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

Christina A Castellani; Ryan J Longchamps; Jason A Sumpter; Charles E Newcomb; John A Lane; Megan L Grove; Jan Bressler; Jennifer A Brody; James S Floyd; Traci M Bartz; Kent D Taylor; Penglong Wang; Adrienne Tin; Josef Coresh; James S Pankow; Myriam Fornage; Eliseo Guallar; Brian O'Rourke; Nathan Pankratz; Chunyu Liu; Daniel Levy; Nona Sotoodehnia; Eric Boerwinkle; Dan E Arking

doi:10.1186/s13073-020-00778-7

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

Genome Med. 2020 Sep 28;12(1):84. doi: 10.1186/s13073-020-00778-7.

Authors

Christina A Castellani¹, Ryan J Longchamps¹, Jason A Sumpter¹, Charles E Newcomb¹, John A Lane², Megan L Grove³, Jan Bressler³, Jennifer A Brody⁴, James S Floyd⁴, Traci M Bartz^{4

5}, Kent D Taylor⁶, Penglong Wang^{7

8}, Adrienne Tin⁹, Josef Coresh⁹, James S Pankow¹⁰, Myriam Fornage^{3

11}, Eliseo Guallar⁹, Brian O'Rourke¹², Nathan Pankratz², Chunyu Liu¹³, Daniel Levy^{7

8}, Nona Sotoodehnia⁴, Eric Boerwinkle³, Dan E Arking^{14

15}

Affiliations

¹ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN, USA.
³ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁵ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Framingham Heart Study, Framingham, MA, USA.
⁸ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Epidemiology and the Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹¹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹² Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁴ McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. arking@jhmi.edu.
¹⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. arking@jhmi.edu.

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.

Keywords: Cardiovascular disease; Epigenomics; Mitochondrial DNA; Mortality.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiovascular Diseases / genetics*
Cardiovascular Diseases / mortality*
CpG Islands*
Cross-Sectional Studies
DNA Copy Number Variations*
DNA Methylation*
DNA, Mitochondrial*
DNA-Binding Proteins / genetics
Disease Susceptibility
Gene Expression
Gene Knockdown Techniques
Genome-Wide Association Study
Humans
Mitochondria / genetics*
Mitochondrial Proteins / genetics
Odds Ratio
Phenotype
Polymorphism, Single Nucleotide
Prognosis
Quantitative Trait Loci
Signal Transduction
Transcription Factors / genetics

Substances

DNA, Mitochondrial
DNA-Binding Proteins
Mitochondrial Proteins
TFAM protein, human
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding