TY - JOUR
T1 - Association of LRRK2 exonic variants with susceptibility to Parkinson's disease
T2 - 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.
N1 - Funding Information:
This report is dedicated to the memory of J Mark Gibson (1953–2010). The work in this study was supported by a grant from the Michael J Fox Foundation for Parkinson's Research (OAR and MJF). Original funding for GEO-PD was supported by a grant from the Michael J Fox Foundation for Parkinson's Research Edmond J Safra Global Genetics Consortia programme. The Mayo Clinic is a Morris K Udall Center of Excellence in Parkinson's Disease Research (P50 NS072187) and was supported by a gift from the family of Carl Edward Bolch Jr and Susan Bass Bolch (DWD, RJU, ZKW, and OAR). This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs programme (MJF and CV-G). Leading Edge Endowment Funds, provided by the Province of British Columbia, LifeLabs, and Genome BC, support the Dr Donald Rix BC Leadership Chair (MJF). Studies at individual sites were supported by different funding agencies worldwide—the Italian Ministry of Health (Ricerca Corrente 2010, Ricerca Finalizzata 2006); Fondazione Livio Patrizi; Swedish Parkinson Academy; the Swedish Parkinson Foundation; Lund University Research Fund, American Fidelity Assurance Insurance and the Royal Physiographic Society, Lund (AP and CN); Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134; RK); NGFNplus (Neuron-Parkinson-subproject 7; SG); South African Medical Research Council and the University of Stellenbosch (SB, JC); Centre Hospitalier Régional Universitaire (CHRU) de Lille, University Lille 2 INSERM; French Ministry Programme Hospitalier de Recherche Clinique (1994/2002/1918, 2005/1914); Association France Parkinson (2005); Fondation de France 2004-013306; Fondation de la Recherche Médicale (2006); Le Programme Pluri-Formations (synucléothèque 2005–2009); Centres de Ressources Biologiques (L'Institut Pasteur de Lille, CHRU-Lille) and their scientific committee; the Agence Nationale de la Recherche (ANR-05-NEUR-019 and ANR-08-MNP-012; AB, SL); grant ES10758 from the National Institutes of Health; Swedish Research Council; Swedish Society for Medical Research; Swedish Society of Medicine; funds from the Karolinska Institutet and the Parkinson Foundation in Sweden (KW); Special Research Fund of the University of Antwerp; Research Foundation Flanders (Fonds Wetenschappelijk Onderzoek–Vlaanderen [FWO]); the Agency for Innovation by Science and Technology in Flanders (IWT); Interuniversity Attraction Poles Program P6/43 of the Belgian Federal Science Policy Office; Methusalem Excellence Grant of the Flanders Government and the Medical Research Foundation Antwerp and Neurosearch, Belgium; National Institutes of Health and National Institute of Neurological Disorders and Stroke 1RC2NS070276, NS057567, P50NS072187; Mayo Clinic Research Committee Clinical Research programmes (MCF and ZKW); Geriatric Medical Foundation of Queensland (GDM); a career development award from the Volkswagen Foundation and from the Hermann and Lilly Schilling Foundation (CK); Research Committee of University of Thessaly (code 2845); and Institute of Biomedical Research and Technology, CERETETH (code 01-04-207; GH and ED); and GlaxoSmithKline for past sponsorship of research into familial parkinsonism in Tunisia (RG and FH). DC is a holder of an FWO PhD fellowship and JT receives an FWO postdoctoral fellowship. For their contributions to make this work possible, we acknowledge Ferdinanda Annesi, Patrizia Tarantino (Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy); Chiara Riva (Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, Monza, Italy); Roberto Piolti (Department of Neurology, Ospedale San Gerardo, Monza, Italy); Magdalena Boczarska-Jedynak (Department of Neurology, Medical University of Silesia, Katowice, Poland); Aurélie Duflot, (UMR837 INSERM-University Lille 2, CHRU de Lille); Jean-Philippe Legendre, Nawal Waucquier (Neurologie et Pathologie du Mouvement, Clinique de Neurologie du CHU de Lille); Anna Rita Bentivoglio, Tamara Ialongo, Arianna Guidubaldi, Carla Piano (Institute of Neurology, Catholic University, Rome, Italy); Karen Nuytemans (Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Vlaams Instituut voor Biotechnologie; Laboratory of Neurogenetics, Institute Born-Bunge and University of Antwerp, Belgium); Sebastiaan Engelborghs; Peter De Deyn (Department of Neurology, ZiekenhuisNetwerk Antwerpen Middelheim and Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge and University of Antwerp); David Crosiers, Patrick Cras (Department of Neurology, University Hospital Antwerp and Laboratory of Neurobiology, Institute Born-Bunge and University of Antwerp, Belgium); Phil Hyu Lee (Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea); Susanne Lindskov (Department of Geriatrics and Neurology, Central Hospital Kristianstad, Northeast Skåne Health Care District, Kristianstad, Sweden); Karin Nilsson (Department of Clinical Science, Section of Geriatric Psychiatry, Lund University, Sweden); Jan Reimer (Department of Neurology, Skåne University Hospital, Sweden); Manabu Funayama, Yuanzhe Li, Hiroyo Yoshino (Juntendo University School of Medicine, Tokyo, Japan); and we acknowledge all the patients and controls who kindly donated DNA to make collaborative studies like these possible. A full list of GEO-PD consortia is provided in webappendix pp 27–30 .
PY - 2011/10
Y1 - 2011/10
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.
UR - http://www.scopus.com/inward/record.url?scp=80052967403&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(11)70175-2
DO - 10.1016/S1474-4422(11)70175-2
M3 - Article
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 -