Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity
Abstract Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), includi...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41467-025-59576-7 |
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| author | Aino Heikkinen Vivienne F. C. Esser Seung Hyuk T. Lee Sara Lundgren Antti Hakkarainen Jesper Lundbom Juho Kuula Per-Henrik Groop Sini Heinonen Sergio Villicaña Jordana T. Bell Alice Maguolo Emma Nilsson Charlotte Ling Allan Vaag Päivi Pajukanta Jaakko Kaprio Kirsi H. Pietiläinen Shuai Li Miina Ollikainen |
| author_facet | Aino Heikkinen Vivienne F. C. Esser Seung Hyuk T. Lee Sara Lundgren Antti Hakkarainen Jesper Lundbom Juho Kuula Per-Henrik Groop Sini Heinonen Sergio Villicaña Jordana T. Bell Alice Maguolo Emma Nilsson Charlotte Ling Allan Vaag Päivi Pajukanta Jaakko Kaprio Kirsi H. Pietiläinen Shuai Li Miina Ollikainen |
| author_sort | Aino Heikkinen |
| collection | DOAJ |
| description | Abstract Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity. |
| format | Article |
| id | doaj-art-9aa8923ac8fc4b5abdb576a6d2b2c335 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-9aa8923ac8fc4b5abdb576a6d2b2c3352025-08-20T03:10:31ZengNature PortfolioNature Communications2041-17232025-05-0116111410.1038/s41467-025-59576-7Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesityAino Heikkinen0Vivienne F. C. Esser1Seung Hyuk T. Lee2Sara Lundgren3Antti Hakkarainen4Jesper Lundbom5Juho Kuula6Per-Henrik Groop7Sini Heinonen8Sergio Villicaña9Jordana T. Bell10Alice Maguolo11Emma Nilsson12Charlotte Ling13Allan Vaag14Päivi Pajukanta15Jaakko Kaprio16Kirsi H. Pietiläinen17Shuai Li18Miina Ollikainen19Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneDepartment of Human Genetics, David Geffen School of Medicine at UCLAInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiHUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University HospitalHUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University HospitalHUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University HospitalFolkhälsan Institute of Genetics, Folkhälsan Research CenterObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiDepartment of Twin Research and Genetic Epidemiology, King’s College LondonDepartment of Twin Research and Genetic Epidemiology, King’s College LondonEpigenetics and Diabetes Unit, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Scania University HospitalEpigenetics and Diabetes Unit, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Scania University HospitalEpigenetics and Diabetes Unit, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Scania University HospitalDepartment of Clinical Sciences in Malmö, Lund University Diabetes Centre, Scania University HospitalDepartment of Human Genetics, David Geffen School of Medicine at UCLAInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of HelsinkiCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of MelbourneInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of HelsinkiAbstract Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.https://doi.org/10.1038/s41467-025-59576-7 |
| spellingShingle | Aino Heikkinen Vivienne F. C. Esser Seung Hyuk T. Lee Sara Lundgren Antti Hakkarainen Jesper Lundbom Juho Kuula Per-Henrik Groop Sini Heinonen Sergio Villicaña Jordana T. Bell Alice Maguolo Emma Nilsson Charlotte Ling Allan Vaag Päivi Pajukanta Jaakko Kaprio Kirsi H. Pietiläinen Shuai Li Miina Ollikainen Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity Nature Communications |
| title | Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity |
| title_full | Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity |
| title_fullStr | Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity |
| title_full_unstemmed | Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity |
| title_short | Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity |
| title_sort | twin pair analysis uncovers links between dna methylation mitochondrial dna quantity and obesity |
| url | https://doi.org/10.1038/s41467-025-59576-7 |
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