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Kishore, A.* ; Ashok Kumar Sreelatha, A.* ; Sturm, M.* ; von-Zweydorf, F.* ; Pihlstrøm, L.* ; Raimondi, F.* ; Russell, R.* ; Lichtner, P. ; Banerjee, M.* ; Krishnan, S.* ; Rajan, R.* ; Puthenveedu, D.K.* ; Chung, S.J.* ; Bauer, P.* ; Riess, O.* ; Gloeckner, C.J.* ; Kruger, R.* ; Gasser, T.* ; Sharma, M.*

Understanding the role of genetic variability in LRRK2 in Indian population.

Mov. Disord. 34, 496-505 (2019)
Postprint DOI PMC
Open Access Green
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. (c) 2018 International Parkinson and Movement Disorder Society
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Neurodegeneration ; Parkinson's Disease ; Lrrk2; Genome-wide Association; Parkinsons-disease; G2019s Mutation; Risk; Variants; Susceptibility; Metaanalysis; Phosphorylation; Families; Reveals
ISSN (print) / ISBN 0885-3185
e-ISSN 1531-8257
Journal Movement Disorders
Quellenangaben Volume: 34, Issue: 4, Pages: 496-505 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CF Genomics (CF-GEN)
Institute of Human Genetics (IHG)