Testing association between LRRK2 and Parkinson's disease and investigating linkage disequilibrium

Abstract

Background: We and others recently identified the gene underlying PARK8 linked Parkinson's disease (PD). This gene, LRRK2, contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease. Methods: We undertook a case-control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel. Results: We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter-population variability in the strength of LD across this locus. Conclusions: To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD.

Genetics of Parkinson's disease and parkinsonism

“…The frequency of these mutations, especially G2019S, is such that it may be worth clinical screening for the mutations, although the incomplete penetrance does raise some complications (see later for a discussion of this point). Variation at the LRRK2 locus does not contribute to the risk for sporadic PD, 41 which is in contrast with the previously discussed results for synuclein.…”

The LRRK2 Arg1628Pro variant is a risk factor for Parkinson’s disease in the Chinese population

“…1a). However, all these variants display much higher allele frequencies than Arg1628Pro (our data not shown), and, more importantly, these variants are also present in Caucasian populations, where association with PD was not detected in previous studies examining common LRRK2 variants using haplotype-tagging SNPs [18,19]. We also explored the frequency of three variants located in exon 34: Gly1624Gly (rs1427263), Lys1637Lys (rs11176013), and Ser1647Thr (rs11564148) in 176 cases and 181 controls from this study (more than 700 chromosomes), but we detected no association with PD (Gly1624Gly minor allele frequency [MAF] 0.45 in cases and 0.53 in controls; Lys1637Lys MAF 0.44 in cases and 0.49 in controls; Ser1647Thr MAF 0.33 in cases and 0.32 in controls).…”

Comprehensive analysis ofLRRK2in publicly available Parkinson's disease cases and neurologically normal controls

“…Previously, we and others have reported that variation at the LRRK2 locus does not contribute to the risk for sporadic PD in three independent European cohorts [Biskup et al, 2005;Paisán-Ruíz et al, 2006] and in a Canadian cohort . However, an association between sporadic PD and SNP haplotypes across LRRK2 has been reported by Skipper et al [2006].…”