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

Ross, Owen, A., Soto-Ortolaza, AIexandra I., Heckman, Michael, G., Aasly, Jan, O., Abahuni, Nadine, Annesi, Grazia, Bacon, Justin, A., Bardien, Soraya, Bozi, Maria, Brice, Alexis, Brighina, Laura, Van Broeckhoven, Christine, Carr, Jonathan, Chartier-Harlin, Marie-Christine, Dardiotis, Efthimios, Dickson, Dennis, W., Diehl, Nancy, N., Elbaz, Alexis, Ferrarese, Carlo, Ferraris, Alessandro, Fiske, Brian, Gibson, J. Mark, Gibson, Rachel, Hadjigeorgiou, Georgios, M., Hattori, Nobutaka, Ioannidis, John, P. A., Jasinska-Myga, Barbara, Jeon, Beom, S., Kim, Yun Joong, Klein, Christine, Kruger, Rejko, Kyratzi, Elli, Lesage, Suzanne, Lin, Chin-Hsien, Lynch, Timothy, Maraganore, Demetruis M., Mellick, George D., Mutez, Eugenie, Nilsson, Christer, Opala, Grzegorz, Park, Sung Sup, Puschmann, Andreas, Quattrone, Aldo, Sharma, Manu, Silburn, Peter A., Sohn, Young Ho, Stefanis, Leonidas, Tadic, Vera, Theuns, Jessie, Tomiyama, Hiroyuki, Uitti, Ryan J., Valente, Enza Maria, van de Loo, Simone, Vassilatis, Demetrios K., Vilarino-Guell, Carles, White, Linda R., Wirdefeldt, Karin, Wszolek, Zbigniew K., Wu, Ruey-Meei, Farrer, Matthew J. and on behalf of the Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study. Lancet Neurology, 10 10: 898-908. doi:10.1016/S1474-4422(11)70175-2

Author Ross, Owen, A.
Soto-Ortolaza, AIexandra I.
Heckman, Michael, G.
Aasly, Jan, O.
Abahuni, Nadine
Annesi, Grazia
Bacon, Justin, A.
Bardien, Soraya
Bozi, Maria
Brice, Alexis
Brighina, Laura
Van Broeckhoven, Christine
Carr, Jonathan
Chartier-Harlin, Marie-Christine
Dardiotis, Efthimios
Dickson, Dennis, W.
Diehl, Nancy, N.
Elbaz, Alexis
Ferrarese, Carlo
Ferraris, Alessandro
Fiske, Brian
Gibson, J. Mark
Gibson, Rachel
Hadjigeorgiou, Georgios, M.
Hattori, Nobutaka
Ioannidis, John, P. A.
Jasinska-Myga, Barbara
Jeon, Beom, S.
Kim, Yun Joong
Klein, Christine
Kruger, Rejko
Kyratzi, Elli
Lesage, Suzanne
Lin, Chin-Hsien
Lynch, Timothy
Maraganore, Demetruis M.
Mellick, George D.
Mutez, Eugenie
Nilsson, Christer
Opala, Grzegorz
Park, Sung Sup
Puschmann, Andreas
Quattrone, Aldo
Sharma, Manu
Silburn, Peter A.
Sohn, Young Ho
Stefanis, Leonidas
Tadic, Vera
Theuns, Jessie
Tomiyama, Hiroyuki
Uitti, Ryan J.
Valente, Enza Maria
van de Loo, Simone
Vassilatis, Demetrios K.
Vilarino-Guell, Carles
White, Linda R.
Wirdefeldt, Karin
Wszolek, Zbigniew K.
Wu, Ruey-Meei
Farrer, Matthew J.
on behalf of the Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium
Title Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study
Formatted title
Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study
Journal name Lancet Neurology   Check publisher's open access policy
ISSN 1474-4422
Publication date 2011-10
Sub-type Article (original research)
DOI 10.1016/S1474-4422(11)70175-2
Volume 10
Issue 10
Start page 898
End page 908
Total pages 11
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Collection year 2012
Language eng
Formatted abstract
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.

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.

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, 1·33—15·09; p=0·012).

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.

Michael J Fox Foundation and National Institutes of Health.
Keyword Genome-wide association
Comprehensive analysis
Protein function
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes On behalf of the Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Medicine Publications
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