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Genetics of Parkinson's disease

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Abstract

Less than a quarter century after the discovery of SNCA as the first attributable gene in Parkinson's disease (PD), our knowledge of the genetic architecture underlying this disease has improved by leaps and bounds. About 5–10% of all patients suffer from a monogenic form of PD where mutations in autosomal-dominant (AD) genes—SNCA, LRRK2, and VPS35 and autosomal recessive (AR) genes—PINK1, DJ-1, and Parkin cause the disease. Whole-exome sequencing has described AR DNAJC6 mutations not only in predominantly atypical, but also in patients with typical PD. Majority of PD is genetically complex, caused by the combination of common genetic variants in concert with environmental factors. Genome-wide association studies have identified twenty six PD risk loci till date; however, these show only moderate effects on the risk for PD. The validation of novel genes and its association with PD remains extremely challenging as families harboring rare genetic variants are sparse and globally widespread. This review article aims to provide a comprehensive overview on PD genetics.

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References

  1. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K et al (2007) Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68(5):384–386

    CAS  Google Scholar 

  2. de Lau LML, Breteler MMB (2006) Epidemiology of Parkinson's disease. LancetNeurol 5(6):525–535

    Google Scholar 

  3. Schrag A, Horsfall L, Walters K, Noyce A, Petersen I (2015) Prediagnostic presentations of Parkinson's disease in primary care: a case-control study. Lancet. https://doi.org/10.1016/S1474-4422(14)70287-X

    Article  Google Scholar 

  4. Moisan F, Kab S, Mohamed F, Canonico M, Le Guern M, Quintin C, Carcaillon L, Nicolau J, Duport N, Singh-Manoux A, Boussac-Zarebska M, Elbaz A (2016) Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis. J Neurol Neurosurg Psychiatry 87(9):952–957

    Google Scholar 

  5. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839e840

    Google Scholar 

  6. Cheng H-C, Ulane CM, Burke RE (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67(6):715–725

    Google Scholar 

  7. Hirsch EC, Jenner P, Przedborski S (2013) Pathogenesis of Parkinson's disease. Mov Disord 28(1):24–30

    CAS  Google Scholar 

  8. Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ (1999) The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 45(5):577–582

    CAS  Google Scholar 

  9. Wirdefeldt K, Margaret G, Reynolds CA, Prescott CA, Pedersen NL (2011) Heritability of Parkinson disease in Swedish twins: a longitudinal study. Neurobiol Aging. 32(10):1923–1923

    Google Scholar 

  10. Zhu M, Zhao S (2007) Candidate Gene Identification Approach: Progress and Challenges. Int J Biol Sci 3(7):420–427

    CAS  Google Scholar 

  11. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simon-Sanchez J et al (2012) Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson’s disease. Hum Mol Genet 21:4996–5009

    CAS  Google Scholar 

  12. Metzker ML (2010) Sequencing technologies – the next generation. Nat Rev Genet 11:31–46

    CAS  Google Scholar 

  13. Gilissen C, Hoischen A, Brunner HG, Veltman JA (2012) Disease gene identification strategies for exome sequencing. Eur J Hum Genet 20:490–497

    CAS  Google Scholar 

  14. Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA et al (1996) Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 274:1197–1199

    CAS  Google Scholar 

  15. OlanowCW BP (2013) Parkinson’s disease and alpha synuclein: is Parkinson’s disease a prion-like disorder? Mov Disord 28:31–40

    Google Scholar 

  16. Tan EK, Tan C, Shen H, Chai A, Lum SY, Teoh ML, Yih Y, Wong MC, Zhao Y (2003) Alpha synuclein promoter and risk of Parkinson's disease microsatellite and allelic size variability. Neurosci Lett 336:70

    CAS  Google Scholar 

  17. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P et al (2013) alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol 125:753–769

    CAS  Google Scholar 

  18. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276(5321):2045–2047

    CAS  Google Scholar 

  19. Hoffman-Zacharska D, Koziorowski D, Ross OA et al (2013) Novel A18T and pA29S substitutions in α-synuclein may be associated with sporadic Parkinson's disease. Parkinsonism Related Dis 19(11):1057–1060

    Google Scholar 

  20. Chartier-Harlin M, Kachergus J, Roumier C et al (2004) α-synuclein locus duplication as a cause of familial Parkinson's disease. The Lancet 364(9440):1167–1169

    CAS  Google Scholar 

  21. Nussbaum RL (2018) Genetics of Synucleinopathies. Cold Spring Harb Perspect Med 8(6):a024109

    Google Scholar 

  22. Bosgraaf LVHP (2003) Roc, a Ras/GTPase domain in complex proteins. Biochim Biophys Acta 1643(1–3):5–10

    CAS  Google Scholar 

  23. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51:296–301

    CAS  Google Scholar 

  24. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Müller-Myhsok B, Farrer MJ, Gasser T, Calne DB, Dickson DW (2004) Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62:1619–1622

