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Longchamps RJ, Yang SY, Castellani CA, et al. Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Hum Genet. 2021;141(1):127-146doi: 10.1007/s00439-021-02394-w.
Longchamps, R. J., Yang, S. Y., Castellani, C. A., Shi, W., Lane, J., Grove, M. L., Bartz, T. M., Sarnowski, C., Liu, C., Burrows, K., Guyatt, A. L., Gaunt, T. R., Kacprowski, T., Yang, J., De Jager, P. L., Yu, L., Bergman, A., Xia, R., Fornage, M., Feitosa, M. F., Wojczynski, M. K., Kraja, A. T., Province, M. A., Amin, N., Rivadeneira, F., Tiemeier, H., Uitterlinden, A. G., Broer, L., Van Meurs, J. B. J., Van Duijn, C. M., Raffield, L. M., Lange, L., Rich, S. S., Lemaitre, R. N., Goodarzi, M. O., Sitlani, C. M., Mak, A. C. Y., Bennett, D. A., Rodriguez, S., Murabito, J. M., Lunetta, K. L., Sotoodehnia, N., Atzmon, G., Ye, K., Barzilai, N., Brody, J. A., Psaty, B. M., Taylor, K. D., Rotter, J. I., Boerwinkle, E., Pankratz, N., & Arking, D. E. (2022). Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Human genetics, 141(1), 127-146. https://doi.org/10.1007/s00439-021-02394-w
Longchamps, R J, et al. "Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation." Human genetics vol. 141,1 (2022): 127-146. doi: https://doi.org/10.1007/s00439-021-02394-w
Longchamps RJ, Yang SY, Castellani CA, Shi W, Lane J, Grove ML, Bartz TM, Sarnowski C, Liu C, Burrows K, Guyatt AL, Gaunt TR, Kacprowski T, Yang J, De Jager PL, Yu L, Bergman A, Xia R, Fornage M, Feitosa MF, Wojczynski MK, Kraja AT, Province MA, Amin N, Rivadeneira F, Tiemeier H, Uitterlinden AG, Broer L, Van Meurs JBJ, Van Duijn CM, Raffield LM, Lange L, Rich SS, Lemaitre RN, Goodarzi MO, Sitlani CM, Mak ACY, Bennett DA, Rodriguez S, Murabito JM, Lunetta KL, Sotoodehnia N, Atzmon G, Ye K, Barzilai N, Brody JA, Psaty BM, Taylor KD, Rotter JI, Boerwinkle E, Pankratz N, Arking DE. 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 02. PMID: 34859289.
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Hum Genet. 2022 Jan;141(1):127-146. doi: 10.1007/s00439-021-02394-w. Epub 2021 Dec 02.

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

Human genetics

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

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. [email protected].

PMID: 34859289 DOI: 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

© 2021. The Author(s).

