Association of mitochondrial DNA copy number with cardiometabolic diseases in a large cross-sectional study of multiple ancestries

Abstract

The mitochondrial genome (mtDNA) is represented at variable copy number (CN) in human cells and plays essential roles in cellular metabolism. Previous studies reported inconsistent associations between mtDNA CN and cardiometabolic disease (CMD) traits. We determined the cross-sectional association of mtDNA CN measured in whole blood with several CMD traits in ∼66,100 individuals (mean age 60, 54% women, and 21% non-European ancestries). Cohort- and ancestry-specific association and meta-analysis were performed adjusting for trait-specific covariates and batch. Because white blood cell (WBC) count, a marker of subclinical inflammation, is associated with mtDNA CN level and multiple CMD traits, we further compared associations with and without adjustment for WBCs in a subset of individuals with WBCs. In meta-analysis without cell count adjustment in European ancestry (EA) participants (n=52,500), lower mtDNA CN was associated with higher odds of obesity (OR with 95% CI=1.13 (1.11, 1.16), P=3.3e-30) and hypertension (OR=1.05 (1.03, 1.08), P=4.0e-07). Further adjusting for WBCs in a subset of EA participants (N=44,100), associations became non-significant (P>0.05) for hypertension, attenuated for obesity (ORwithout cell counts=1.15 (1.12, 1.18) versus ORcell counts=1.06 (1.03, 1.08)) but strengthened for hyperlipidemia (ORwithout cell counts =1.03 (1.00, 1.06) versus ORcell counts =1.06 (1.03, 1.09)). The magnitude and directionality of most associations were consistent between participants of European and other ancestries. Understanding the role of mtDNA CN in CMD will provide insight into the pathobiology underlying metabolic diseases. Further research on modifiable factors that influence mtDNA CN may help develop therapeutic strategies for preventing and treating metabolic diseases.

Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies

“…Neutrophils have relatively lower mtDNAcn compared to other leukocytes (62), and they form the largest proportion of WBC, which may explain the negative association of WBC count with mtDNAcn. A similar negative association between mtDNAcn and WBC count was observed by Liu et al (66). The current study and other recent publications (67)(68)(69) have highlighted the importance of adjusting for white blood cell parameters and platelet count when testing the association between traits and mtDNAcn measured in whole blood.…”

“…The consistency of the results with the previous literature also clearly demonstrates the reproducibility of this study. The way mtDNAcn is estimated using whole-genome sequence information from the two study cohorts is also seen as the gold standard going forward in this line of research ( Filograna et al, 2021 ), with major mitochondria consortia such as TopMed ( Liu et al, 2020 ) employing the same approach. A limitation of this study was the one-time assessment of mtDNAcn, which precluded a longitudinal analysis of changes in mtDNAcn.…”

Epigenome-wide association study of mitochondrial genome copy number

“…Human mtDNA CN generally declines after middle age, and this decline progresses at different rates across tissues in mice (9) and in humans (10,11). Reduced mtDNA CN has also been reported in several complex diseases, including cancers (12), cardiovascular diseases (CVDs) (13), metabolic traits (14,15), kidney diseases (16) and neurodegenerative disorders (17)(18)(19). These observations suggest a link between mtDNA CN, mitochondrial dysfunction and impaired energy metabolism in the pathogenesis of these disorders.…”

Personality traits are consistently associated with blood mitochondrial DNA copy number estimated from genome sequences in two genetic cohort studies

“…The consistency of the results with the previous literature also clearly demonstrates the reproducibility of this current study. The way mtDNAcn is estimated using whole-genome sequence information from the two study cohorts is also seen as the gold standard going forward in this line of research (70), with major mitochondria consortia such as TopMed (66) employing the same approach. A limitation of the current study was the one-time assessment of mtDNAcn, which precluded a longitudinal analysis of changes in mtDNAcn.…”