title: Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease.
abstract: 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.
authors.affiliation: Population Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Lisa
authors.initials: L
authors.lastname: Skipper
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.forename: Ratnagopal
authors.initials: R
authors.lastname: Pavanni
authors.forename: Yuen
authors.initials: Y
authors.lastname: Yih
authors.forename: Eva
authors.initials: E
authors.lastname: Chua
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Louis
authors.initials: L
authors.lastname: Tan
authors.forename: Meng-Cheong
authors.initials: MC
authors.lastname: Wong
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases