Epigenome-wide Association Analysis of Mitochondrial Heteroplasmy Provides Insight into Molecular Mechanisms of Disease.

Meng Lai, Kyeezu Kim, Yinan Zheng, Christina A Castellani, Scott M Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, 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 R Ferrier, Lifang Hou, Charles Kooperberg, Alexander 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,, medRxiv : the preprint server for health sciences (2024)
DOI
10.1101/2024.12.05.24318557
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Abstract

The relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA (nDNA) methylation (CpGs) remains to be studied. We conducted an epigenome-wide association analysis of heteroplasmy burden scores across 10,986 participants (mean age 77, 63% women, and 54% non-White races/ethnicities) from seven population-based observational cohorts. We identified 412 CpGs (FDR p < 0.05) associated with mtDNA heteroplasmy. Higher levels of heteroplasmy burden were associated with lower nDNA methylation levels at most significant CpGs. Functional inference analyses of genes annotated to heteroplasmy-associated CpGs emphasized mitochondrial functions and showed enrichment in cardiometabolic conditions and traits. We developed CpG-scores based on heteroplasmy-count associated CpGs (MHC-CpG scores) using elastic net Cox regression in a training cohort. A one-unit higher level of the standardized MHC-CpG scores were associated with 1.26-fold higher hazard of all-cause mortality (95% CI: 1.14, 1.39) and 1.09-fold higher hazard of CVD (95% CI: 1.01-1.17) in the meta-analysis of testing cohorts, adjusting for age, sex, and smoking. These findings shed light on the relationship between mtDNA heteroplasmy and DNA methylation, and the role of heteroplasmy-associated CpGs as biomarkers in predicting all-cause mortality and cardiovascular disease.