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Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

ABSTRACT: Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries.Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies.

SUBMITTER: Heckman MG

PROVIDER: S-EPMC4108155 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Heckman Michael G MG Soto-Ortolaza Alexandra I AI Aasly Jan O JO Abahuni Nadine N Annesi Grazia G Bacon Justin A JA Bardien Soraya S Bozi Maria M Brice Alexis A Brighina Laura L Carr Jonathan J Chartier-Harlin Marie-Christine MC Dardiotis Efthimios E Dickson Dennis W DW Diehl Nancy N NN Elbaz Alexis A Ferrarese Carlo C Fiske Brian B Gibson J Mark JM Gibson Rachel R Hadjigeorgiou Georgios M GM Hattori Nobutaka N Ioannidis John P A JP Boczarska-Jedynak Magdalena M Jasinska-Myga Barbara B Jeon Beom S BS Kim Yun Joong YJ Klein Christine C Kruger Rejko R Kyratzi Elli E Lesage Suzanne S Lin Chin-Hsien CH Lynch Timothy T Maraganore Demetrius M DM Mellick George D GD Mutez Eugénie E Nilsson Christer C Opala Grzegorz G Park Sung Sup SS Petrucci Simona S Puschmann Andreas A Quattrone Aldo A Sharma Manu M Silburn Peter A PA Sohn Young Ho YH Stefanis Leonidas L Tadic Vera V Theuns Jessie J Tomiyama Hiroyuki H Uitti Ryan J RJ Valente Enza Maria EM Van Broeckhoven Christine C van de Loo Simone S Vassilatis Demetrios K DK Vilariño-Güell Carles C White Linda R LR Wirdefeldt Karin K Wszolek Zbigniew K ZK Wu Ruey-Meei RM Hentati Faycal F Farrer Matthew J MJ Ross Owen A OA

Movement disorders : official journal of the Movement Disorder Society 20130802 12

<h4>Background</h4>Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease.<h4>Methods</h4>The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich r ...[more]

PMID: 23913756

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Project description: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.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.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).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.Michael J Fox Foundation and National Institutes of Health.

Dataset Information

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Publications

Population-specific frequencies for LRRK2 susceptibility variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium.

Similar Datasets

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