Natural selection shaped the protective effect of the mtDNA lineage against obesity in Han Chinese populations.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index, waist circumference, and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort, verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function. Specifically, we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers, indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints. We also find that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.