Abbreviations. PD = Parkinson's disease, LRRK2 = Leucine-rich repeat kinase 2, AAO = age at onset, DNM3 = Dynamin 3, KASP = 'Kompetitive' allele-specific polymerase chain reaction, MAF = minor allele frequency, GWAS = Genome-wide association study, SNP = single nucleotide polymorphism Abstract Objective: To assess the reported LRRK2 age-at-onset (AAO) modifier DNM3 rs2421947, and the proximate genome wide association signal VAMP4 rs11578699 on AAO of Parkinson's disease (PD), with rare (rs34637584; p.G2019S) or common risk factors (rs10878226) in the LRRK2 locus.
Methods:We assessed the extent of linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699, and between LRRK2 rs34637584 and LRRK2 rs10878226.We analysed DNM3 rs2421947 in 724 LRRK2 p.G2019S heterozygotes using the Cox proportional hazards model and linear regression of AAO. We then meta-analysed this with previously published data (n=754). We analysed the rs11578699 variant in the nearby VAMP4 gene in 786 LRRK2 p.G2019S heterozygotes. We evaluated the impact of VAMP4 variants using AAO regression in 4882 patients with PD carrying a common LRRK2 risk variant (rs10878226).
Results:There was no evidence for linkage disequilibrium between DNM3 rs2421947 and VAMP4 rs11578699, or between LRRK2 rs34637584 and LRRK2 rs10878226. Our survival analysis of 724 p.G2019S carriers showed no relationship between DNM3 rs2421947 and AAO (hazard ratio [HR] 1.09, 95% CI 0. 95-1.25, p=0.20) or PD affected status. However, meta-analysis with previously published LRRK2 p.G2019S data indicates an effect on AAO (HR 1.14, 95% CI 1.02-1.27, p=0.025), and furthermore reveals a significant relationship between DNM3 rs2421947 genotype and parkinsonism in people with LRRK2 p.G2019S (p=3.1x10 -5 ). The VAMP4 rs11578699 variant was not associated with AAO (HR 1.02, 95% CI 0.88-1.17, p=0.84) overall. However, VAMP4 rs11578699 was associated with AAO in patients dichotomized by LRRK2 rs10878226 genotype status (TT versus CC and TC (beta=1.68, se=0.81 p=0.037)).Interpretation: Our analysis suggests that DNM3 and VAMP4 play a modest and independent role in determining AAO in LRRK2 PD; there is some evidence for ethnicspecific effects, and for effects on case-control status in LRRK2 p.G2019S heterozygotes. Analysis of sporadic PD patients stratified by the LRRK2 PD risk allele rs10878226 indicates a potential interaction between LRRK2 and VAMP4.
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