References

  1. Ali AT, Idaghdour Y, Hodgkinson A (2020) Analysis of mitochondrial m1A/G RNA modification reveals links to nuclear genetic variants and associated disease processes. Commun Biol 3:1–11 - PubMed
  2. Ashar FN, Moes A, Moore AZ, Grove ML, Chaves PHM, Coresh J, Newman AB, Matteini AM, Bandeen-Roche K, Boerwinkle E et al (2015) Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med 93:177–186 - PubMed
  3. Ashar FN, Zhang Y, Longchamps RJ, Lane J, Moes A, Grove ML, Mychaleckyj JC, Taylor KD, Coresh J, Rotter JI et al (2017) Association of mitochondrial DNA copy number with cardiovascular disease. JAMA Cardiol 2:1247–1255 - PubMed
  4. Auton A, Abecasis GR, Altshuler DM, Durbin RM, Abecasis GR, Bentley DR, Chakravarti A, Clark AG, Donnelly P, Eichler EE et al (2015) A global reference for human genetic variation. Nature 526:68–74 - PubMed
  5. Barbeira AN, Dickinson SP, Bonazzola R, Zheng J, Wheeler HE, Torres JM, Torstenson ES, Shah KP, Garcia T, Edwards TL et al (2018) Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat Commun 9:1825 - PubMed
  6. Barbeira AN, Pividori M, Zheng J, Wheeler HE, Nicolae DL, Im HK (2019) Integrating predicted transcriptome from multiple tissues improves association detection. PLoS Genet 15:e1007889 - PubMed
  7. Basel D (2020) Mitochondrial DNA depletion syndromes. Clin Perinatol 47:123–141 - PubMed
  8. Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K, Motyer A, Vukcevic D, Delaneau O, O’Connell J et al (2018) The UK Biobank resource with deep phenotyping and genomic data. Nature 562:203–209 - PubMed
  9. Cai B, Giridharan SSP, Zhang J, Saxena S, Bahl K, Schmidt JA, Sorgen PL, Guo W, Naslavsky N, Caplan S (2013) Differential roles of C-terminal Eps15 homology domain proteins as vesiculators and tubulators of recycling endosomes. J Biol Chem 288:30172–30180 - PubMed
  10. Cai N, Li Y, Chang S, Liang J, Lin C, Zhang X, Liang L, Hu J, Chan W, Kendler KS et al (2015) Genetic control over mtDNA and its relationship to major depressive disorder. Curr Biol 25:3170–3177 - PubMed
  11. Cai N, Gomez-Duran A, Yonova-Doing E, Kundu K, Burgess AI, Golder Z, Calabrese C, Bonder MJ, Camacho M, Lawson RA, et al. (2021) Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases. Nat Med 1–12 - PubMed
  12. Carling PJ, Cree LM, Chinnery PF (2011) The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion 11:686–692 - PubMed
  13. Cavdar Koc E, Burkhart W, Blackburn K, Moseley A, Spremulli LL (2001) The small subunit of the mammalian mitochondrial ribosome. Identification of the full complement of ribosomal proteins present. J Biol Chem 276:19363–19374 - PubMed
  14. Chen C, Turnbull DM, Reeve AK (2019) Mitochondrial dysfunction in Parkinson’s disease-cause or consequence? Biology (basel) 8:38 - PubMed
  15. Chew H, Solomon VA, Fonteh AN (2020) Involvement of lipids in Alzheimer’s disease pathology and potential therapies. Front Physiol 11:598 - PubMed
  16. Clay Montier LL, Deng JJ, Bai Y (2009) Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics 36:125–131 - PubMed
  17. Clayton DA (2000) Transcription and replication of mitochondrial DNA. Hum Reprod 15(Suppl 2):11–17 - PubMed
  18. Cohen T, Levin L, Mishmar D (2016) Ancient Out-of-Africa mitochondrial DNA variants associate with distinct mitochondrial gene expression patterns. PLoS Genet 12:e1006407 - PubMed
  19. Copeland WC (2014) Defects of mitochondrial DNA replication. J Child Neurol 29:1216–1224 - PubMed
