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Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation
Human Genetics
  • R. J. Longchamps, Johns Hopkins School of Medicine
  • S. Y. Yang, Johns Hopkins School of Medicine
  • C. A. Castellani, Johns Hopkins School of Medicine
  • W. Shi, Johns Hopkins School of Medicine
  • J. Lane, University of Minnesota Medical School
  • M. L. Grove, University of Texas School of Public Health
  • T. M. Bartz, University of Washington School of Medicine
  • C. Sarnowski, School of Public Health
  • C. Liu, School of Public Health
  • K. Burrows, MRC Integrative Epidemiology Unit
  • A. L. Guyatt, University of Leicester
  • T. R. Gaunt, MRC Integrative Epidemiology Unit
  • T. Kacprowski, Universität Greifswald
  • J. Yang, Rush Alzheimer’s Disease Center
  • P. L. De Jager, Columbia University Irving Medical Center
  • L. Yu, Rush Alzheimer’s Disease Center
  • A. Bergman, Albert Einstein College of Medicine of Yeshiva University
  • R. Xia, University of Texas Health Science Center at Houston
  • M. Fornage, University of Texas Health Science Center at Houston
  • M. F. Feitosa, Washington University School of Medicine in St. Louis
  • M. K. Wojczynski, Washington University School of Medicine in St. Louis
  • A. T. Kraja, Washington University School of Medicine in St. Louis
  • M. A. Province, Washington University School of Medicine in St. Louis
  • N. Amin, Erasmus MC
  • F. Rivadeneira, Erasmus MC
  • H. Tiemeier, Erasmus MC
  • A. G. Uitterlinden, Erasmus MC
  • L. Broer, Erasmus MC
  • J. B.J. Van Meurs, Erasmus MC
Document Type
Article
Publication Date
1-1-2022
URL with Digital Object Identifier
10.1007/s00439-021-02394-w
Abstract

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

Citation Information
R. J. Longchamps, S. Y. Yang, C. A. Castellani, W. Shi, et al.. "Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation" Human Genetics Vol. 141 Iss. 1 (2022) p. 127 - 146
Available at: http://works.bepress.com/christina-castellani/17/