Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

Authors

Christina A. Castellani, Johns Hopkins School of MedicineFollow
Ryan J. Longchamps, Johns Hopkins School of Medicine
Jason A. Sumpter, Johns Hopkins School of Medicine
Charles E. Newcomb, Johns Hopkins School of Medicine
John A. Lane, University of Minnesota Medical School
Megan L. Grove, University of Texas Health Science Center at Houston
Jan Bressler, University of Texas Health Science Center at Houston
Jennifer A. Brody, University of Washington School of Medicine
James S. Floyd, University of Washington School of Medicine
Traci M. Bartz, University of Washington School of Medicine
Kent D. Taylor, Harbor-UCLA Medical Center
Penglong Wang, Framingham Heart Study
Adrienne Tin, Welch Center for Prevention Epidemiology and Clinical Research
Josef Coresh, Welch Center for Prevention Epidemiology and Clinical Research
James S. Pankow, School of Public Health
Myriam Fornage, University of Texas Health Science Center at Houston
Eliseo Guallar, Welch Center for Prevention Epidemiology and Clinical Research
Brian O'Rourke, Johns Hopkins School of Medicine
Nathan Pankratz, University of Minnesota Medical School
Chunyu Liu, School of Public Health
Daniel Levy, Framingham Heart Study
Nona Sotoodehnia, University of Washington School of Medicine
Eric Boerwinkle, University of Texas Health Science Center at Houston
Dan E. Arking, Johns Hopkins School of Medicine

Document Type

Article

Publication Date

9-28-2020

Journal

Genome Medicine

Volume

12

Issue

1

URL with Digital Object Identifier

10.1186/s13073-020-00778-7

Abstract

Background: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation. Methods: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9. Results: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10-8). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10-8). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction"KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10-12), as well as the TFAM knockout methylation (P = 4.41 × 10-4) and expression (P = 4.30 × 10-4) studies. Conclusions: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.