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Wang P, Castellani CA, Yao J, et al. Epigenome-wide association study of mitochondrial genome copy number. Hum Mol Genet. 2021;31(2):309-319doi: 10.1093/hmg/ddab240.
Wang, P., Castellani, C. A., Yao, J., Huan, T., Bielak, L. F., Zhao, W., Haessler, J., Joehanes, R., Sun, X., Guo, X., Longchamps, R. J., Manson, J. E., Grove, M. L., Bressler, J., Taylor, K. D., Lappalainen, T., Kasela, S., Van Den Berg, D. J., Hou, L., Reiner, A., Liu, Y., Boerwinkle, E., Smith, J. A., Peyser, P. A., Fornage, M., Rich, S. S., Rotter, J. I., Kooperberg, C., Arking, D. E., Levy, D., Liu, C. (2021). Epigenome-wide association study of mitochondrial genome copy number. Human molecular genetics, 31(2), 309-319. https://doi.org/10.1093/hmg/ddab240
Wang, Penglong, et al. "Epigenome-wide association study of mitochondrial genome copy number." Human molecular genetics vol. 31,2 (2021): 309-319. doi: https://doi.org/10.1093/hmg/ddab240
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. Epigenome-wide association study of mitochondrial genome copy number. Hum Mol Genet. 2021 Dec 27;31(2):309-319. doi: 10.1093/hmg/ddab240. PMID: 34415308; PMCID: PMC8742999.
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Hum Mol Genet. 2021 Dec 27;31(2):309-319. doi: 10.1093/hmg/ddab240.

Epigenome-wide association study of mitochondrial genome copy number.

Human molecular genetics

Penglong Wang, Christina A Castellani, Jie Yao, Tianxiao Huan, Lawrence F Bielak, Wei Zhao, Jeffrey Haessler, Roby Joehanes, Xianbang Sun, Xiuqing Guo, Ryan J Longchamps, JoAnn E Manson, Megan L Grove, Jan Bressler, Kent D Taylor, Tuuli Lappalainen, Silva Kasela, David J Van Den Berg, Lifang Hou, Alexander Reiner, Yongmei Liu, Eric Boerwinkle, Jennifer A Smith, Patricia A Peyser, Myriam Fornage, Stephen S Rich, Jerome I Rotter, Charles Kooperberg, Dan E Arking, Daniel Levy, Chunyu Liu,

Affiliations

  1. Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  2. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  3. Department of Pathology and Laboratory Medicine, Western University, London, Ontario N6A 5C1, Canada.
  4. Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
  5. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
  6. Division of Public Health Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  7. Department of Biostatistics, Boston University, Boston, MA 02118, USA.
  8. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  9. Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  10. New York Genome Center, New York, NY 10013, USA.
  11. Department of Systems Biology, Columbia University, New York, NY 10034, USA.
  12. Department of Population and Public Health Sciences, Center for Genetic Epidemiology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90033, USA.
  13. Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  14. Department of Medicine, Divisions of Cardiology and Neurology, Duke University Medical Center, Durham, NC 27704, USA.
  15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  16. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
  17. Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA.
  18. Framingham Heart Study, National Heart, Lung, and Blood Institute (NHLBI), Framingham, MA 01702, USA.

PMID: 34415308 PMCID: PMC8742999 DOI: 10.1093/hmg/ddab240

Abstract

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.

© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

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