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Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity

Heikkinen, Aino ; Esser, Vivienne F.C. ; Lee, Seung Hyuk T. ; Lundgren, Sara ; Hakkarainen, Antti ; Lundbom, Jesper ; Kuula, Juho ; Groop, Per Henrik ; Heinonen, Sini and Villicaña, Sergio , et al. (2025) In Nature Communications 16(1).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
issue
1
article number
4374
publisher
Nature Publishing Group
external identifiers
  • scopus:105004746419
  • pmid:40355419
ISSN
2041-1723
DOI
10.1038/s41467-025-59576-7
language
English
LU publication?
yes
id
14dd76d5-c23a-4f6d-8748-2cdf39874c82
date added to LUP
2025-07-14 10:03:10
date last changed
2025-07-15 03:00:09
@article{14dd76d5-c23a-4f6d-8748-2cdf39874c82,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Heikkinen, Aino and Esser, Vivienne F.C. and Lee, Seung Hyuk T. and Lundgren, Sara and Hakkarainen, Antti and Lundbom, Jesper and Kuula, Juho and Groop, Per Henrik and Heinonen, Sini and Villicaña, Sergio and Bell, Jordana T. and Maguolo, Alice and Nilsson, Emma and Ling, Charlotte and Vaag, Allan and Pajukanta, Päivi and Kaprio, Jaakko and Pietiläinen, Kirsi H. and Li, Shuai and Ollikainen, Miina}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-59576-7}},
  doi          = {{10.1038/s41467-025-59576-7}},
  volume       = {{16}},
  year         = {{2025}},
}