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

2007· article· en· 635 citations· W6921988819 sur OpenAlex· 10.1016/s1474

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Résumé

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.\n\nMETHODS: 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 0쨌5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.\n\nFINDINGS: 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 1쨌43, 95% CI 1쨌15-1쨌78; p=0쨌0012) and Asian individuals (A419V, 2쨌27, 1쨌35-3쨌83; p=0쨌0011). 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 0쨌82, 0쨌72-0쨌94; p=0쨌0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1쨌73, 1쨌20-2쨌49; p=0쨌0026), but no association was noted for R1628P (0쨌62, 0쨌36-1쨌07; p=0쨌087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4쨌48, 1쨌33-15쨌09; p=0쨌012).\n\nINTERPRETATION: 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.\n\nFUNDING: Michael J Fox Foundation and National Institutes of Health.

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La notice

Revue: YUHSpace (Yonsei University Medical Library)
Thématique: History of Computing Technologies
Domaine: Computer Science
Établissements canadiens: —
Organismes subventionnaires: Yonsei University College of MedicineMedical Research CouncilInstituut Born-BungeCentre hospitalier régional universitaire de LilleVlaamse regeringSkånes universitetssjukhusŚląski Uniwersytet Medyczny w KatowicachSvenska LäkaresällskapetUniversiteit AntwerpenBijzonder Onderzoeksfonds UGentAssociation France ParkinsonSvenska Sällskapet för Medicinsk ForskningVetenskapsrådetParkinsonfondenUniversitair Ziekenhuis AntwerpenMinistero della SaluteUniversità degli Studi di Milano-BicoccaKarolinska InstitutetUniwersytet Śląski w KatowicachYonsei UniversityUniversity of ThessalyInstitut National de la Santé et de la Recherche MédicaleAgence Nationale de la RechercheSouth African Medical Research CouncilEli Lilly and CompanyFonds Wetenschappelijk OnderzoekHermann und Lilly Schilling-Stiftung für Medizinische ForschungGenome British ColumbiaCentralsjukhuset KristianstadFondation de FranceBundesministerium für Bildung und ForschungGlaxoSmithKlineLunds UniversitetNational Institutes of HealthVolkswagen FoundationMichael J. Fox Foundation for Parkinson's Research
Mots-clés: LRRK2Odds ratioGenotypingMinor allele frequencyHaplotypeAlleleDiseaseGenetic associationGenotypeAllele frequency
Résumé présent dans OpenAlex: oui
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