The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Michael G. Heckman, Alexis Elbaz, Alexandra I. Soto-Ortolaza, Daniel J. Serie, Jan O. Aasly, Grazia Annesi, Georg Auburger, Justin A. Bacon, Magdalena Boczarska-Jedynak, Maria Bozi, Laura Brighina, Marie Christine Chartier-Harlin, Efthimios Dardiotis, Alain Destée, Carlo Ferrarese, Alessandro Ferraris, Brian Fiske, Suzana Gispert, Georgios M. Hadjigeorgiou, Nobutaka HattoriJohn P.A. Ioannidis, Barbara Jasinska-Myga, Beom S. Jeon, Yun Joong Kim, Christine Klein, Rejko Kruger, Elli Kyratzi, Chin Hsien Lin, Katja Lohmann, Marie Anne Loriot, Timothy Lynch, George D. Mellick, Eugénie Mutez, Grzegorz Opala, Sung Sup Park, Simona Petrucci, Aldo Quattrone, Manu Sharma, Peter A. Silburn, Young Ho Sohn, Leonidas Stefanis, Vera Tadic, Hiroyuki Tomiyama, Ryan J. Uitti, Enza Maria Valente, Demetrios K. Vassilatis, Carles Vilariño-Güell, Linda R. White, Karin Wirdefeldt, Zbigniew K. Wszolek, Ruey Meei Wu, Georgia Xiromerisiou, Demetrius M. Maraganore, Matthew J. Farrer, Owen A. Ross


The best validated susceptibility variants for Parkinson's disease are located in the α-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined 4 SNCA variants (rs181489, rs356219, rs11931074, and rs2583988), the MAPT H1-haplotype-defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (n= 10,322) and Asian (n= 2289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all p ≥ 0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations. © 2014 Elsevier Inc.
Original languageEnglish
Title of host publicationNeurobiology of Aging
Publication date01.01.2014
Pages5 - 266
Article number35
ISBN (Print)5106432685
Publication statusPublished - 01.01.2014


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