Word count: 4391Abstract word count: 253 ABSTRACT BackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality. ObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson's disease (PD) in a large, unbiased manner, and to create a public resource for research. MethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest. ResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD.The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions. DiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.
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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