Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Sara Hägg,Juulia Jylhävä,Felix Grassmann,Yunzhang Wang,Kamila Czene

doi:10.1007/s00439-020-02249-w

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.

Highlights

Mitochondria (MT), in addition to producing energy through oxidative processes, are involved in heat production, ion storage, apoptosis, intra- and extra-cellular cell signalling, biosynthesis and degradation of important metabolites as well as the processing of therapeutic agents
We found that male sex [slope and 95% confidence intervals (CI) − 0.05 (− 0.057; − 0.043); P < 10–43] and advanced age (slope per SD and 95% CI − 0.06 (− 0.064; − 0.056); P < 10–238] was strongly associated with mitochondrial DNA (mtDNA) abundance
Since mtDNA abundance may depend on oestrogen levels and may be influenced by menopausal status in women, we investigated whether menopausal status influences mtDNA abundance changes with advanced age

Summary

Introduction

Mitochondria (MT), in addition to producing energy through oxidative processes, are involved in heat production, ion storage, apoptosis, intra- and extra-cellular cell signalling, biosynthesis and degradation of important metabolites as well as the processing of therapeutic agents. Several haplogroups are defined by ancestral and stable mutations in the MT genome. Those haplogroups are derived from adaptation to different geographic areas under distinctive selection pressure (Torroni et al 1996) and may influence the abundance of mitochondrial DNA (mtDNA) (Liou et al 2010; Gómez-Durán et al 2012), there is conflicting evidence (Hulgan et al 2019; Pyle et al 2016). Different haplogroups have been reported to be associated with diseases as well as longevity (Benedictis et al 1999; Chinnery and Gomez-Duran 2018) and as such contribute to phenotypic variety within human populations. MT dysfunction and a reduction in MT biogenesis are hallmarks of aging (López-Otín et al (2013)), and have been associated with most aging-related diseases (Haas 2019) as well as immunological processes (McGuire 2019)

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