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

Abstract The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson’s disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients who carry the LRRK2 p.G2019S mutation. We analysed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n = 724) and meta-analysed our data with previously published data (n=754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analysed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers, however the inter-study heterogeneity may indicate ethnic or population specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.