TY - JOUR
T1 - Understanding the role of genetic variability in LRRK2 in Indian population
AU - Kishore, Asha
AU - Ashok Kumar Sreelatha, Ashwin
AU - Sturm, Marc
AU - von-Zweydorf, Felix
AU - Pihlstrøm, Lasse
AU - Raimondi, Francesco
AU - Russell, Rob
AU - Lichtner, Peter
AU - Banerjee, Moinak
AU - Krishnan, Syam
AU - Rajan, Roopa
AU - Puthenveedu, Divya Kalikavil
AU - Chung, Sun Ju
AU - Bauer, Peter
AU - Riess, Olaf
AU - Gloeckner, Christian Johannes
AU - Kruger, Rejko
AU - Gasser, Thomas
AU - Sharma, Manu
AU - International Parkinson's Disease Genomics Consortium (IPDGC)
AU - Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD)
N1 - Funding Information:
*Correspondence to: Dr. Manu Sharma, Centre for Genetic Epidemiol-programme (FNR; FNR/P13/6682797 to R.K.), the German ogy, Institute for Clinical Epidemiology and Applied Biometry, University Research Council (DFG; KR2119/8-1 to R.K. and T.G.), and by the ofTubingen,Silcherstraße5,Tübingen,70276,Germany; European Union’s Horizon2020 research and innovation program E-mail:manu.sharma@uni-tuebingen.de under grant agreement no. 692320 (WIDESPREAD; CENTRE-PD).
Funding Information:
Funding agencies: The project underlying this publication was funded by the Michael J Fox Foundation, USA (M.S. and A.K.). This work was further supported by the grants from the German Research Council (DFG/SH 599/6-1 to M.S.), the EU Joint Program-Neurodegenerative diseases (JPND; COURAGE-PD to M.S., R.K., and T.G.), and Multiple System Atrophy Coalition, USA (to M.S.). R.K. gratefully acknowledges the support from the Luxembourg National Research Fund (FNR) within the National Centre of Excellence in Research on Parkinson’s disease (NCER-PD), PEARL
Funding Information:
Sharma and Asha Kishore received funding for this study from the Michael J Fox Foundation. Christian Johannes Gloeckner, the work which was done for the article, was financed by iMed and the Michael J Fox Foundation.
Funding Information:
agencies: The project underlying this publication was funded by the Michael J Fox Foundation, USA (M.S. and A.K.). This work was further supported by the grants from the German Research Council (DFG/SH 599/6-1 to M.S.), the EU Joint Program-Neurodegenerative diseases (JPND; COURAGE-PD to M.S., R.K., and T.G.), and Multiple System Atrophy Coalition, USA (to M.S.). R.K. gratefully acknowledges the support from the Luxembourg National Research Fund (FNR) within the National Centre of Excellence in Research on Parkinson's disease (NCER-PD), PEARL programme (FNR; FNR/P13/6682797 to R.K.), the German Research Council (DFG; KR2119/8-1 to R.K. and T.G.), and by the European Union's Horizon2020 research and innovation program under grant agreement no. 692320 (WIDESPREAD; CENTRE-PD).We thank all subjects who have contributed in this study.
Publisher Copyright:
© 2018 International Parkinson and Movement Disorder Society
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
KW - LRRK2
KW - Parkinson's disease
KW - neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=85057820096&partnerID=8YFLogxK
U2 - 10.1002/mds.27558
DO - 10.1002/mds.27558
M3 - Article
C2 - 30485545
AN - SCOPUS:85057820096
SN - 0885-3185
VL - 34
SP - 496
EP - 505
JO - Movement Disorders
JF - Movement Disorders
IS - 4
ER -