The role of mitochondrial DNA copy number in cardiometabolic disease: a bidirectional two-sample mendelian randomization study

Abstract

Background: This study used a bidirectional 2-sample Mendelian randomization study to investigate the potential causal links between mtDNA copy number and cardiometabolic disease (obesity, hypertension, hyperlipidaemia, type 2 diabetes [T2DM], coronary artery disease [CAD], stroke, ischemic stroke, and heart failure).

Methods: Genetic associations with mtDNA copy number were obtained from a genome-wide association study (GWAS) summary statistics from the UK biobank (n = 395,718) and cardio-metabolic disease were from largest available GWAS summary statistics. Inverse variance weighting (IVW) was conducted, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. We repeated this in the opposite direction using instruments for cardio-metabolic disease.

Results: Genetically predicted mtDNA copy number was not associated with risk of obesity (P = 0.148), hypertension (P = 0.515), dyslipidemia (P = 0.684), T2DM (P = 0.631), CAD (P = 0.199), stroke (P = 0.314), ischemic stroke (P = 0.633), and heart failure (P = 0.708). Regarding the reverse directions, we only found that genetically predicted dyslipidemia was associated with decreased levels of mtDNA copy number in the IVW analysis (β= - 0.060, 95% CI - 0.044 to - 0.076; P = 2.416e-14) and there was suggestive of evidence for a potential causal association between CAD and mtDNA copy number (β= - 0.021, 95% CI - 0.003 to - 0.039; P = 0.025). Sensitivity and replication analyses showed the stable findings.

Conclusions: Findings of this Mendelian randomization study did not support a causal effect of mtDNA copy number in the development of cardiometabolic disease, but found dyslipidemia and CAD can lead to reduced mtDNA copy number. These findings have implications for mtDNA copy number as a biomarker of dyslipidemia and CAD in clinical practice.

Keywords: Bidirectional; Cardiometabolic disease; Mitochondrial DNA copy number; Two-sample mendelian randomization study.

Fig. 1

Overview of study design of the bidirectional Mendelian randomization framework used to investigate the causal effect of mitochondrial DNA copy number on cardiometabolic disease. We performed a total of 16 MR analyses to investigate the bidirectional association between mitochondrial DNA copy number on cardiometabolic disease including obesity, hypertension, dyslipidemia, type 2 diabetes mellitus, coronary artery disease, stroke, ischaemic stroke, and heart failure. All genetic instruments were single nucleotide polymorphisms (SNPs). T2DM, type 2 diabetes mellitus

Fig. 2

The forward MR analyses: Scatter plot of the association between mtDNA copy number and cardiometabolic disease. A Obesity, B hypertension, C dyslipidemia, D T2DM, E CAD, F stroke, G ischemic stroke, H heart failure. Lines in black, red, green, and blue represent IVW, MR-Egger, weighted median, and weight mode methods. CAD coronary artery disease, HF heart failure, IVW inverse variance weighting, IS ischemic stroke, mtDNA-CN mtDNA copy number, SNPs single nucleotide polymorphisms, T2DM type 2 diabetes mellitus

Fig. 3

The reverse MR analyses: Scatter plot of the association between cardiometabolic disease and mtDNA copy number. A Obesity, B hypertension, C dyslipidemia, D T2DM, E CAD, F stroke, G ischemic stroke, H heart failure. Lines in black, red, green, and blue represent IVW, MR-Egger, weighted median, and weight mode methods. CAD coronary artery disease, HF heart failure, IVW inverse variance weighting, IS ischemic stroke, mtDNA-CN mtDNA copy number, SNPs single nucleotide polymorphisms, T2DM type 2 diabetes mellitus