scholarly journals Mitochondrial DNA Copy Number (mtDNA-CN) Can Influence Mortality and Cardiovascular Disease via Methylation of Nuclear DNA CpGs

2019 ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

ABSTRACTBackgroundMitochondrial 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.MethodsTo 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.ResultsThirty-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.ConclusionsThese 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.

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

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Christina A. Castellani ◽  
Ryan J. Longchamps ◽  
Jason A. Sumpter ◽  
Charles E. Newcomb ◽  
John A. Lane ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Genome Wide Significance ◽  
Experimental Modification

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.

scholarly journals Luteal phase-derived oocyte-cumulus complexes: gene expression and mitochondrial DNA copy number

2019 ◽  
Vol 112 (3) ◽  
pp. e257-e258
Author(s):  
Bella Martazanova ◽  
Nona Mishieva ◽  
Anna Korolkova ◽  
Khava Bogatyreva ◽  
Maria Veykova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Luteal Phase ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number

scholarly journals PCR‐Based Analysis of Mitochondrial DNA Copy Number, Mitochondrial DNA Damage, and Nuclear DNA Damage

2016 ◽  
Vol 67 (1) ◽  
Author(s):  
Claudia P. Gonzalez‐Hunt ◽  
John P. Rooney ◽  
Ian T. Ryde ◽  
Charumathi Anbalagan ◽  
Rashmi Joglekar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Nuclear Dna ◽  
Dna Copy Number ◽  
Mitochondrial Dna Damage ◽  
Mitochondrial Dna Copy Number

scholarly journals Mitochondrial DNA copy number and trimethylamine levels in the blood: New insights on cardiovascular disease biomarkers

2021 ◽  
Vol 35 (7) ◽  
Author(s):  
Laura Bordoni ◽  
Irene Petracci ◽  
Iwona Pelikant‐Malecka ◽  
Adriana Radulska ◽  
Marco Piangerelli ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Mitochondrial Dna ◽  
Copy Number ◽  
Dna Copy Number ◽  
Disease Biomarkers ◽  
Mitochondrial Dna Copy Number

scholarly journals A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts

2018 ◽  
Author(s):  
Anna L. Guyatt ◽  
Rebecca R. Brennan ◽  
Kimberley Burrows ◽  
Philip A. I. Guthrie ◽  
Raimondo Ascione ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Copy Number ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
A Genome

AbstractMitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist.We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC), and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay), and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA, and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children, and UKBS males.A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], β[SE] −0.084 [0.016], p=1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, β[SE] 0.262 [0.034], p=1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N=11253), we replicated a published association in TFAM β[SE] 0.046 [0.017], p=0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS.In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN, and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.

Sign in / Sign up

Export Citation Format

Share Document