  20. Crabos M, Yamakado T, Heizmann CW, Cerletti N, Bühler FR, Erne P (1991) The calcium binding protein tropomyosin in human platelets and cardiac tissue: elevation in hypertensive cardiac hypertrophy. Eur J Clin Invest 21:472–478 - PubMed
  21. Cui H, Kong Y, Zhang H (2012) Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduct 2012:646354 - PubMed
  22. Dai D-F, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110:1109–1124 - PubMed
  23. De Botton S, Sabri S, Daugas E, Zermati Y, Guidotti JE, Hermine O, Kroemer G, Vainchenker W, Debili N (2002) Platelet formation is the consequence of caspase activation within megakaryocytes. Blood 100:1310–1317 - PubMed
  24. DeBarmore B, Longchamps RJ, Zhang Y, Kalyani RR, Guallar E, Arking DE, Selvin E, Young JH (2020) Mitochondrial DNA copy number and diabetes: the Atherosclerosis Risk in Communities (ARIC) study. BMJ Open Diabetes Res Care 8:e001204 - PubMed
  25. Delaneau O, Zagury J-F, Robinson MR, Marchini JL, Dermitzakis ET (2019) Accurate, scalable and integrative haplotype estimation. Nat Commun. https://doi.org/10.1038/s41467-019-13225-y - PubMed
  26. Di Buduo CA, Moccia F, Battiston M, De Marco L, Mazzucato M, Moratti R, Tanzi F, Balduini A (2014) The importance of calcium in the regulation of megakaryocyte function. Haematologica 99:769–778 - PubMed
  27. Dölle C, Flønes I, Nido GS, Miletic H, Osuagwu N, Kristoffersen S, Lilleng PK, Larsen JP, Tysnes O-B, Haugarvoll K et al (2016) Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease. Nat Commun 7:13548 - PubMed
  28. El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197:1657–1666 - PubMed
  29. El-Hattab AW, Scaglia F (2013) Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 10:186–198 - PubMed
  30. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, Plagnol V (2014) Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet 10:e1004383 - PubMed
  31. Gibellini L, De Gaetano A, Mandrioli M, Van Tongeren E, Bortolotti CA, Cossarizza A, Pinti M (2020) The biology of Lonp1: more than a mitochondrial protease. Int Rev Cell Mol Biol 354:1–61 - PubMed
  32. Gómez-Durán A, Pacheu-Grau D, López-Gallardo E, Díez-Sánchez C, Montoya J, López-Pérez MJ, Ruiz-Pesini E (2010) Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum Mol Genet 19:3343–3353 - PubMed
  33. Grainha TRR, da Silva Jorge PA, Pérez-Pérez M, Pérez Rodríguez G, Pereira MOBO, Lourenço AMG (2018) Exploring anti-quorum sensing and anti-virulence based strategies to fight Candida albicans infections: an in silico approach. FEMS Yeast Res. https://doi.org/10.1093/femsyr/foy022 - PubMed
  34. GTEx Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45:580–585 - PubMed
  35. Guha M, Avadhani NG (2013) Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 13:577–591 - PubMed
  36. Guyatt AL, Brennan RR, Burrows K, Guthrie PAI, Ascione R, Ring SM, Gaunt TR, Pyle A, Cordell HJ, Lawlor DA et al (2019) A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts. Hum Genomics 13:6 - PubMed
  37. Hägg S, Jylhävä J, Wang Y, Czene K, Grassmann F (2020) Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum Genet - PubMed
  38. Hahsler M, Piekenbrock M, Arya S, Mount D (2019). dbscan: Density Based Clustering of Applications with Noise (DBSCAN) and Related Algorithms. https://cran.csiro.au/web/packages/dbscan/dbscan.pdf - PubMed
  39. Han B, Eskin E (2011) Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet 88:586–598 - PubMed
  40. Hannah-Shmouni F, MacNeil L, Brady L, Nilsson MI, Tarnopolsky M (2019) Expanding the clinical spectrum of LONP1-related mitochondrial cytopathy. Front Neurol 10:981 - PubMed
