Human Molecular Genetics Advance Access originally published online on November 3, 2005
Human Molecular Genetics 2005 14(23):3549-3556; doi:10.1093/hmg/ddi376
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Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease
1Population Genetics and 2Information and Mathematical Sciences, Genome Institute of Singapore, Singapore 138672, 3Department of Neurology and 4Division of Research, SingHealth, Singapore General Hospital, Singapore 169611 and 5National Neuroscience Institute, Singapore, 308433
* To whom correspondence should be addressed at: Population Genetics, Genome, Genome Institute of Singapore, #02-01 60 Biopolis Street, Singapore 138672, Singapore. Tel: +65 64788088; Fax: +65 64789059; Email: liuj3{at}gis.a-star.edu.sg
Received August 15, 2005; Accepted September 30, 2005
Parkinson's disease (PD) is a complex neurodegenerative disorder whose aetiologies are largely unknown. To date, mutations in six genes have been found causal for some rare familial forms of the disease and common variation within at least three 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 first characterized the linkage disequilibrium within LRRK2 using a panel of densely spaced SNPs across the gene. We then identified a subset of tagging-SNPs (tSNP) 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 the risk of sporadic PD in the Chinese population.
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