Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

English version České info

There is a growing body of evidence indicating that mitochondrial dysfunction, a result of genetic variation in the mitochondrial genome, is a critical component in the aetiology of a number of complex traits. Here, we take advantage of recent technical and methodological advances to examine the role of common mitochondrial DNA variants in several complex diseases. By examining over 50,000 individuals, from 11 different diseases we show that mitochondrial DNA variants can both increase or decrease an individual's risk of disease, replicating and expanding upon several previously reported studies. Moreover, by analysing several large disease groups in tandem, we are able to show a commonality of association, with the same mitochondrial DNA variants associated with several distinct disease phenotypes. These shared genetic associations implicate a shared underlying functional effect, likely changing cellular energy, which manifests as distinct phenotypes. Our study confirms the important role that mitochondrial DNA variation plays on complex traits and additionally supports the utility of a GWAS-based approach for analysing mitochondrial genetics.

Vyšlo v časopise: Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004369
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004369

Souhrn

Zdroje

1. TorroniA, RichardsM, MacaulayV, ForsterP, VillemsR, et al. (2000) mtDNA haplogroups and frequency patterns in Europe. Am J Hum Genet 66: 1173–1177.

2. CarelliV, VerganiL, BernazziB, ZampieronC, BucchiL, et al. (2002) Respiratory function in cybrid cell lines carrying European mtDNA haplogroups: implications for Leber's hereditary optic neuropathy. Biochim Biophys Acta 1588: 7–14.

3. Gomez-DuranA, Pacheu-GrauD, Martinez-RomeroI, Lopez-GallardoE, Lopez-PerezMJ, et al. (2012) Oxidative phosphorylation differences between mitochondrial DNA haplogroups modify the risk of Leber's hereditary optic neuropathy. Biochim Biophys Acta 1822: 1216–1222.

4. SamuelsDC, CarothersAD, HortonR, ChinneryPF (2006) The power to detect disease associations with mitochondrial DNA haplogroups. Am J Hum Genet 78: 713–720.

5. ChinneryPF, ElliottHR, SyedA, RothwellPM (2010) Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study. Lancet Neurol 9: 498–503.

6. HagenCM, AidtFH, HedleyPL, JensenMK, HavndrupO, et al. (2013) Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population. PLoS One 8: e71904.

7. Fernandez-CaggianoM, Barallobre-BarreiroJ, Rego-PerezI, Crespo-LeiroMG, PaniaguaMJ, et al. (2013) Mitochondrial DNA haplogroup H as a risk factor for idiopathic dilated cardiomyopathy in Spanish population. Mitochondrion 13: 263–268.

8. Ruiz-PesiniE, LapenaAC, Diez-SanchezC, Perez-MartosA, MontoyaJ, et al. (2000) Human mtDNA haplogroups associated with high or reduced spermatozoa motility. Am J Hum Genet 67: 682–696.

9. CarrieriG, BonafeM, De LucaM, RoseG, VarcasiaO, et al. (2001) Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease. Hum Genet 108: 194–198.

10. van der WaltJM, DementievaYA, MartinER, ScottWK, NicodemusKK, et al. (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365: 28–32.

11. MancusoM, ConfortiFL, RocchiA, TessitoreA, MugliaM, et al. (2004) Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis? Neurosci Lett 371: 158–162.

12. HudsonG, NallsM, EvansJR, BreenDP, Winder-RhodesS, et al. (2013) Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology 80: 2042–2048.

13. Gaweda-WalerychK, MaruszakA, SafranowK, BialeckaM, Klodowska-DudaG, et al. (2008) Mitochondrial DNA haplogroups and subhaplogroups are associated with Parkinson's disease risk in a Polish PD cohort. J Neural Transm 115: 1521–1526.

14. GhezziD, MarelliC, AchilliA, GoldwurmS, PezzoliG, et al. (2005) Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians. Eur J Hum Genet 13: 748–752.

15. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

16. BanM, ElsonJ, WaltonA, TurnbullD, CompstonA, et al. (2008) Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility. PLoS One 3: e2891.