  41. Harvey A, Gibson T, Lonergan T, Brenner C (2011) Dynamic regulation of mitochondrial function in preimplantation embryos and embryonic stem cells. Mitochondrion 11:829–838 - PubMed
  42. Herst PM, Rowe MR, Carson GM, Berridge MV (2017) Functional mitochondria in health and disease. Front Endocrinol (lausanne) 8:296 - PubMed
  43. Hong YS, Longchamps RJ, Zhao D, Castellani CA, Loehr LR, Chang PP, Matsushita K, Grove ML, Boerwinkle E, Arking DE et al (2020) Mitochondrial DNA copy number and incident heart failure: the atherosclerosis risk in communities (ARIC) study. Circulation 141:1823–1825 - PubMed
  44. Hurtado-Roca Y, Ledesma M, Gonzalez-Lazaro M, Moreno-Loshuertos R, Fernandez-Silva P, Enriquez JA, Laclaustra M (2016) Adjusting MtDNA quantification in whole blood for peripheral blood platelet and leukocyte counts. PLoS One 11:e0163770 - PubMed
  45. Ishihara N, Eura Y, Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. J Cell Sci 117:6535–6546 - PubMed
  46. Josefsson EC, James C, Henley KJ, Debrincat MA, Rogers KL, Dowling MR, White MJ, Kruse EA, Lane RM, Ellis S et al (2011) Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets. J Exp Med 208:2017–2031 - PubMed
  47. Josefsson EC, Burnett DL, Lebois M, Debrincat MA, White MJ, Henley KJ, Lane RM, Moujalled D, Preston SP, O’Reilly LA et al (2014) Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways. Nat Commun 5:3455 - PubMed
  48. Knez J, Winckelmans E, Plusquin M, Thijs L, Cauwenberghs N, Gu Y, Staessen JA, Nawrot TS, Kuznetsova T (2016) Correlates of peripheral blood mitochondrial DNA content in a general population. Am J Epidemiol 183:138–146 - PubMed
  49. Konopka T (2020) umap: Uniform Manifold Approximation and Projection. https://cran.r-project.org/web/packages/umap/index.html - PubMed
  50. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A et al (2013) Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet 45:214–219 - PubMed
  51. Kostan J, Salzer U, Orlova A, Törö I, Hodnik V, Senju Y, Zou J, Schreiner C, Steiner J, Meriläinen J et al (2014) Direct interaction of actin filaments with F-BAR protein pacsin2. EMBO Rep 15:1154–1162 - PubMed
  52. Kumar P, Efstathopoulos P, Millischer V, Olsson E, Wei YB, Brüstle O, Schalling M, Villaescusa JC, Ösby U, Lavebratt C (2018) Mitochondrial DNA copy number is associated with psychosis severity and anti-psychotic treatment. Sci Rep 8:12743 - PubMed
  53. Lämsä R, Helisalmi S, Herukka S-K, Tapiola T, Pirttilä T, Vepsäläinen S, Hiltunen M, Soininen H (2008) Genetic study evaluating LDLR polymorphisms and Alzheimer’s disease. Neurobiol Aging 29:848–855 - PubMed
  54. Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G (2008) Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 27:1133–1163 - PubMed
  55. Linsel-Nitschke P, Götz A, Erdmann J, Braenne I, Braund P, Hengstenberg C, Stark K, Fischer M, Schreiber S, El Mokhtari NE et al (2008) Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease–a Mendelian Randomisation study. PLoS One 3:e2986 - PubMed
  56. Liu C-S, Tsai C-S, Kuo C-L, Chen H-W, Lii C-K, Ma Y-S, Wei Y-H (2003) Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res 37:1307–1317 - PubMed
  57. Liu T, Lu B, Lee I, Ondrovicová G, Kutejová E, Suzuki CK (2004) DNA and RNA binding by the mitochondrial lon protease is regulated by nucleotide and protein substrate. J Biol Chem 279:13902–13910 - PubMed
