Understanding the role of genetic variability in LRRK2 in Indian population

Asha Kishore, Ashwin Ashok Kumar Sreelatha, Marc Sturm, Felix von-Zweydorf, Lasse Pihlstrøm, Francesco Raimondi, Rob Russell, Peter Lichtner, Moinak Banerjee, Syam Krishnan, Roopa Rajan, Divya Kalikavil Puthenveedu, Sun Ju Chung, Peter Bauer, Olaf Riess, Christian Johannes Gloeckner, Rejko Kruger, Thomas Gasser, Manu Sharma*, International Parkinson's Disease Genomics Consortium (IPDGC)Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD)

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)


Background: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. Objectives: To resolve the role of LRRK2 in the Indian population. Methods: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. Results: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. Conclusions: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro.

Original languageEnglish
Pages (from-to)496-505
Number of pages10
JournalMovement Disorders
Issue number4
Publication statusPublished - Apr 2019
Externally publishedYes


  • LRRK2
  • Parkinson's disease
  • neurodegeneration


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