Epigenome-wide association study of mitochondrial genome copy number.
We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P < 1 × 10-7), with a 0.7-3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes [PR/SET domain 16, nuclear receptor subfamily 1 group H member 3 (NR1H3), DNA repair protein, DNA polymerase kappa and decaprenyl-diphosphate synthase subunit 2], which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, P = 4 × 10-8) and was positively associated with the NR1H3 expression level (effect size = 0.43, P = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.
Wang, P; Castellani, CA; Yao, J; Huan, T; Bielak, LF; Zhao, W; Haessler, J; Joehanes, R; Sun, X; Guo, X; Longchamps, RJ; Manson, JE; Grove, ML; Bressler, J; Taylor, KD; Lappalainen, T; Kasela, S; Van Den Berg, DJ; Hou, L; Reiner, A; Liu, Y; Boerwinkle, E; Smith, JA; Peyser, PA; Fornage, M; Rich, SS; Rotter, JI; Kooperberg, C; Arking, DE; Levy, D; Liu, C; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
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