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

Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, crucial for adapting to changing metabolic demands. Epigenetic modifications, particularly DNA methylation, may influence this intricate interplay, though the specifics remain poorly understood. Leveraging data from the subcohort of the Finnish Twin Cohort (n=173; 86 full twin pairs) that includes comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity (mtDNAq) and nuclear DNA methylation levels in adipose and muscle tissue, we identified one locus at SH3BP4 (cg19998400) significantly associated with mtDNAq in adipose tissue (FDR<0.05). SH3BP4 methylation correlated with its gene expression. Additionally, 14 out of the 35 obesity-related traits displayed significant associations with both SH3BP4 methylation and mtDNAq in adipose tissue. Using the method that infers causality from examination of familial confounding (ICE FALCON) our data suggests that mtDNAq, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. The examination of mtDNAq and obesity-related traits suggested causation from mtDNAq to obesity which could not, however, be distinguished from potential unmeasured within-individual confounding. In conclusion, our findings underscore the impact of mtDNAq on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.