  58. Loh P-R, Tucker G, Bulik-Sullivan BK, Vilhjálmsson BJ, Finucane HK, Salem RM, Chasman DI, Ridker PM, Neale BM, Berger B et al (2015) Efficient Bayesian mixed model analysis increases association power in large cohorts. Nat Genet 47:284–290 - PubMed
  59. Longchamps RJ, Castellani CA, Yang SY, Newcomb CE, Sumpter JA, Lane J, Grove ML, Guallar E, Pankratz N, Taylor KD et al (2020) Evaluation of mitochondrial DNA copy number estimation techniques. PLoS One 15:e0228166 - PubMed
  60. Malik AN, Czajka A (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13:481–492 - PubMed
  61. Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337–341 - PubMed
  62. Marom S, Friger M, Mishmar D (2017) MtDNA meta-analysis reveals both phenotype specificity and allele heterogeneity: a model for differential association. Sci Rep 7:43449 - PubMed
  63. Márquez-Jurado S, Díaz-Colunga J, das Neves RP, Martinez-Lorente A, Almazán F, Guantes R, Iborra FJ (2018) Mitochondrial levels determine variability in cell death by modulating apoptotic gene expression. Nat Commun 9:389 - PubMed
  64. McArthur K, Chappaz S, Kile BT (2018) Apoptosis in megakaryocytes and platelets: the life and death of a lineage. Blood 131:605–610 - PubMed
  65. Millard LAC, Davies NM, Gaunt TR, Davey Smith G, Tilling K (2018) Software Application Profile: PHESANT: a tool for performing automated phenome scans in UK Biobank. Int J Epidemiol 47:29–35 - PubMed
  66. MitoPipeline (2021) Generating Mitochondrial copy number estimates from SNP array data in Genvisis. http://genvisis.org/MitoPipeline/ . Accessed 30 Oct 2021 - PubMed
  67. Mizumachi T, Muskhelishvili L, Naito A, Furusawa J, Fan C-Y, Siegel ER, Kadlubar FF, Kumar U, Higuchi M (2008) Increased distributional variance of mitochondrial DNA content associated with prostate cancer cells as compared with normal prostate cells. Prostate 68:408–417 - PubMed
  68. Nuytemans K, Maldonado L, Ali A, John-Williams K, Beecham GW, Martin E, Scott WK, Vance JM (2016) Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants. Neurol Genet 2:e44 - PubMed
  69. O’Leary NA, Wright MW, Brister JR, Ciufo S, Haddad D, McVeigh R, Rajput B, Robbertse B, Smith-White B, Ako-Adjei D et al (2016) Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 44:D733-745 - PubMed
  70. Olkowicz M, Tomczyk M, Debski J, Tyrankiewicz U, Przyborowski K, Borkowski T, Zabielska-Kaczorowska M, Szupryczynska N, Kochan Z, Smeda M et al (2021) Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern. Metabolism 114:154400 - PubMed
  71. PathCards :: Apoptosis and Autophagy Pathway and related pathways. - PubMed
  72. PathCards :: Factors involved in megakaryocyte development and platelet production Pathway and related pathways. - PubMed
  73. Pers TH, Karjalainen JM, Chan Y, Westra H-J, Wood AR, Yang J, Lui JC, Vedantam S, Gustafsson S, Esko T et al (2015) Biological interpretation of genome-wide association studies using predicted gene functions. Nat Commun 6:5890 - PubMed
  74. Pinto M, Moraes CT (2014) Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta 1842:1198–1207 - PubMed
  75. Psaty BM, O’Donnell CJ, Gudnason V, Lunetta KL, Folsom AR, Rotter JI, Uitterlinden AG, Harris TB, Witteman JC, Boerwinkle E (2009) Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Circulation 2:73–80 - PubMed
  76. Pyle A, Anugrha H, Kurzawa-Akanbi M, Yarnall A, Burn D, Hudson G (2016) Reduced mitochondrial DNA copy number is a biomarker of Parkinson’s disease. Neurobiol Aging 38:216.e7-216.e10 - PubMed
