H., Reus, L. M., van Gils, V., Jansen, W. J., Vos, S. J. B., Alam, K. A., Martinez, A., Haavik, J., Wimberley, T., Dalsgaard, S., Fóthi, Á., Barta, C., ... Bralten, J. (2024). Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions. https://doi.org/10.1101/2024.03.07.24303921

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title = "Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions",

abstract = "The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex 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 underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.",

author = "Giuseppe Fanelli and Barbara Franke and Chiara Fabbri and Josefin Werme and Izel Erdogan and {De Witte}, Ward and Geert Poelmans and Ruisch, {I Hyun} and Reus, {Lianne Maria} and {van Gils}, Veerle and Jansen, {Willemijn J} and Vos, {Stephanie J B} and Alam, {Kazi Asraful} and Aurora Martinez and Jan Haavik and Theresa Wimberley and S{\o}ren Dalsgaard and {\'A}bel F{\'o}thi and Csaba Barta and Fernando Fernandez-Aranda and Susana Jimenez-Murcia and Simone Berkel and Silke Matura and Jordi Salas-Salvad{\'o} and Martina Arenella and Alessandro Serretti and Mota, {Nina Roth} and Janita Bralten",

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Fanelli, G, Franke, B, Fabbri, C, Werme, J, Erdogan, I, De Witte, W, Poelmans, G, Ruisch, IH, Reus, LM, van Gils, V, Jansen, WJ, Vos, SJB, Alam, KA, Martinez, A, Haavik, J, Wimberley, T, Dalsgaard, S, Fóthi, Á, Barta, C, Fernandez-Aranda, F, Jimenez-Murcia, S, Berkel, S, Matura, S, Salas-Salvadó, J, Arenella, M, Serretti, A, Mota, NR & Bralten, J 2024 'Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions'. https://doi.org/10.1101/2024.03.07.24303921

TY - UNPB

T1 - Local patterns of genetic sharing challenge the boundaries 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 - 2024/3/8

Y1 - 2024/3/8

N2 - The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex 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 underscore the complex genetic landscape 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 complex 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 underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

U2 - 10.1101/2024.03.07.24303921

DO - 10.1101/2024.03.07.24303921

M3 - Preprint

C2 - 38496672

BT - Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

ER -

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

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