    CAS  Google Scholar 

  25. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607

    CAS  Google Scholar 

  26. Ross OA, Soto-Ortolaza AI, Heckman MG, Aasly JO, Abahuni N, Annesi G et al (2011 ) Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study. Lancet Neurol 10(10):898–908

    CAS  Google Scholar 

  27. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S et al (2008 ) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 7(7):583–590

    CAS  Google Scholar 

  28. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9:1231–1233

    CAS  Google Scholar 

  29. Lee BD, Shin J-H, VanKampen J, Petrucelli L, West AB, Ko HS, Lee Y-I, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nature Med 16:998–1000

    CAS  Google Scholar 

  30. Vilari-no-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ et al (2011) VPS35 mutations in Parkinson disease. Am J Hum Genet 89(1):162–167

    Google Scholar 

  31. Trinh J, Farrer M (2013 ) Advances in the genetics of Parkinson disease. Nat Rev Neurol 9(8):445–454

    CAS  Google Scholar 

  32. Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN et al (2011) A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 89(1):168–175

    CAS  Google Scholar 

  33. Deng H, Wu Y, Jankovic J (2015) The EIF4G1 gene and Parkinson's disease. Acta Neurol Scand 132(2):73–78

    CAS  Google Scholar 

  34. Chartier-Harlin MC, Dachsel JC, Vilarino-Guell C, Lincoln SJ, Lepretre F, Hulihan MM et al (2011) Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 89:398–406

    CAS  Google Scholar 

  35. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–1661

    CAS  Google Scholar 

  36. Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T et al (2013) Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain 136(Pt 2):392–399

    Google Scholar 

  37. Lopez G, Kim J, Wiggs E, Cintron D, Groden C, Tayebi N et al (2016) Clinical course and prognosis in patients with Gaucher disease and parkinsonism. Neurol Genet 2:e57

    Google Scholar 

  38. Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM et al (2016) GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95–102

    CAS  Google Scholar 

  39. Cilia R, Tunesi S, Marotta G, Cereda E, Siri C, Tesei S et al (2016) Survival and dementia in GBA-associated Parkinson's disease: the mutation matters. Ann Neurol 80:662–673

    CAS  Google Scholar 

  40. Sudhaman S, Muthane UB, Behari M, Govindappa ST, Juyal RC, Thelma BK (2016) Evidence of mutations in RIC3 acetylcholine receptor chaperone as a novel cause of autosomal-dominant Parkinson's disease with non-motor phenotypes. J Med Genet 53(8):559–566

    CAS  Google Scholar 

  41. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S et al (1998) Mutations in the Parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676):605–608

    CAS  Google Scholar 

  42. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MMK, Harvey K, Gispert S et al (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304(5674):1158–1160

    CAS  Google Scholar 

  43. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E et al (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299(5604):256–259

    CAS  Google Scholar 

  44. Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MDW, Misbahuddin A et al (2012 ) Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Mov Disord 27(12):1522–1529

    CAS  Google Scholar 

  45. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW et al (2000) Association between early-onset Parkinson’s disease and mutations in the Parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med 342:1560–1567

    CAS  Google Scholar 

  46. Klein C, Lohmann-Hedrich K (2007) Impact of recent genetic findings in Parkinson’s disease. Curr Opin Neurol 20:453–464

    CAS  Google Scholar 

  47. Cazeneuve C, San C, Ibrahim SA, Mukhtar MM, Kheir MM, Leguern E, Brice A, Salih MA (2009) A new complex homozygous large rearrangement of the PINK1 gene in a Sudanese family with early onset Parkinson’s disease. Neurogenetics 10:265–270

    CAS  Google Scholar 

  48. Camargos ST, Dornas LO, Momeni P, Lees A, Hardy J, Singleton A, Cardoso F (2009) Familial Parkinsonism and early onset Parkinson’s disease in a Brazilian movement disorders clinic: Phenotypic characterization and frequency of SNCA, PRKN, PINK1, and LRRK2 mutations. Mov Disord 24:662–666

    Google Scholar 

  49. Marongiu R, Brancati F, Antonini A, Ialongo T, Ceccarini C, Scarciolla O, Capalbo A, Benti R, Pezzoli G, Dallapiccola B et al (2007) Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Hum Mutat 28:98

    Google Scholar 

  50. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14

    CAS  Google Scholar 

  51. Pankratz N, Pauciulo MW, Elsaesser VE, Marek DK, Halter CA, Wojcieszek J, Rudolph A, Shults CW, Foroud T, Nichols WC (2006) Mutations in DJ-1 are rare in familial Parkinson disease. Neurosci Lett 408:209–213

    CAS  Google Scholar 

  52. Junn E, Taniguchi H, Jeong BS, Zhao X, Ichijo H, Mouradian MM (2005) Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proc Natl Acad Sci 102:9691–9696

    CAS  Google Scholar 

  53. Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S et al (2005 ) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 102(14):5215–5220

