scholarly journals Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

2021 ◽  
Author(s):  
R. J. Longchamps ◽  
S. Y. Yang ◽  
C. A. Castellani ◽  
W. Shi ◽  
J. Lane ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Platelet Activation ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Nucleotide Metabolism ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Mitochondrial Dna Depletion ◽  
A Genome

AbstractMitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

scholarly journals Genome-wide analysis of mitochondrial DNA copy number reveals multiple loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

2021 ◽  
Author(s):  
RJ Longchamps ◽  
SY Yang ◽  
CA Castellani ◽  
W Shi ◽  
J Lane ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Platelet Activation ◽  
Copy Number ◽  
Nucleotide Metabolism ◽  
European Ancestry ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
Mitochondrial Dna Depletion ◽  
A Genome

AbstractBlood-derived mitochondrial DNA copy number (mtDNA-CN) is a minimally invasive proxy measure of mitochondrial function that exhibits both inter-individual and intercellular variation. While mtDNA-CN has been previously associated with various aging-related diseases, little is known about the genetic factors that may modulate this phenotype. We performed a genome-wide association study (GWAS) in 465,809 individuals of White (European) ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 129 SNPs with statistically significant, independent effects associated with mtDNA-CN across 96 loci. A combination of fine-mapping, variant annotation, co-localization, and gene set enrichment analyses were used to prioritize genes within each of the 129 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10−15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10−8) and mtDNA replication (p = 1.2 × 10−7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 42 mtDNA-CN associated phenotypes to identify functional domains, revealing five distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. In conclusion, in a GWAS of mtDNA-CN conducted in >450,000 individuals, we identified SNPs within loci that implicate novel pathways that provide a framework for defining the underlying mechanisms involved in genetic control of mtDNA-CN.

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

2019 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna L. Guyatt ◽  
Rebecca R. Brennan ◽  
Kimberley Burrows ◽  
Philip A. I. Guthrie ◽  
Raimondo Ascione ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Association Study ◽  
Copy Number ◽  
Genome Wide Association Study ◽  
Population Based ◽  
Genome Wide Association ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
A Genome

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.

Abstract 049: Mitochondrial DNA Copy Number and Incident Atrial Fibrillation: The Atherosclerosis Risk in Communities Study (ARIC)

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Di Zhao ◽  
Eliseo Guallar ◽  
Ryan Longchamps ◽  
Christina Castellani ◽  
Yunsoo Hong ◽  
...  
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Mitochondrial Dna ◽  
General Population ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Cvd Risk Factors ◽  
Dna Copy Number ◽  
Cvd Risk ◽  
Mitochondrial Dna Copy Number

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia. Molecular studies suggest that mitochondrial dysfunction is associated with increased risk of AF through reduced production of adenosine triphosphate and increased production of reactive oxidative species. Mitochondrial DNA copy number (mtDNA CN), a marker of mitochondrial function, has been found to be associated with sudden cardiac death and cardiovascular disease (CVD) in ARIC. However, the association between mtDNA CN and incident AF in the general population is unknown. Objective: To examine the prospective association between mtDNA CN and the risk of incident AF. Methods: Cohort study of 10,764 ARIC participants without AF at baseline (1987-89) and followed through December 31, 2014. AF were identified through electrocardiograms, review of hospital discharge codes, and death certificates. DNA samples were isolated from buffy coat. mtDNA CN was calculated from probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms (SNP) Array and standardized using the residual method. Cox proportional hazards models adjusted for demographics and CVD risk factors were used to estimate hazard ratios (HR) for AF comparing the four lowest quintiles of mtDNA CN to the highest quintile. Results: The mean (SD) age was 57.4 (6.0) years. During 21 years of median follow-up, 1,946 participants developed AF. In fully-adjusted models, the HRs (95% CI) for AF comparing quintiles 1 - 4 to quintile 5 of mtDNA CN were 1.17 (1.00, 1.37), 1.17 (0.99, 1.37), 0.92 (0.78, 1.10) and 1.05 (0.89, 1.24), respectively (p-trend 0.044; Figure). The HR for AF comparing 10 th vs 90 th percentile of mtDNA-CN was 1.16 (1.04, 1.30). Conclusions: mtDNA CN was inversely associated with the risk of AF independent of traditional CVD risk factors. Decline in mitochondrial function may be a novel mechanism underlying biological changes that increase the risk of AF in the general population. mtDNA CN may provide potential for novel AF prevention strategies.

scholarly journals Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

Aging Cell ◽  
2018 ◽  
Vol 17 (4) ◽  
pp. e12773 ◽  
Author(s):  
Kirsty Foote ◽  
Johannes Reinhold ◽  
Emma P. K. Yu ◽  
Nichola L. Figg ◽  
Alison Finigan ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Vascular Aging ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number

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 Genetic variations related to maternal whole blood mitochondrial DNA copy number: a genome-wide and candidate gene study

2017 ◽  
Vol 30 (20) ◽  
pp. 2433-2439 ◽  
Author(s):  
Tsegaselassie Workalemahu ◽  
Daniel A. Enquobahrie ◽  
Mahlet G. Tadesse ◽  
Karin Hevner ◽  
Bizu Gelaye ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Candidate Gene ◽  
Whole Blood ◽  
Copy Number ◽  
Genetic Variations ◽  
Candidate Gene Study ◽  
Mitochondrial Dna Copy Number ◽  
Genome Wide ◽  
A Genome ◽  
Gene Study

Maintenance of mitochondrial DNA copy number and expression are essential for preservation of mitochondrial function and cell growth

2008 ◽  
Vol 103 (2) ◽  
pp. 347-357 ◽  
Author(s):  
Jaan-Yeh Jeng ◽  
Tien-Shun Yeh ◽  
Jing-Wen Lee ◽  
Shyh-Hsiang Lin ◽  
Tsorng-Han Fong ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Cell Growth ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Dna Copy Number ◽  
Mitochondrial Dna Copy Number

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.

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