Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease



Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain < 20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT) SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (also angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (P < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active and their average body height was ~2.00 cm lower compared to controls, both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (P < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (P < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT- SNV data in even larger study cohorts may be needed to conclusively determine the role of MT-DNA in CAD.
Date made available30 Aug 2022
PublisherRiga Stradins University
Date of data production1 Dec 2020 - 15 Mar 2022

Field of Science

  • 1.6 Biological sciences
  • 3.3 Health sciences


  • coronary artery disease
  • mitochondria
  • mitochondrial DNA variants
  • haplogroups
  • association
  • common and rare variants

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