Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson’s disease

Abstract

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.

Age at Onset ofLRRK2p.Gly2019SerIs Related to Environmental and Lifestyle Factors

“…Because AAO genetic modifiers have been nominated for LRRK2 + /PD + , effect sizes have been small and ethnicity/populations seem to play a role 11,15–18 . This study establishes a connection between environmental and lifestyle factors that adds to the complexity in LRRK2 + /PD + .…”

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

“…Thirteen variants from seven genes passed our QC (rs4273468 from BST1; rs2421947 from DNM3; rs1564282 from GAK; rs1052553, rs242562, and rs2435207 from MAPT; rs823144 from PARK16; rs11931074, rs1372525, rs181489, rs2583988, and rs356219 from SNCA; rs11578699 from VAMP4). [19][20][21][22][23][24][25][26][27][28][29][30][31]33,34 Only four variants from three genes had P-values < 0.05: rs823144 from PARK16 in the penetrance model (P-value=0.01); rs1564282 from GAK in both the penetrance (P-value=0.03) and age-at-onset models (P-value=7.1E-03); rs2345207 (P-value=5.1E-04) and rs1052553 (P-value=0.02) from MAPT in the penetrance model. Unfortunately, since some individuals in our study may have also been included in the previous studies where these candidate genes were first reported, our findings do not represent independent replication.…”

“…33 This finding was not independently replicated, although it was still significant in a meta-analysis including the participants reported in the original finding. 24,34 Genome-wide association studies have successfully detected many disease genes/variants, including those associated with PD. However, to date, no GWAS for LRRK2 modifiers has been reported, probably due to limitations in sample size and corresponding statistical power.…”

Ten Years of the International Parkinson Disease Genomics Consortium: Progress and Next Steps

“…Another recent topic is penetrance or age of onset modifiers in carriers of LRRK2 and GBA damaging variants. Where for LRRK2 the GRS was shown to play a role in penetrance and age of onset [22,23] and for GBA besides the GRS affecting penetrance and age of onset variants in close proximity to CTSB and SNCA were affecting penetrance [24].…”