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Fox Foundation for Parkinson\u2019s Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Michael J. Fox Foundation for Parkinson\u2019s Research"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"},{"name":"U.S. Department of Health & Human Services | National Institutes of Health"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The effects of one genetic factor upon Parkinson\u2019s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G\u00d7G) could explain some of the \u2018missing heritability\u2019 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\u2019s Disease Genomics Consortium, we studied G\u00d7G 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\u00d7G 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\u00d7G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the <jats:italic>LRRK2<\/jats:italic> gene. It yielded the lowest interaction <jats:italic>p<\/jats:italic>-value overall with SNP rs1007709 in the promoter region of the <jats:italic>SYT10<\/jats:italic> gene (interaction OR\u2009=\u20091.80, 95% CI: 1.65\u20131.95, <jats:italic>p<\/jats:italic>\u2009=\u20092.7\u2009\u00d7\u200910<jats:sup>\u221243<\/jats:sup>). SNPs around <jats:italic>SYT10<\/jats:italic> were also associated with the age-at-onset of PD in an independent cohort of carriers of <jats:italic>LRRK2<\/jats:italic> mutation p.G2019S. Moreover, <jats:italic>SYT10<\/jats:italic> gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G\u00d7G interaction on PD risk, involving the <jats:italic>LRRK2<\/jats:italic> and <jats:italic>SYT10<\/jats:italic> gene regions, is biologically plausible owing to the known link between PD and <jats:italic>LRRK2<\/jats:italic>, its involvement in neural plasticity, and the contribution of <jats:italic>SYT10<\/jats:italic> to the exocytosis of secretory vesicles in neurons.<\/jats:p>","DOI":"10.1038\/s41531-023-00550-9","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T08:02:55Z","timestamp":1688025775000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genome-wide case-only analysis of gene-gene interactions with known Parkinson\u2019s disease risk variants reveals link between LRRK2 and 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