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

Owen A. Ross; Alexandra I. Soto-Ortolaza; Michael G. Heckman; Jan O. Aasly; Nadine Abahuni; Grazia Annesi; Justin A. Bacon; Soraya Bardien; Maria Bozi; Alexis Brice; Laura Brighina; Christine Van Broeckhoven; Jonathan Carr; Marie Christine Chartier-Harlin; Efthimios Dardiotis; Dennis W. Dickson; Nancy N. Diehl; Alexis Elbaz; Carlo Ferrarese; Alessandro Ferraris; Brian Fiske; J. Mark Gibson; Rachel Gibson; Georgios M. Hadjigeorgiou; Nobutaka Hattori; John P.A. Ioannidis; Barbara Jasinska-Myga; Beom S. Jeon; Yun Joong Kim; Christine Klein; Rejko Kruger; Elli Kyratzi; Suzanne Lesage; Chin Hsien Lin; Timothy Lynch; Demetrius M. Maraganore; George D. Mellick; Eugénie Mutez; Christer Nilsson; Grzegorz Opala; Sung Sup Park; Andreas Puschmann; Aldo Quattrone; Manu Sharma; Peter A. Silburn; Young Ho Sohn; Leonidas Stefanis; Vera Tadic; Jessie Theuns; Hiroyuki Tomiyama; Ryan J. Uitti; Enza Maria Valente; Simone van de Loo; Demetrios K. Vassilatis; Carles Vilariño-Güell; Linda R. White; Karin Wirdefeldt; Zbigniew K. Wszolek; Ruey Meei Wu; Matthew J. Farrer

doi:10.1016/S1474-4422(11)70175-2

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

Owen A. Ross^*, Alexandra I. Soto-Ortolaza, Michael G. Heckman, Jan O. Aasly, Nadine Abahuni, Grazia Annesi, Justin A. Bacon, Soraya Bardien, Maria Bozi, Alexis Brice, Laura Brighina, Christine Van Broeckhoven, Jonathan Carr, Marie Christine Chartier-Harlin, Efthimios Dardiotis, Dennis W. Dickson, Nancy N. Diehl, Alexis Elbaz, Carlo Ferrarese, Alessandro FerrarisBrian Fiske, J. Mark Gibson, Rachel Gibson, Georgios M. Hadjigeorgiou, Nobutaka Hattori, John P.A. Ioannidis, Barbara Jasinska-Myga, Beom S. Jeon, Yun Joong Kim, Christine Klein, Rejko Kruger, Elli Kyratzi, Suzanne Lesage, Chin Hsien Lin, Timothy Lynch, Demetrius M. Maraganore, George D. Mellick, Eugénie Mutez, Christer Nilsson, Grzegorz Opala, Sung Sup Park, Andreas Puschmann, Aldo Quattrone, Manu Sharma, Peter A. Silburn, Young Ho Sohn, Leonidas Stefanis, Vera Tadic, Jessie Theuns, Hiroyuki Tomiyama, Ryan J. Uitti, Enza Maria Valente, Simone van de Loo, Demetrios K. Vassilatis, Carles Vilariño-Güell, Linda R. White, Karin Wirdefeldt, Zbigniew K. Wszolek, Ruey Meei Wu, Matthew J. Farrer

^*Corresponding author for this work

142 Citations (Scopus)

Abstract

Background: 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, 1·33-15·09; 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.

Original language	English
Journal	The Lancet Neurology
Volume	10
Issue number	10
Pages (from-to)	898-908
Number of pages	11
ISSN	1474-4422
DOIs	https://doi.org/10.1016/S1474-4422(11)70175-2
Publication status	Published - 01.10.2011

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10.1016/S1474-4422(11)70175-2

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Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Aasly, J. O., Abahuni, N., Annesi, G., Bacon, J. A., Bardien, S., Bozi, M., Brice, A., Brighina, L., Van Broeckhoven, C., Carr, J., Chartier-Harlin, M. C., Dardiotis, E., Dickson, D. W., Diehl, N. N., Elbaz, A., Ferrarese, C., ... Farrer, M. J. (2011). Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study. The Lancet Neurology, 10(10), 898-908. https://doi.org/10.1016/S1474-4422(11)70175-2

@article{3aadc5a8d45c4bb8802e181a44b63ba8,

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

abstract = "Background: 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, 1·33-15·09; 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 Nadine Abahuni and Grazia Annesi and Bacon, {Justin A.} and Soraya Bardien and Maria Bozi and Alexis Brice and Laura Brighina and {Van Broeckhoven}, Christine and Jonathan Carr and Chartier-Harlin, {Marie Christine} and Efthimios Dardiotis and Dickson, {Dennis W.} and Diehl, {Nancy N.} and Alexis Elbaz and Carlo Ferrarese and Alessandro Ferraris and Brian Fiske and Gibson, {J. Mark} and Rachel Gibson and Hadjigeorgiou, {Georgios M.} and Nobutaka Hattori and Ioannidis, {John P.A.} and Barbara Jasinska-Myga and Jeon, {Beom S.} and Kim, {Yun Joong} and Christine Klein and Rejko Kruger and Elli Kyratzi and Suzanne Lesage and Lin, {Chin Hsien} and Timothy Lynch and Maraganore, {Demetrius M.} and Mellick, {George D.} and Eug{\'e}nie Mutez and Christer Nilsson and Grzegorz Opala and Park, {Sung Sup} and Andreas Puschmann and Aldo Quattrone and Manu Sharma and Silburn, {Peter A.} and Sohn, {Young Ho} and Leonidas Stefanis and Vera Tadic and Jessie Theuns and Hiroyuki Tomiyama and Uitti, {Ryan J.} and Valente, {Enza Maria} and {van de Loo}, Simone and Vassilatis, {Demetrios K.} and Carles Vilari{\~n}o-G{\"u}ell and White, {Linda R.} and Karin Wirdefeldt and Wszolek, {Zbigniew K.} and Wu, {Ruey Meei} and Farrer, {Matthew J.}",

