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Human Molecular Genetics Advance Access published online on November 3, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi376
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 15, 2005
Revised September 30, 2005
Accepted September 30, 2005

Article

Comprehensive Evaluation of Common Genetic Variation within LRRK2 Reveals Evidence for Association with Sporadic Parkinson's Disease

Lisa Skipper 1, Yi Li 2, Carine Bonnard 1, Ratnagopal Pavanni 3, Yuan Yih 3, Eva Chua 4, Wing-Kin Sung 2, Louis Tan 5, Meng-Cheong Wong 5, Eng-King Tan 4, and Jianjun Liu 6*

1 Population Genetics; Genome Institute of Singapore Singapore 138672
2 Information and Mathematical Sciences; Genome Institute of Singapore Singapore 138672
3 Department of Neurology; Singapore General Hospital Singapore 169611
4 Department of Neurology; Singapore General Hospital Singapore 169611; Division of Research, SingHealth; Singapore General Hospital Singapore 169611
5 National Neuroscience Institute Singapore
6 Population Genetics; #02-01 Genome Genome Institute of Singapore 60, Biopolis Street Singapore 138672

* To whom correspondence should be addressed.
Jianjun Liu, E-mail: liuj3{at}gis.a-star.edu.sg


  Abstract

Parkinson's disease (PD) is a complex neurodegenerative disorder whose etiologies are largely unknown. To date, mutations in 6 genes have been found causal for some rare familial forms of the disease and common variation within at least 3 of these is associated with the more common sporadic forms of PD. LRRK2 is the most recently identified familial PD gene, although its role in sporadic disease is unknown. In this study, we have performed the first comprehensive evaluation of common genetic variation within LRRK2 and investigated its contribution to risk of sporadic PD. We firstly characterised the linkage disequilibrium within LRRK2 using a panel of densely spaced SNPs across the gene. We then identified a subset of tagging-SNPs that capture the majority of common variation within LRRK2. Both single tSNP and tSNP haplotype analyses, using a large epidemiologically-matched sporadic case-control series comprising 932 individuals, yielded significant evidence for disease association. We identified a haplotype that dramatically increases disease risk when present in two copies (OR = 5.5, 95%CI = 2.1-14.0, p = 0.0001). Thus we provide the first evidence that common genetic variation within LRRK2 contributes to risk of sporadic PD in the Chinese population.


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