Nuclear genome-wide associations with mitochondrial heteroplasmy

Sci Adv. 2021 Mar 17;7(12):eabe7520. doi: 10.1126/sciadv.abe7520. Print 2021 Mar.


The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / genetics
  • DNA, Mitochondrial / genetics
  • Genome, Mitochondrial*
  • Genome-Wide Association Study
  • Heteroplasmy
  • Humans
  • Mitochondrial Diseases* / genetics


  • DNA, Mitochondrial