year = "2011",

month = oct,

day = "1",

doi = "10.1016/S1474-4422(11)70175-2",

language = "English",

volume = "10",

pages = "898--908",

journal = "The Lancet Neurology",

issn = "1474-4422",

number = "10",

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Ross, OA, Soto-Ortolaza, AI, Heckman, MG, Aasly, JO, Abahuni, N, Annesi, G, Bacon, JA, Bardien, S, Bozi, M, Brice, A, Brighina, L, Van Broeckhoven, C, Carr, J, Chartier-Harlin, MC, Dardiotis, E, Dickson, DW, Diehl, NN, Elbaz, A, Ferrarese, C, Ferraris, A, Fiske, B, Gibson, JM, Gibson, R, Hadjigeorgiou, GM, Hattori, N, Ioannidis, JPA, Jasinska-Myga, B, Jeon, BS, Kim, YJ, Klein, C, Kruger, R, Kyratzi, E, Lesage, S, Lin, CH, Lynch, T, Maraganore, DM, Mellick, GD, Mutez, E, Nilsson, C, Opala, G, Park, SS, Puschmann, A, Quattrone, A, Sharma, M, Silburn, PA, Sohn, YH, Stefanis, L, Tadic, V, Theuns, J, Tomiyama, H, Uitti, RJ, Valente, EM, van de Loo, S, Vassilatis, DK, Vilariño-Güell, C, White, LR, Wirdefeldt, K, Wszolek, ZK, Wu, RM & Farrer, MJ 2011, 'Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study', The Lancet Neurology, vol. 10, no. 10, pp. 898-908. https://doi.org/10.1016/S1474-4422(11)70175-2

TY - JOUR

T1 - Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

AU - Ross, Owen A.

AU - Soto-Ortolaza, Alexandra I.

AU - Heckman, Michael G.

AU - Aasly, Jan O.

AU - Abahuni, Nadine

AU - Annesi, Grazia

AU - Bacon, Justin A.

AU - Bardien, Soraya

AU - Bozi, Maria

AU - Brice, Alexis

AU - Brighina, Laura

AU - Van Broeckhoven, Christine

AU - Carr, Jonathan

AU - Chartier-Harlin, Marie Christine

AU - Dardiotis, Efthimios

AU - Dickson, Dennis W.

AU - Diehl, Nancy N.

AU - Elbaz, Alexis

AU - Ferrarese, Carlo

AU - Ferraris, Alessandro

AU - Fiske, Brian

AU - Gibson, J. Mark

AU - Gibson, Rachel

AU - Hadjigeorgiou, Georgios M.

AU - Hattori, Nobutaka

AU - Ioannidis, John P.A.

AU - Jasinska-Myga, Barbara

AU - Jeon, Beom S.

AU - Kim, Yun Joong

AU - Klein, Christine

AU - Kruger, Rejko

AU - Kyratzi, Elli

AU - Lesage, Suzanne

AU - Lin, Chin Hsien

AU - Lynch, Timothy

AU - Maraganore, Demetrius M.

AU - Mellick, George D.

AU - Mutez, Eugénie

AU - Nilsson, Christer

AU - Opala, Grzegorz

AU - Park, Sung Sup

AU - Puschmann, Andreas

AU - Quattrone, Aldo

AU - Sharma, Manu

AU - Silburn, Peter A.

AU - Sohn, Young Ho

AU - Stefanis, Leonidas

AU - Tadic, Vera

AU - Theuns, Jessie

AU - Tomiyama, Hiroyuki

AU - Uitti, Ryan J.

AU - Valente, Enza Maria

AU - van de Loo, Simone

AU - Vassilatis, Demetrios K.

AU - Vilariño-Güell, Carles

AU - White, Linda R.

AU - Wirdefeldt, Karin

AU - Wszolek, Zbigniew K.

AU - Wu, Ruey Meei

AU - Farrer, Matthew J.

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Background: 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, 1·33-15·09; 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.

AB - Background: 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, 1·33-15·09; 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.

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U2 - 10.1016/S1474-4422(11)70175-2

DO - 10.1016/S1474-4422(11)70175-2

M3 - Journal articles

C2 - 21885347

AN - SCOPUS:80052967403

SN - 1474-4422

VL - 10

SP - 898

EP - 908

JO - The Lancet Neurology

JF - The Lancet Neurology

IS - 10

ER -

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

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