LRRK2 mutations and risk variants in Japanese patients with Parkinson's disease

Mov Disord. 2009 May 15;24(7):1034-41. doi: 10.1002/mds.22514.


Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic determinant of Parkinson's disease (PD) in European-derived populations, but far less is known about LRRK2 mutations and susceptibility alleles in Asians. To address this issue, we sequenced the LRRK2 coding region in 36 patients with familial PD, then genotyped variants of interest in an additional 595 PD cases and 1,641 controls who were all of Japanese ancestry. We also performed a meta-analysis of studies on G2385R, a polymorphism previously reported to associate with PD. One pathogenic (G2019S) and one putative pathogenic (R1067Q) mutation were each observed in two patients with sporadic PD. The overall mutation frequency among patients was 0.6%. G2385R was highly associated with PD under a dominant model in our dataset (adjusted OR, 1.83; 95% CI, 1.31-2.54; P = 3.3 x 10(-4)) and similar results were seen in the meta-analysis (summary OR assuming fixed effects, 2.55; 95% CI, 2.10-3.10). G2385R represents the first consistently replicated common PD susceptibility variant in a non-European population and its effect size is substantially greater than that reported for other well-validated genetic risk factors for the disease. However, LRRK2 mutations appear to be rare among Japanese patients with PD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Arginine / genetics
  • DNA Mutational Analysis
  • Exons / genetics
  • Family Health
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Glycine / genetics
  • Humans
  • Japan
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Male
  • Meta-Analysis as Topic
  • Middle Aged
  • Models, Statistical
  • Molecular Sequence Data
  • Mutation / genetics*
  • Parkinson Disease / etiology*
  • Parkinson Disease / genetics*
  • Protein Serine-Threonine Kinases / genetics*
  • Risk Factors


  • Arginine
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • Glycine