Original Investigation

Human Genetics

, Volume 120, Issue 6, pp 857-863

The LRRK2 Gly2385Arg variant is associated with Parkinson’s disease: genetic and functional evidence

  • E. K. TanAffiliated withDepartment of Neurology, Singapore General HospitalNational Neuroscience InstituteSingHealth Research Email author 
  • , Y. ZhaoAffiliated withDepartment of Clinical Research, Singapore General Hospital
  • , L. SkipperAffiliated withPopulation Genetics, Genome Institute of Singapore
  • , M. G. TanAffiliated withDepartment of Clinical Research, Singapore General Hospital
  • , A. Di FonzoAffiliated withDepartment of Clinical Genetics, Erasmus MC Rotterdam
  • , L. SunAffiliated withDepartment of Clinical Research, Singapore General Hospital
  • , S. Fook-ChongAffiliated withDepartment of Clinical Research, Singapore General Hospital
  • , S. TangAffiliated withKnowledge Discovery Department, Institute for Infocomm Research
  • , E. ChuaAffiliated withDepartment of Neurology, Singapore General Hospital
    • , Y. YuenAffiliated withDepartment of Health Screening, Singapore General Hospital
    • , L. TanAffiliated withNational Neuroscience Institute
    • , R. PavanniAffiliated withDepartment of Neurology, Singapore General HospitalSingHealth Research
    • , M. C. WongAffiliated withDepartment of Neurology, Singapore General HospitalSingHealth Research
    • , P. KolatkarAffiliated withPopulation Genetics, Genome Institute of Singapore
    • , C. S. LuAffiliated withDepartment of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University
    • , V. BonifatiAffiliated withDepartment of Clinical Genetics, Erasmus MC Rotterdam
    • , J. J. LiuAffiliated withPopulation Genetics, Genome Institute of Singapore

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Abstract

Evidence of LRRK2 haplotypes associated with Parkinson’s disease (PD) risk was recently found in the Chinese population from Singapore, and a common LRRK2 missense variant, Gly2385Arg, was independently detected as a putative risk factor for PD in the Chinese population from Taiwan. To test the association between the Gly2385Arg variant in a large case-control sample of Chinese ethnicity from Singapore, and to perform functional studies of the wild type and Gly2385Arg LRRK2 protein in human cell lines. In a case-control study involving 989 Chinese subjects, the frequency of the heterozygous Gly2385Arg genotype was higher in PD compared to controls (7.3 vs. 3.6%, odds ratio = 2.1, 95% CI: 1.1–3.9, P = 0.014); these values yield an estimated population attributable risk (PAR) of ∼4%. In a multivariate logistic regression analysis with the disease group (PD vs. controls) as the dependent variable and the genotype as an independent factor with adjustments made for the effect of age and gender, the heterozygous Gly2385Arg genotype remained associated with an increased risk of PD compared to wild type genotype (odds ratio = 2.67, 95% CI: 1.43–4.99, P = 0.002). The glycine at position 2385 is a candidate site for N-myristoylation, and the Gly2385Arg variant replaces the hydrophobic glycine with the hydrophilic arginine, and increases the net positive charge of the LRRK2 WD40 domain. In transfection studies, we demonstrated that both the wild type and Gly2385Arg variant LRRK2 protein localize to the cytoplasm and form aggregates. However, under condition of oxidative stress, the Gly2385Arg variant was more toxic and associated with a higher rate of apoptosis. Our study lends support to the contention that the Gly2385Arg is a common risk factor for PD in the Chinese population. Our bioinformatics and in-vitro studies also suggest that the Gly2385Arg variant is biologically relevant and it might act through pro-apoptotic mechanisms.