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

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 LiuDaniel Levy, Nona Sotoodehnia, Eric Boerwinkle, Dan E. Arking

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	84
Journal	Genome Medicine
Volume	12
Issue number	1
DOIs	https://doi.org/10.1186/s13073-020-00778-7
State	Published - Sep 28 2020

Keywords

Cardiovascular disease
Epigenomics
Mitochondrial DNA
Mortality

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

Access to Document

10.1186/s13073-020-00778-7

Cite this

Castellani, C. A., Longchamps, R. J., Sumpter, J. A., Newcomb, C. E., Lane, J. A., Grove, M. L., Bressler, J., Brody, J. A., Floyd, J. S., Bartz, T. M., Taylor, K. D., Wang, P., Tin, A., Coresh, J., Pankow, J. S., Fornage, M., Guallar, E., O'Rourke, B., Pankratz, N., ... Arking, D. E. (2020). Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs. Genome Medicine, 12(1), Article 84. https://doi.org/10.1186/s13073-020-00778-7

Castellani, CA, Longchamps, RJ, Sumpter, JA, Newcomb, CE, Lane, JA, Grove, ML, Bressler, J, Brody, JA, Floyd, JS, Bartz, TM, Taylor, KD, Wang, P, Tin, A, Coresh, J, Pankow, JS, Fornage, M, Guallar, E , O'Rourke, B, Pankratz, N, Liu, C, Levy, D, Sotoodehnia, N, Boerwinkle, E & Arking, DE 2020, 'Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs', Genome Medicine, vol. 12, no. 1, 84. https://doi.org/10.1186/s13073-020-00778-7

@article{408d0739238b4c8bbc1daa4ad5eb924b,

title = "Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs",

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",

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

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = sep,

day = "28",

doi = "10.1186/s13073-020-00778-7",

language = "English (US)",

volume = "12",

journal = "Genome Medicine",

issn = "1756-994X",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs

AU - Castellani, Christina A.

AU - Longchamps, Ryan J.

AU - Sumpter, Jason A.

AU - Newcomb, Charles E.

AU - Lane, John A.

AU - Grove, Megan L.

AU - Bressler, Jan

AU - Brody, Jennifer A.

AU - Floyd, James S.

AU - Bartz, Traci M.

AU - Taylor, Kent D.

AU - Wang, Penglong

AU - Tin, Adrienne

AU - Coresh, Josef

AU - Pankow, James S.

AU - Fornage, Myriam

AU - Guallar, Eliseo

AU - O'Rourke, Brian

AU - Pankratz, Nathan

AU - Liu, Chunyu

AU - Levy, Daniel

AU - Sotoodehnia, Nona

AU - Boerwinkle, Eric

AU - Arking, Dan E.

PY - 2020/9/28

Y1 - 2020/9/28

N2 - 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.

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 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.

KW - Cardiovascular disease

KW - Epigenomics

KW - Mitochondrial DNA

KW - Mortality

UR - http://www.scopus.com/inward/record.url?scp=85092024886&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85092024886&partnerID=8YFLogxK

U2 - 10.1186/s13073-020-00778-7

DO - 10.1186/s13073-020-00778-7

M3 - Article

C2 - 32988399

AN - SCOPUS:85092024886

SN - 1756-994X

VL - 12

JO - Genome Medicine

JF - Genome Medicine

IS - 1

M1 - 84

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this