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Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study
- Source :
- The lancet neurology, The lancet
/ Neurology 10(10), 898-908 (2011). doi:10.1016/S1474-4422(11)70175-2, The Lancet Neurology, Vol. 10, No 10 (2011) pp. 898-908 - Publication Year :
- 2011
- Publisher :
- Elsevier, 2011.
-
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. Lancet Neurol
- Subjects :
- Male
Polymorphism, Single Nucleotide/*genetics
International Cooperation
Ethnic Groups/genetics
Ethnic Group
Genome-wide association study
Protein-Serine-Threonine Kinase
methods [Genome-Wide Association Study]
genetics [Ethnic Groups]
0302 clinical medicine
Gene Frequency
genetics [Parkinson Disease]
Risk Factors
Exons/genetics
Ethnicity
Parkinson Disease/genetics
Medicine(all)
Genetics
Aged, 80 and over
0303 health sciences
Parkinson Disease
Exons
genetics [Exons]
Middle Aged
Polymorphism, Single Nucleotide/genetics
Protein-Serine-Threonine Kinases
LRRK2
3. Good health
genetics [Polymorphism, Single Nucleotide]
Genome-Wide Association Study/methods
Female
Case-Control Studie
Human
Adult
Parkinson Disease/*genetics
Genotype
Adolescent
Protein-Serine-Threonine Kinases/*genetics
Protein-Serine-Threonine Kinases/genetics
Exon
Protein Serine-Threonine Kinases
Biology
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
genetics [Protein-Serine-Threonine Kinases]
Polymorphism, Single Nucleotide
03 medical and health sciences
Young Adult
Humans
Genetic Predisposition to Disease
ddc:610
LRRK2 protein, human
Risk factor
Allele frequency
030304 developmental biology
Aged
Risk Factor
Case-control study
Exons/*genetics
Odds ratio
nervous system diseases
ddc:616.8
Minor allele frequency
Genetic epidemiology
Case-Control Studies
Neurology (clinical)
Human medicine
030217 neurology & neurosurgery
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 14744422
- Database :
- OpenAIRE
- Journal :
- The lancet neurology, The lancet <London> / Neurology 10(10), 898-908 (2011). doi:10.1016/S1474-4422(11)70175-2, The Lancet Neurology, Vol. 10, No 10 (2011) pp. 898-908
- Accession number :
- edsair.doi.dedup.....6c760baf6e72eae84c3dd69f2ee368f5