Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy
We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
Authors
- Christina A. Castellani (ORCID: https://orcid.org/0000-0003-2737-0549)
- Jan Bressler (ORCID: https://orcid.org/0000-0001-6578-4772)
- Charles Kooperberg (ORCID: https://orcid.org/0000-0002-7986-8560)
- Patricia A. Peyser (ORCID: https://orcid.org/0000-0002-9717-8459)
- Tianxiao Huan (ORCID: https://orcid.org/0000-0001-5840-9413)
- Lifang Hou (ORCID: https://orcid.org/0000-0003-4877-0031)
- Kendra Ferrier (ORCID: https://orcid.org/0000-0002-8813-6871)
- Kent D. Taylor (ORCID: https://orcid.org/0000-0002-2756-4370)
- Jiantao Ma (ORCID: https://orcid.org/0000-0001-7478-7203)
- Jerome I. Rotter (ORCID: https://orcid.org/0000-0001-7191-1723)
- Kyler McKessy (ORCID: https://orcid.org/0000-0002-6302-1584)
- Laura M. Raffield (ORCID: https://orcid.org/0000-0002-7892-193X)
- Eric Boerwinkle (ORCID: https://orcid.org/0000-0001-8813-0544)
- Stephen C. Ekker (ORCID: https://orcid.org/0000-0003-0726-4212)
- Yinan Zheng (ORCID: https://orcid.org/0000-0002-2006-7320)
- Megan L. Grove (ORCID: https://orcid.org/0000-0001-6764-2508)
- JoAnn E. Manson (ORCID: https://orcid.org/0000-0002-9426-7595)
- Roby Joehanes (ORCID: https://orcid.org/0000-0001-5549-9054)
- Dan E. Arking (ORCID: https://orcid.org/0000-0001-8980-8695)
- Scott M. Ratliff (ORCID: https://orcid.org/0000-0002-6109-662X)
- Charles Newcomb (ORCID: https://orcid.org/0000-0002-2646-7288)
- Jennifer A. Smith (ORCID: https://orcid.org/0000-0002-3575-5468)
- Tuuli Lappalainen (ORCID: https://orcid.org/0000-0002-7746-8109)
- Kyeezu Kim (ORCID: https://orcid.org/0000-0002-9094-9011)
- Nicole J. Lake (ORCID: https://orcid.org/0000-0003-4103-6387)
- Stephen S. Rich (ORCID: https://orcid.org/0000-0003-3872-7793)
- Silva Kasela (ORCID: https://orcid.org/0000-0003-4362-0034)
- Daniel A Levy (ORCID: https://orcid.org/0000-0003-1843-8724)
- M M Lai (ORCID: https://orcid.org/0000-0003-3666-838X)
- Lawrence F. Bielak (ORCID: https://orcid.org/0000-0002-3443-8030)
- Alex P. Reiner (ORCID: https://orcid.org/0000-0002-1427-4470)
- Wei Zhao (ORCID: https://orcid.org/0000-0001-7388-0692)
- April P. Carson (ORCID: https://orcid.org/0000-0002-7970-6756)
- Xiuqing Guo (ORCID: https://orcid.org/0000-0002-5264-5068)
- Dan Arking
- Kwadwo Bonsu (ORCID: https://orcid.org/0000-0002-1279-7315)
- Kai Zhang (ORCID: https://orcid.org/0000-0003-2800-0531)
- Chunyu Liu (ORCID: https://orcid.org/0000-0002-9160-0153)
- Xue Liu (ORCID: https://orcid.org/0000-0002-4196-3597)
- Myriam Fornage (ORCID: https://orcid.org/0000-0003-0677-8158)
- Yongmei Liu (ORCID: https://orcid.org/0000-0002-6562-1858)
- Thomas W. Blackwell
- Jeffrey Haessler
- Jessica D. Faul
- Mengyao Wang (ORCID: https://orcid.org/0009-0005-5135-0224)
Institutions
- Boston University (US)
- Northwestern University (US)
- University of North Carolina at Chapel Hill (US)
- Tufts University (US)
- University of North Texas (US)
- Western University (CA)
- Brigham and Women's Hospital (US)
- National Institutes of Health (US)
- Harvard University (US)
- Johns Hopkins University (US)
- University of North Texas Health Science Center (US)
- Baylor College of Medicine (US)
- University of Michigan (US)
- Johns Hopkins Medicine (US)
- UCLA Medical Center (US)
- Jackson Memorial Hospital (US)
- University of Mississippi Medical Center (US)
- Yale University (US)
- Fred Hutch Cancer Center (US)
- National Heart, Lung, and Blood Institute (US)
- Framingham Heart Study (US)
- Duke Medical Center (US)
- Brown Foundation (US)
- New York Genome Center (US)
- Harbor–UCLA Medical Center (US)
- University of Virginia (US)
- University of Colorado Anschutz Medical Campus (US)
- Columbia University (US)
- Sungkyunkwan University (KR)
- The University of Texas at Austin (US)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1038/s41467-025-65845-2
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Institutes of Health
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Eye Institute
- National Institute on Minority Health and Health Disparities