Connect
MJA
MJA

Identifying genes in Parkinson disease: state of the art

Elaine GY Chew, Jia Nee Foo and Eng-King Tan
Med J Aust 2018; 208 (9): . || doi: 10.5694/mja17.01254
Published online: 21 May 2018

Recent studies are expanding our understanding of the genetic basis of Parkinson disease

Parkinson disease (PD) is a common neurodegenerative disorder which manifests as bradykinesia, movement rigidity and tremors in affected individuals. Our understanding of the genetic basis of PD has been steadily increasing since the initial report of α-synuclein mutations two decades ago.1 Mutations implicated in familial PD fully account for monogenic inheritance and point to potential functional mechanisms underlying PD.2,3 However, most sporadic PD cannot be accounted for by known familial PD genes, with the late-onset nature of PD making further linkage studies challenging. Genome-wide association and whole exome sequencing studies have implicated a growing list of mutations and genes in PD, which are expected to provide new insights into potential pathways involved in PD pathogenicity.


  • 1 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
  • 2 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
  • 3 National Neuroscience Institute, Singapore
  • 4 Duke–NUS Medical School, Singapore



Acknowledgements: 

Eng-King Tan acknowledges funding from the National Medical Research Council Singapore under the Singapore Translational Research Investigator Award and the Translational and Clinical Research Flagship Programme (NMRC/TCR/013-NNI/2014); Duke–NUS Medical School; and the Singapore Millennium Foundation. Jia Nee Foo is a Singapore National Research Foundation Fellow (NRF-NRFF2016-03).

Competing interests:

No relevant disclosures.

  • 1. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045-2047.
  • 2. Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson’s disease: progress and therapeutic implications. Mov Disord 2013; 28: 14-23.
  • 3. Mohan M, Mellick GD. Role of the VPS35 D620N mutation in Parkinson’s disease. Parkinsonism Relat Disord 2017; 36: 10-18.
  • 4. Chang D, Nalls MA, Hallgrimsdottir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 2017; 49: 1511-1516.
  • 5. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 2014; 46: 989-993.
  • 6. International Parkinson's Disease Genomics Consortium (IPDGC); Wellcome Trust Case Control Consortium 2 (WTCCC2). A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLOS Genet 2011; 7: e1002142.
  • 7. Robak LA, Jansen IE, van Rooij J, et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 2017; 140: 3191-3203.
  • 8. Siitonen A, Nalls MA, Hernandez D, et al. Genetics of early-onset Parkinson’s disease in Finland: exome sequencing and genome-wide association study. Neurobiol Aging 2017; 53: 195.e197-195.e110.
  • 9. Jansen IE, Ye H, Heetveld S, et al. Discovery and functional prioritization of Parkinson’s disease candidate genes from large-scale whole exome sequencing. Genome Biol 2017; 18: 22.
  • 10. Chartier-Harlin MC, Dachsel JC, Vilarino-Guell C, et al. Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet 2011; 89: 398-406.
  • 11. Vilarino-Guell C, Wider C, Ross OA, et al. VPS35 mutations in Parkinson disease. Am J Hum Genet 2011; 89: 162-167.
  • 12. Vilarino-Guell C, Rajput A, Milnerwood AJ, et al. DNAJC13 mutations in Parkinson disease. Hum Mol Genet 2014; 23: 1794-1801.
  • 13. Funayama M, Ohe K, Amo T, et al. CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol 2015; 14: 274-282.
  • 14. Deng HX, Shi Y, Yang Y, et al. Identification of TMEM230 mutations in familial Parkinson’s disease. Nat Genet 2016; 48: 733-739.
  • 15. Farrer MJ, Milnerwood AJ, Follett J, Guella I. TMEM230 is not a gene for Parkinson disease. bioRxiv 2017. doi:10.1101/097030.
  • 16. Ibanez L, Dube U, Budde J, et al. TMEM230 in Parkinson’s disease. Neurobiol Aging 2017; 56: 212.e211-212.e213.
  • 17. Nichols N, Bras JM, Hernandez DG, et al. EIF4G1 mutations do not cause Parkinson’s disease. Neurobiol Aging 2015; 36: 2444.e2441-2444.e2444.
  • 18. Mok KY, Sheerin U, Simon-Sanchez J, et al. Deletions at 22q11.2 in idiopathic Parkinson’s disease: a combined analysis of genome-wide association data. Lancet Neurol 2016; 15: 585-596.
  • 19. Butcher NJ, Kiehl TR, Hazrati LN, et al. Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. JAMA Neurol 2013; 70: 1359-1366.
  • 20. Jo J, Xiao Y, Sun Alfred X, et al. Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons. Cell Stem Cell 2016; 19: 248-257.
  • 21. Monzel AS, Smits LM, Hemmer K, et al. Derivation of human midbrain-specific organoids from neuroepithelial stem cells. Stem Cell Reports 2017; 8: 1144-1154.
  • 22. Kumari U, Tan EK. LRRK2 in Parkinson’s disease: genetic and clinical studies from patients. FEBS J 2009; 276: 6455-6463.
  • 23. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 2009; 361: 1651-1661.
  • 24. Espay AJ, Brundin P, Lang AE. Precision medicine for disease modification in Parkinson disease. Nat Rev Neurol 2017; 13: 119.
  • 25. Payami H. The emerging science of precision medicine and pharmacogenomics for Parkinson’s disease. Mov Disord 2017; 32: 1139-1146.
  • 26. Bae T, Tomasini L, Mariani J, et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science 2018; 359: 550-555.
  • 27. Lodato MA, Rodin RE, Bohrson CL, et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 2018; 359: 555-559.
  • 28. Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science 2013; 341: 1237758.
  • 29. Kennedy SR, Loeb LA, Herr AJ. Somatic mutations in aging, cancer and neurodegeneration. Mech Ageing Dev 2012; 133: 118-126.
  • 30. Ammal Kaidery N, Tarannum S, Thomas B. Epigenetic landscape of Parkinson’s disease: emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics 2013; 10: 698-708.
  • 31. Jakubowski JL, Labrie V. Epigenetic biomarkers for Parkinson’s disease: from diagnostics to therapeutics. J Parkinsons Dis 2016; 7: 1-12.
  • 32. Migdalska-Richards A, Daly L, Bezard E, Schapira AH. Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann Neurol 2016; 80: 766-775.
  • 33. Chan SL, Tan E-K. Targeting LRRK2 in Parkinson’s disease: an update on recent developments. Expert Opin Ther Targets 2017; 21: 601-610.

Author

remove_circle_outline Delete Author
add_circle_outline Add Author

Comment
Do you have any competing interests to declare? *

I/we agree to assign copyright to the Medical Journal of Australia and agree to the Conditions of publication *
I/we agree to the Terms of use of the Medical Journal of Australia *
Email me when people comment on this article

Online responses are no longer available. Please refer to our instructions for authors page for more information.