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

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Abstract

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, 133-15.09; 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.

Details

Authors
  • Owen A. Ross
  • Alexandra I. Soto-Ortolaza
  • Michael G. Heckman
  • Jan O. Aasly
  • Nadine Abahuni
  • Grazia Annesi
  • Justin A. Bacon
  • Soraya Bardien
  • Maria Bozi
  • Alexis Brice
  • Laura Brighina
  • Christine Van Broeckhoven
  • Jonathan Carr
  • Marie-Christine Chartier-Harlin
  • Efthimios Dardiotis
  • Dennis W. Dickson
  • Nancy N. Diehl
  • Alexis Elbaz
  • Carlo Ferrarese
  • Alessandro Ferraris
  • Brian Fiske
  • J. Mark Gibson
  • Rachel Gibson
  • Georgios M. Hadjigeorgiou
  • Nobutaka Hattori
  • John P. A. Ioannidis
  • Barbara Jasinska-Myga
  • Beom S. Jeon
  • Yun Joong Kim
  • Christine Klein
  • Rejko Kruger
  • Elli Kyratzi
  • Suzanne Lesage
  • Chin-Hsien Lin
  • Timothy Lynch
  • Demetrius M. Maraganore
  • George D. Mellick
  • Eugenie Mutez
  • Christer Nilsson
  • Grzegorz Opala
  • Sung Sup Park
  • Aldo Quattrone
  • Manu Sharma
  • Peter A. Silburn
  • Young Ho Sohn
  • Leonidas Stefanis
  • Vera Tadic
  • Jessie Theuns
  • Hiroyuki Tomiyama
  • Ryan J. Uitti
  • Enza Maria Valente
  • Simone van de Loo
  • Demetrios K. Vassilatis
  • Cartes Vilarino-Gueell
  • Linda R. White
  • Karin Wirdefeldt
  • Zbigniew K. Wszolek
  • Ruey-Meei Wu
  • Matthew J. Farrer
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
Original languageEnglish
Pages (from-to)898-908
JournalLancet Neurology
Volume10
Issue number10
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Psychogeriatrics (013304000), Division IV (013230800)