Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

R J Longchamps; S Y Yang; C A Castellani; W Shi; J Lane; M L Grove; T M Bartz; C Sarnowski; C Liu; K Burrows; A L Guyatt; T R Gaunt; T Kacprowski; J Yang; P L De Jager; L Yu; A Bergman; R Xia; M Fornage; M F Feitosa; M K Wojczynski; A T Kraja; M A Province; N Amin; F Rivadeneira; H Tiemeier; A G Uitterlinden; L Broer; J B J Van Meurs; C M Van Duijn; L M Raffield; L Lange; S S Rich; R N Lemaitre; M O Goodarzi; C M Sitlani; A C Y Mak; D A Bennett; S Rodriguez; J M Murabito; K L Lunetta; N Sotoodehnia; G Atzmon; K Ye; N Barzilai; J A Brody; B M Psaty; K D Taylor; J I Rotter; E Boerwinkle; N Pankratz; D E Arking

doi:10.1007/s00439-021-02394-w

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

Hum Genet. 2022 Jan;141(1):127-146. doi: 10.1007/s00439-021-02394-w. Epub 2021 Dec 2.

Authors

R J Longchamps^#¹, S Y Yang^#¹, C A Castellani^{1

2}, W Shi¹, J Lane³, M L Grove⁴, T M Bartz⁵, C Sarnowski⁶, C Liu⁶, K Burrows^{7

8}, A L Guyatt⁹, T R Gaunt^{7

8}, T Kacprowski^{10

11}, J Yang¹², P L De Jager^{13

14}, L Yu¹², A Bergman¹⁵, R Xia¹⁶, M Fornage^{16

17}, M F Feitosa¹⁸, M K Wojczynski¹⁸, A T Kraja¹⁸, M A Province¹⁸, N Amin¹⁹, F Rivadeneira²⁰, H Tiemeier^{19

21}, A G Uitterlinden^{19

20}, L Broer²⁰, J B J Van Meurs^{19

20}, C M Van Duijn¹⁹, L M Raffield²², L Lange²³, S S Rich²⁴, R N Lemaitre²⁵, M O Goodarzi²⁶, C M Sitlani²⁵, A C Y Mak²⁷, D A Bennett¹², S Rodriguez^{7

8}, J M Murabito²⁸, K L Lunetta⁶, N Sotoodehnia²⁹, G Atzmon^{30

31}, K Ye³², N Barzilai³¹, J A Brody²⁵, B M Psaty³³, K D Taylor³⁴, J I Rotter³⁴, E Boerwinkle^{4

35}, N Pankratz³, D E Arking³⁶

Affiliations

¹ Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
³ Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA.
⁴ Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵ Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁷ MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
⁹ Department of Health Sciences, University of Leicester, University Road, Leicester, UK.
¹⁰ Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
¹¹ Data Science in Biomedicine, Peter L. Reichertz Institute for Medical Informatics, TU Braunschweig and Hannover Medical School, Brunswick, Germany.
¹² Rush Alzheimer's Disease Center and Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
¹³ Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
¹⁵ Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
¹⁶ Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁷ Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, USA.
¹⁸ Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, USA.
¹⁹ Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
²⁰ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
²¹ Department of Social and Behavioral Science, Harvard T.H. School of Public Health, Boston, USA.
²² Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²³ Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
²⁴ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁵ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁶ Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²⁷ Cardiovascular Research Institute and Institute for Human Genetics, University of California, San Francisco, CA, USA.
²⁸ Boston University School of Medicine, Boston University, Boston, MA, USA.
²⁹ Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA, USA.
³⁰ Department of Natural Science, University of Haifa, Haifa, Israel.
³¹ Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
³² Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
³³ Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, USA.
³⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
³⁵ Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX, USA.
³⁶ Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. arking@jhmi.edu.

^# Contributed equally.

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).

MeSH terms

Aged
Cell Proliferation
DNA Copy Number Variations*
DNA, Mitochondrial*
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Megakaryocytes / physiology*
Middle Aged
Mitochondria / genetics*
Nucleotides / metabolism
Phenotype
Platelet Activation*
Polymorphism, Single Nucleotide*

Substances

DNA, Mitochondrial
Nucleotides

Abstract

MeSH terms

Substances

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