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Common variation in the LRRK2 gene is a risk factor for Parkinson's disease.

ABSTRACT: Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear.We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs (P < .05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the United States and Spain (tier 2). Logistic regression was used to model additive SNP genotype effects adjusted for age and sex among white individuals.Two regions showed independent association with PD in tier 1, and SNPs in both regions were successfully replicated in tier 2 (rs10878226, combined odds ratio [OR], 1.20; 95% confidence interval [CI], 1.08-1.33; P = 6.3 × 10(-4); rs11176013, OR, 0.89; CI, 0.83-0.95; P = 4.6 × 10(-4)).Our data suggest that common variation within LRRK2 conveys susceptibility for PD in individuals of European ancestry.

SUBMITTER: Mata IF

PROVIDER: S-EPMC3536918 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Common variation in the LRRK2 gene is a risk factor for Parkinson's disease.

Mata Ignacio F IF Checkoway Harvey H Hutter Carolyn M CM Samii Ali A Roberts John W JW Kim Hojoong M HM Agarwal Pinky P Alvarez Victoria V Ribacoba Renee R Pastor Pau P Lorenzo-Betancor Oswaldo O Infante Jon J Sierra María M Gómez-Garre Pilar P Mir Pablo P Ritz Beate B Rhodes Shannon L SL Colcher Amy A Van Deerlin Vivianna V Chung Kathryn A KA Quinn Joseph F JF Yearout Dora D Martinez Erica E Farin Federico M FM Wan Jia Y JY Edwards Karen L KL Zabetian Cyrus P CP

Movement disorders : official journal of the Movement Disorder Society 20121031 14

<h4>Background</h4>Common variants in the LRRK2 gene influence the risk of Parkinson's disease (PD) in Asians, but whether the same is true in European-derived populations is less clear.<h4>Methods</h4>We genotyped 66 LRRK2 tagging single-nucleotide polymorphisms (SNPs) in 575 PD patients and 689 controls from the northwestern United States (tier 1). PD-associated SNPs (P < .05) were then genotyped in an independent sample of 3617 cases and 2512 controls from the United States and Spain (tier 2) ...[more]

PMID: 23115130

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Project description:BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.ObjectivesThis study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants.MethodsWe performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D.ResultsLRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers.ConclusionsThese data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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Common variation in the LRRK2 gene is a risk factor for Parkinson's disease.

Publications

Common variation in the LRRK2 gene is a risk factor for Parkinson's disease.

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