Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Abstract

Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.

The degree of frailty as a translational measure of health in aging

“…At the individual level, these influences give rise to deficit accumulation through a variety of mechanisms, including intrinsic processes that result in damage going unremoved or unrepaired 15,19,161,162 . Such damage is detectable across the levels at which maladaptive aging-related changes can be observed, for example, with decline in telomere length 163 , mitochondrial DNA abundance 164 or DNA methylation changes 18,19,162 . Deficits arising from disruptions in cellular and molecular processes then affect tissues, promote organ dysfunction and lead to clinical manifestations and frailty 21,162 .…”

Low mitochondrial copy number drives atherogenic cardiovascular disease: evidence from prospective cohort analyses in the UK Biobank combined with Mendelian Randomization

“…The exposure of interest for our analysis is the somatic mtDNA-CN as assessed from the intensities of genotyping probes on the mitochondrial chromosome on the Affymetrix Array. The method for computing mtDNA-CN has been described in detail previously (16). We followed the same analysis pipeline to calculate mtDNA-CN in the available data of UKB (https://github.com/GrassmannLab/MT_UKB).…”

“…To account for this heterogeneity, we additionally performed sensitivity analyses restricting to genetic instruments identified in the UKB only. Therefore, 66 independent (linkage disequilibrium < 0.1) SNPs were used that were associated with mtDNA-CN at a genome-wide significance threshold (p < 5e-08) from 295,150 participants conducted by Hä gg et al (16). Genetic associations were adjusted for PCs, age, sex, genotyping batch, genotyping missingness/call rate and cell composition.…”

“…In addition, the initial calculation of mtDNA-CN from chip arrays might have introduced noise due to the small number of variants. To this end, a weighted mtDNA-CN was implemented, which approximates what would be estimated from exome sequencing and has been validated previously (16). Second, despite over 100 instrumental variables by Longchamps et al were used from in the main MR analyses, the variation of mtDNA-CN explained by theses SNPs was very small.…”

The association between lymphocyte mitochondrial DNA abundance and Stroke: a combination of multivariable-adjusted survival and mendelian randomization analyses

“…[8,9] mtDNA-CN in lymphocytes can be assessed relatively easy by estimating the mtDNA abundance from the intensities of genotyping probes representing mitochondrial DNA on genotyping arrays. [10] Due to the extraordinary energy demand of the brain, which is produced by the mitochondria, there is an increased amount of ROS production. [11] Given the postulated detrimental biological effect of oxidative stress on the cerebrovascular system and its role in secondary damage after stroke occurrence, we hypothesized that lower mtDNA-CN could also be associated with a higher risk of stroke.…”