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Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study

Ross, Owen A.; Soto-Ortolaza, Alexandra I.; Heckman, Michael G.; Aasly, Jan O.; Abahuni, Nadine; Annesi, Grazia; Bacon, Justin A.; Bardien, Soraya; Bozi, Maria and Brice, Alexis, et al. (2011) In Lancet Neurology 10(10). p.898-908
Abstract
Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal... (More)
Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 133-15.09; p=0.012). Interpretation The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Funding Michael J Fox Foundation and National Institutes of Health. (Less)
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Lancet Neurology
volume
10
issue
10
pages
898 - 908
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Lancet Ltd
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  • wos:000295814600011
  • scopus:80052967403
ISSN
1474-4465
DOI
10.1016/S1474-4422(11)70175-2
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English
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2011-12-01 08:36:50
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@article{fbe2089e-e2b7-4665-b777-55c99e6906d6,
  abstract     = {Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 133-15.09; p=0.012). Interpretation The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Funding Michael J Fox Foundation and National Institutes of Health.},
  author       = {Ross, Owen A. and Soto-Ortolaza, Alexandra I. and Heckman, Michael G. and Aasly, Jan O. and Abahuni, Nadine and Annesi, Grazia and Bacon, Justin A. and Bardien, Soraya and Bozi, Maria and Brice, Alexis and Brighina, Laura and Van Broeckhoven, Christine and Carr, Jonathan and Chartier-Harlin, Marie-Christine and Dardiotis, Efthimios and Dickson, Dennis W. and Diehl, Nancy N. and Elbaz, Alexis and Ferrarese, Carlo and Ferraris, Alessandro and Fiske, Brian and Gibson, J. Mark and Gibson, Rachel and Hadjigeorgiou, Georgios M. and Hattori, Nobutaka and Ioannidis, John P. A. and Jasinska-Myga, Barbara and Jeon, Beom S. and Kim, Yun Joong and Klein, Christine and Kruger, Rejko and Kyratzi, Elli and Lesage, Suzanne and Lin, Chin-Hsien and Lynch, Timothy and Maraganore, Demetrius M. and Mellick, George D. and Mutez, Eugenie and Nilsson, Christer and Opala, Grzegorz and Park, Sung Sup and Puschmann, Andreas and Quattrone, Aldo and Sharma, Manu and Silburn, Peter A. and Sohn, Young Ho and Stefanis, Leonidas and Tadic, Vera and Theuns, Jessie and Tomiyama, Hiroyuki and Uitti, Ryan J. and Valente, Enza Maria and van de Loo, Simone and Vassilatis, Demetrios K. and Vilarino-Gueell, Cartes and White, Linda R. and Wirdefeldt, Karin and Wszolek, Zbigniew K. and Wu, Ruey-Meei and Farrer, Matthew J.},
  issn         = {1474-4465},
  language     = {eng},
  number       = {10},
  pages        = {898--908},
  publisher    = {Lancet Ltd},
  series       = {Lancet Neurology},
  title        = {Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study},
  url          = {http://dx.doi.org/10.1016/S1474-4422(11)70175-2},
  volume       = {10},
  year         = {2011},
}