17. RollinsB, MartinMV, SequeiraPA, MoonEA, MorganLZ, et al. (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One 4: e4913.

18. SevonP, ToivonenH, OllikainenV (2006) TreeDT: tree pattern mining for gene mapping. IEEE/ACM Trans Comput Biol Bioinform 3: 174–185.

19. WilsonIJ, HoweyRA, HounietDT, Santibanez-KorefM (2011) Finding genes that influence quantitative traits with tree-based clustering. BMC Proc 5 Suppl 9S98.

20. KeightleyJA, AnitoriR, BurtonMD, QuanF, BuistNR, et al. (2000) Mitochondrial encephalomyopathy and complex III deficiency associated with a stop-codon mutation in the cytochrome b gene. Am J Hum Genet 67: 1400–1410.

21. De CooIF, RenierWO, RuitenbeekW, Ter LaakHJ, BakkerM, et al. (1999) A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann Neurol 45: 130–133.

22. AndreuAL, CheccarelliN, IwataS, ShanskeS, DiMauroS (2000) A missense mutation in the mitochondrial cytochrome b gene in a revisited case with histiocytoid cardiomyopathy. Pediatr Res 48: 311–314.

23. HudsonG, CarelliV, SpruijtL, GerardsM, MowbrayC, et al. (2007) Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet 81: 228–233.

24. HuertaC, CastroMG, CotoE, BlazquezM, RibacobaR, et al. (2005) Mitochondrial DNA polymorphisms and risk of Parkinson's disease in Spanish population. J Neurol Sci 236: 49–54.

25. Gomez-DuranA, Pacheu-GrauD, Lopez-GallardoE, Diez-SanchezC, MontoyaJ, et al. (2010) Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum Mol Genet 19: 3343–3353.

26. KulawiecM, OwensKM, SinghKK (2009) Cancer cell mitochondria confer apoptosis resistance and promote metastasis. Cancer Biol Ther 8: 1378–1385.

27. Mkaouar-RebaiE, EllouzeE, ChamkhaI, KammounF, TrikiC, et al. (2011) Molecular-clinical correlation in a family with a novel heteroplasmic Leigh syndrome missense mutation in the mitochondrial cytochrome c oxidase III gene. J Child Neurol 26: 12–20.

28. BrownMD, TorroniA, HuoponenK, ChenYS, LottMT, et al. (1994) Pathological significance of the mtDNA COX III mutation at nucleotide pair 9438 in Leber hereditary optic neuropathy. Am J Hum Genet 55: 410–412.

29. HambletNS, RaglandB, AliM, ConyersB, CastoraFJ (2006) Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II, and III genes detected in Alzheimer's disease using single-strand conformation polymorphism. Electrophoresis 27: 398–408.

30. TranahGJ, NallsMA, KatzmanSM, YokoyamaJS, LamET, et al. (2012) Mitochondrial DNA sequence variation associated with dementia and cognitive function in the elderly. J Alzheimers Dis 32: 357–372.

31. FinnilaS, HassinenIE, MajamaaK (2001) Phylogenetic analysis of mitochondrial DNA in patients with an occipital stroke. Evaluation of mutations by using sequence data on the entire coding region. Mutat Res 458: 31–39.

32. BosleyTM, BrodskyMC, GlasierCM, Abu-AmeroKK (2008) Sporadic bilateral optic neuropathy in children: the role of mitochondrial abnormalities. Invest Ophthalmol Vis Sci 49: 5250–5256.

33. SuissaS, WangZ, PooleJ, WittkoppS, FederJ, et al. (2009) Ancient mtDNA genetic variants modulate mtDNA transcription and replication. PLoS Genet 5: e1000474.

34. CoskunPE, BealMF, WallaceDC (2004) Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A 101: 10726–10731.

35. FuW, O'ConnorTD, JunG, KangHM, AbecasisG, et al. (2013) Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493: 216–220.

36. KeinanA, ClarkAG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336: 740–743.

37. PelloR, MartinMA, CarelliV, NijtmansLG, AchilliA, et al. (2008) Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet 17: 4001–4011.

