Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants.

in Neurobiology of Aging (2014), 35(1), 2665-14

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H ... [more ▼]

The best validated susceptibility variants for Parkinson's disease are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n = 10,322) and Asian (n = 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p >/= 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. [less ▲]

A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants.

in Journal of medical genetics (2012), 49(11), 721-6

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense ... [more ▼]

BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide. [less ▲]

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

in Lancet Neurology (2011), 10(10), 898-908

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 ... [more ▼]

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. [less ▲]