PT  - JOURNAL ARTICLE
AU  - Christina A. Castellani
AU  - Ryan J. Longchamps
AU  - Jason A. Sumpter
AU  - Charles E. Newcomb
AU  - John A. Lane
AU  - Megan L. Grove
AU  - Jan Bressler
AU  - Jennifer A. Brody
AU  - James S. Floyd
AU  - Traci M. Bartz
AU  - Kent D. Taylor
AU  - Penglong Wang
AU  - Adrienne Tin
AU  - Josef Coresh
AU  - James S. Pankow
AU  - Myriam Fornage
AU  - Eliseo Guallar
AU  - Brian O’Rourke
AU  - Nathan Pankratz
AU  - Chunyu Liu
AU  - Daniel Levy
AU  - Nona Sotoodehnia
AU  - Eric Boerwinkle
AU  - Dan E. Arking
TI  - Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs
AID  - 10.1101/673293
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 673293
4099  - http://biorxiv.org/content/early/2020/03/11/673293.short
4100  - http://biorxiv.org/content/early/2020/03/11/673293.full
AB  - 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 2,507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings we assayed an additional 2,528 participants from the Cardiovascular Health Study (CHS) (N=533) and Framingham Heart Study (FHS) (N=1,995). 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 directly drives 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.AAAfrican AmericanARICAtherosclerosis Risk in CommunitiesCHDCoronary Heart DiseaseCHSCardiovascular Health StudyCVDCardiovascular diseaseEAEuropean AmericanFHSFramingham Heart StudymeQTLsmethylation quantitative trait lociMRMendelian RandomizationmtDNAmitochondrial DNAmtDNA-CNMitochondrial DNA copy numbernDNAnuclear DNAqPCRquantitative polymerase chain reactionSNPssingle nucleotide polymorphismsSVASurrogate Variable AnalysisTOPMedTrans-Omics in Precision MedicineWGSWhole genome sequencing