  77. Reznik E, Miller ML, Şenbabaoğlu Y, Riaz N, Sarungbam J, Tickoo SK, Al-Ahmadie HA, Lee W, Seshan VE, Hakimi AA et al (2016) Mitochondrial DNA copy number variation across human cancers. Elife 5:e10769 - PubMed
  78. Rodríguez-Santiago B, Casademont J, Nunes V (2001) Is mitochondrial DNA depletion involved in Alzheimer’s disease? Eur J Hum Genet 9:279–285 - PubMed
  79. Rubinacci S, Delaneau O, Marchini J (2020) Genotype imputation using the Positional Burrows Wheeler Transform. PLoS Genet 16:e1009049 - PubMed
  80. Rusecka J, Kaliszewska M, Bartnik E, Tońska K (2018) Nuclear genes involved in mitochondrial diseases caused by instability of mitochondrial DNA. J Appl Genet 59:43–57 - PubMed
  81. Schrepfer E, Scorrano L (2016) Mitofusins, from mitochondria to metabolism. Mol Cell 61:683–694 - PubMed
  82. Sever S (2002) Dynamin and endocytosis. Curr Opin Cell Biol 14:463–467 - PubMed
  83. Sharma MR, Koc EC, Datta PP, Booth TM, Spremulli LL, Agrawal RK (2003) Structure of the mammalian mitochondrial ribosome reveals an expanded functional role for its component proteins. Cell 115:97–108 - PubMed
  84. Shen L, Attimonelli M, Bai R, Lott MT, Wallace DC, Falk MJ, Gai X (2018) MSeqDR mvTool: a mitochondrial DNA Web and API resource for comprehensive variant annotation, universal nomenclature collation, and reference genome conversion. Hum Mutat 39:806–810 - PubMed
  85. Sherry ST, Ward M, Sirotkin K (1999) dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res 9:677–679 - PubMed
  86. Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399:483–487 - PubMed
  87. Smyth G, Hu Y, Ritchie M, Silver J, Wettenhall J, McCarthy D, Wu D, Shi W, Phipson B, Lun A et al. (2021) limma: linear models for microarray data (Bioconductor version: Release (3.12)) - PubMed
  88. Sookoian S, Rosselli MS, Gemma C, Burgueño AL, Gianotti TF, Castaño GO, Pirola CJ (2010) Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator–activated receptor γ coactivator 1α promoter. Hepatology 52:1992–2000 - PubMed
  89. Speed D (2019) SumHer better estimates the SNP heritability of complex traits from summary statistics. Nat Genet 51:12 - PubMed
  90. Stiles AR, Simon MT, Stover A, Eftekharian S, Khanlou N, Wang HL, Magaki S, Lee H, Partynski K, Dorrani N et al (2016) Mutations in TFAM, encoding mitochondrial transcription factor A, cause neonatal liver failure associated with mtDNA depletion. Mol Genet Metab 119:91–99 - PubMed
  91. Supek F, Bošnjak M, Škunca N, Šmuc T (2011) REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One 6:e21800 - PubMed
  92. Tang Y, Schon EA, Wilichowski E, Vazquez-Memije ME, Davidson E, King MP (2000) Rearrangements of Human Mitochondrial DNA (mtDNA): New Insights into the Regulation of mtDNA Copy Number and Gene Expression. Mol Biol Cell 11:1471–1485 - PubMed
  93. Tin A, Grams ME, Ashar FN, Lane JA, Rosenberg AZ, Grove ML, Boerwinkle E, Selvin E, Coresh J, Pankratz N et al (2016) Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the atherosclerosis risk in communities study. J Am Soc Nephrol 27:2467–2473 - PubMed
  94. Tomioka M, Toda Y, Mañucat NB, Akatsu H, Fukumoto M, Kono N, Arai H, Kioka N, Ueda K (2017) Lysophosphatidylcholine export by human ABCA7. Biochim Biophys Acta Mol Cell Biol Lipids 1862:658–665 - PubMed
  95. Urata M, Koga-Wada Y, Kayamori Y, Kang D (2008) Platelet contamination causes large variation as well as overestimation of mitochondrial DNA content of peripheral blood mononuclear cells. Ann Clin Biochem 45:513–514 - PubMed
