Publication
Title
Association of **LRRK2** exonic variants with susceptibility to Parkinson's disease : a casecontrol study
Author
Institution/Organisation
Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium
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 ArabBerber) 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 ArabBerber 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 1·151·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·353·83; 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 ArabBerber series (combined odds ratio 0·82, 0·720·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·202·49; p=0·0026), but no association was noted for R1628P (0·62, 0·361·07; p=0·087). In the ArabBerber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·3315·09; 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.
Language
English
Source (journal)
The lancet neurology. - London
Publication
London : 2011
ISSN
1474-4422
Volume/pages
10:10(2011), p. 898-908
ISI
000295814600011
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 17.01.2012
Last edited 04.10.2017
To cite this reference