Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy

作者：M M Lai, Kyeezu Kim, Yinan Zheng, Christina A. Castellani, Scott M. Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, Kwadwo Bonsu, Charles Newcomb, Kyler McKessy, Lawrence F. Bielak, Wei Zhao, Roby Joehanes, Jiantao Ma, Xiuqing Guo, JoAnn E. Manson, Megan L. Grove, Jan Bressler, Kent D. Taylor, Tuuli Lappalainen, Silva Kasela, Thomas W. Blackwell, Nicole J. Lake, Jessica D. Faul, Kendra Ferrier, Stephen C. Ekker, Lifang Hou, Charles Kooperberg, Alex P. Reiner, Kai Zhang, Patricia A. Peyser, Myriam Fornage, Eric Boerwinkle, Laura M. Raffield, April P. Carson, Stephen S. Rich, Yongmei Liu, Daniel Levy, Jerome I. Rotter, Jennifer A. Smith, Dan E. Arking, Chunyu Liu, NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group, Dan Arking, Christina A. Castellani, JoAnn E. Manson, Wei Zhao, Chunyu Liu · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65845-2 · 被引用次数：1 · 研究领域：Epigenetics and DNA Methylation、Mitochondrial Function and Pathology、Genetic Associations and Epidemiology

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. Mitochondrial DNA heteroplasmy associates with context-specific nuclear CpG methylation, supported by a cell model. Heteroplasmy–CpG scores relate to mortality and cardiovascular risk, though direction and mechanisms remain unclear.