The effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of theLRRK2gene. It yielded the lowest interactionp-value overall with SNP rs1007709 in the promoter region of theSYT10gene (interaction OR = 1.80, 95% CI: 1.65–1.95,p= 2.7 × 10−43). SNPs aroundSYT10were also associated with the age-at-onset of PD in an independent cohort of carriers ofLRRK2mutation p.G2019S. Moreover,SYT10gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving theLRRK2andSYT10gene regions, is biologically plausible owing to the known link between PD andLRRK2, its involvement in neural plasticity, and the contribution ofSYT10to the exocytosis of secretory vesicles in neurons.