38. Wellcome Trust Case ControlC, Australo-Anglo-American SpondylitisC, BurtonPR, ClaytonDG, CardonLR, et al. (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39: 1329–1337.

39. International Stroke GeneticsC, Wellcome Trust Case-ControlC (2010) Failure to validate association between 12p13 variants and ischemic stroke. N Engl J Med 362: 1547–1550.

40. BanM, GorisA, LorentzenAR, BakerA, MihalovaT, et al. (2009) Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet 17: 1309–1313.

41. International Parkinson Disease GenomicsC, NallsMA, PlagnolV, HernandezDG, SharmaM, et al. (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377: 641–649.

42. EvansDM, SpencerCC, PointonJJ, SuZ, HarveyD, et al. (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43: 761–767.

43. International Stroke GeneticsC, Wellcome Trust Case ControlC, BellenguezC, BevanS, GschwendtnerA, et al. (2012) Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 44: 328–333.

44. FisherSA, TremellingM, AndersonCA, GwilliamR, BumpsteadS, et al. (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet 40: 710–712.

45. FerreiraMA, O'DonovanMC, MengYA, JonesIR, RuderferDM, et al. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40: 1056–1058.

46. VoightBF, KangHM, DingJ, PalmerCD, SidoreC, et al. (2012) The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 8: e1002793.

47. LangleyRG, KruegerGG, GriffithsCE (2005) Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 64 Suppl 2ii18–23 discussion ii24–15.

48. AlonsoA, JickSS, OlekMJ, HernanMA (2007) Incidence of multiple sclerosis in the United Kingdom: findings from a population-based cohort. J Neurol 254: 1736–1741.

49. MarkusH (2004) Genes for stroke. J Neurol Neurosurg Psychiatry 75: 1229–1231.

50. PrinceMI, JamesOF (2003) The epidemiology of primary biliary cirrhosis. Clin Liver Dis 7: 795–819.

51. de LauLM, BretelerMM (2006) Epidemiology of Parkinson's disease. Lancet Neurol 5: 525–535.

52. GranJT, HusbyG (1993) The epidemiology of ankylosing spondylitis. Semin Arthritis Rheum 22: 319–334.

53. PodolskyDK (2002) Inflammatory bowel disease. N Engl J Med 347: 417–429.

54. SahaS, ChantD, McGrathJ (2008) Meta-analyses of the incidence and prevalence of schizophrenia: conceptual and methodological issues. Int J Methods Psychiatr Res 17: 55–61.

55. HexN, BartlettC, WrightD, TaylorM, VarleyD (2012) Estimating the current and future costs of Type 1 and Type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabet Med 29: 855–862.

56. LiuJL, ManiadakisN, GrayA, RaynerM (2002) The economic burden of coronary heart disease in the UK. Heart 88: 597–603.

57. ManciaG, FagardR, NarkiewiczK, RedonJ, ZanchettiA, et al. (2013) 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 34: 2159–2219.

58. PurcellS, ChernySS, ShamPC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19: 149–150.

59. Wellcome Trust Case ControlConsortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661–678.

60. TorroniA, HuoponenK, FrancalacciP, PetrozziM, MorelliL, et al. (1996) Classification of European mtDNAs from an analysis of three European populations. Genetics 144: 1835–1850.

61. HudsonG, PanoutsopoulouK, WilsonI, SouthamL, RaynerNW, et al. (2013) No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls. Ann Rheum Dis 72: 136–139.

62. BiffiA, AndersonCD, NallsMA, RahmanR, SonniA, et al. (2010) Principal-component analysis for assessment of population stratification in mitochondrial medical genetics. Am J Hum Genet 86: 904–917.

63. Team RC (2013) R: A language and environment for statistical computing.: R Foundation for Statistical Computing, Vienna, Austria.

64. EdgarRC (2004) MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 5: 113.

65. Kloss-BrandstatterA, PacherD, SchonherrS, WeissensteinerH, BinnaR, et al. (2011) HaploGrep: a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. Hum Mutat 32: 25–32.

66. van OvenM, KayserM (2009) Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat 30: E386–394.