  96. Vagdatli E, Gounari E, Lazaridou E, Katsibourlia E, Tsikopoulou F, Labrianou I (2010) Platelet distribution width: a simple, practical and specific marker of activation of coagulation. Hippokratia 14:28–32 - PubMed
  97. Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E (2017) The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun 482:426–431 - PubMed
  98. Võsa U, Claringbould A, Westra H-J, Bonder MJ, Deelen P, Zeng B, Kirsten H, Saha A, Kreuzhuber R, Kasela S, et al. (2018) Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis. BioRxiv 447367 - PubMed
  99. Vyas CM, Ogata S, Reynolds CF, Mischoulon D, Chang G, Cook NR, Manson JE, Crous-Bou M, De Vivo I, Okereke OI (2020) Lifestyle and behavioral factors and mitochondrial DNA copy number in a diverse cohort of mid-life and older adults. PLoS One 15:e0237235 - PubMed
  100. Wallace DC (1992) Diseases of the mitochondrial DNA. Annu Rev Biochem 61:1175–1212 - PubMed
  101. Wang L, Limongelli A, Vila MR, Carrara F, Zeviani M, Eriksson S (2005) Molecular insight into mitochondrial DNA depletion syndrome in two patients with novel mutations in the deoxyguanosine kinase and thymidine kinase 2 genes. Mol Genet Metab 84:75–82 - PubMed
  102. Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164–e164 - PubMed
  103. Wang G, Sarkar A, Carbonetto P, Stephens M (2020) A simple new approach to variable selection in regression, with application to genetic fine mapping. J R Stat Soc B 82:1273–1300 - PubMed
  104. Wei W, Keogh MJ, Wilson I, Coxhead J, Ryan S, Rollinson S, Griffin H, Kurzawa-Akanbi M, Santibanez-Koref M, Talbot K et al (2017) Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains. Acta Neuropathol Commun 5:13 - PubMed
  105. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191 - PubMed
  106. Workalemahu T, Enquobahrie DA, Tadesse MG, Hevner K, Gelaye B, Sanchez S, Williams MA (2017) Genetic variations related to maternal whole blood mitochondrial DNA copy number: a genome-wide and candidate gene study. J Matern Fetal Neonatal Med 30:2433–2439 - PubMed
  107. Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, Amos CI, Shields PG, Benowitz NL, Gu J et al (2008) Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 100:1104–1112 - PubMed
  108. Yang SY, Castellani CA, Longchamps RJ, Pillalamarri VK, O’Rourke B, Guallar E, Arking DE (2021) Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease. Genome Res 31:349–358 - PubMed
  109. Yin J, Reiman EM, Beach TG, Serrano GE, Sabbagh MN, Nielsen M, Caselli RJ, Shi J (2020) Effect of ApoE isoforms on mitochondria in Alzheimer disease. Neurology 94:e2404–e2411 - PubMed
  110. Young MD, Wakefield MJ, Smyth GK, Oshlack A (2010) Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol 11:R14 - PubMed
  111. Yuan Y, Ju YS, Kim Y, Li J, Wang Y, Yoon CJ, Yang Y, Martincorena I, Creighton CJ, Weinstein JN et al (2020) Comprehensive molecular characterization of mitochondrial genomes in human cancers. Nat Genet 52:342–352 - PubMed
  112. Zhang D, Xi Y, Coccimiglio ML, Mennigen JA, Jonz MG, Ekker M, Trudeau VL (2012) Functional prediction and physiological characterization of a novel short trans-membrane protein 1 as a subunit of mitochondrial respiratory complexes. Physiol Genomics 44:1133–1140 - PubMed
  113. Zhao D, Bartz TM, Sotoodehnia N, Post WS, Heckbert SR, Alonso A, Longchamps RJ, Castellani CA, Hong YS, Rotter JI et al (2020) Mitochondrial DNA copy number and incident atrial fibrillation. BMC Med 18:246 - PubMed

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