    CAS  Google Scholar 

  54. Olgiati S, Quadri M, Fang M, Rood JPMA, Saute JA, Chien HF et al (2016 ) DNAJC6 mutations associated with early-onset Parkinson's disease. Ann Neurol 79(2):244–256

    CAS  Google Scholar 

  55. Elsayed LEO, Drouet V, Usenko T, Mohammed IN, Hamed AAA, Elseed MA et al (2016 ) A novel nonsense mutation in DNAJC6 expands the phenotype of autosomal-recessive juvenile-onset Parkinson's disease. Ann Neurol 79(2):335–337

    Google Scholar 

  56. Eisenberg E, Greene LE (2007 ) Multiple roles of auxilin and hsc70 in clathrin-mediated endocytosis. Traffic 8(6):640–646

    CAS  Google Scholar 

  57. Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ (2012) Mutation of the Parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum MolGenet 21:2646–2650

    CAS  Google Scholar 

  58. Paisan-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D et al (2012) Widespread Lewy body and tau accumulation in childhood and adult onset dystonia parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 33:814–823

    CAS  Google Scholar 

  59. Zhao T, Severijnen LA, van der Weiden M, Zheng PP, Oostra BA, Hukema RK et al (2013) FBXO7 immunoreactivity in alpha-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. J Neuropathol Exp Neurol 72:482–488

    CAS  Google Scholar 

  60. Krebs CE, Karkheiran S, Powell JC, Cao M, Makarov V, Darvish H et al (2013) The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat 34(1200–7):30

    Google Scholar 

  61. Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J et al (2013) Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset parkinsonism. Hum Mutat 34:1208–1215

    CAS  Google Scholar 

  62. Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J et al (2005 ) A common inversion under selection in Europeans. Nat Genet 37(2):129–137

    CAS  Google Scholar 

  63. Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC et al (2001) Association of single-nucleotide polymorphisms of the tau gene with late onset Parkinson disease. JAMA 286(18):2245–2250

    CAS  Google Scholar 

  64. Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide B-MM et al (2012) Comprehensive research synopsis and systematic meta analyses in Parkinson's disease genetics: the PDGene database. PLoS Genet 8(3):e1002548

    CAS  Google Scholar 

  65. Moore KM, Nicholas J, Grossman M et al (2020) Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 19(2):145–156

    CAS  Google Scholar 

  66. Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM et al (2011 ) Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet 7(8):e1002237

    CAS  Google Scholar 

  67. Ahmed I, Lee P-C, Lill CM, Searles Nielsen S, Artaud F, Gallagher LG et al (2014) Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease. PLoS Genet 10(11):e1004788

    Google Scholar 

  68. Hill-Burns EM, Singh N, Ganguly P, Hamza TH, Montimurro J, Kay DM et al (2013) A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease. Pharmacogenomics J 13(6):530e537

    Google Scholar 

  69. Deng H, Shi Y, Yang Y et al (2016) Identification of TMEM230 mutations in familial Parkinson's disease. Nat Genet 48:733–739

    CAS  Google Scholar 

  70. Farrer MJ (2019) Doubts about TMEM230 as a gene for Parkinsonism. Nat Genet 51:367–368

    CAS  Google Scholar 

  71. Quadri M, Mandemakers W, Grochowska MM, Masius R, Geut H, Fabrizio E, Breedveld GJ et al (2018) LRP10 genetic variants in familial Parkinson’s disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study. Lancet Neurol 17(7):597–608

    CAS  Google Scholar 

  72. Chen Y, Cen Z, Zheng X, Pan Q, Chen X, Zhu L, Si C et al (2019) LRP10 in autosomal-dominant Parkinson’s disease. Mov Disord 34(6):912–916

    CAS  Google Scholar 

  73. Guo J-F, Zhang L, Li K, Mei J-P, Xue J, Chen J, Tang X et al (2018) Coding mutations in contribute to Parkinson’s disease. Proc Natl Acad Sci U S A 115(45):11567–11572

    CAS  Google Scholar 

  74. Lee JS, Kanai K, Suzuki M, Kim WS, Yoo HS, Yuhong F, Kim D-K et al (2019) Arylsulfatase A, a genetic modifier of Parkinson’s disease, is an α-synuclein chaperone. Neurol Brain J. https://doi.org/10.1093/brain/awz205

    Article  Google Scholar 

  75. Makarious MB, Diez-Fairen M, Krohn L, Blauwendraat C, Bandres-Ciga S, Ding J, Pihlstrøm L, Houlden H, Scholz SW, Gan-Or Z (2019) ARSA variants in α-synucleinopathies. Brain A J Neurol. https://doi.org/10.1093/brain/awz340

    Article  Google Scholar 

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  1. Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India, 695011

    Ajith Cherian & K. P. Divya

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Cherian, A., Divya, K.P. Genetics of Parkinson's disease. Acta Neurol Belg 120, 1297–1305 (2020). https://doi.org/10.1007/s13760-020-01473-5

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