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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalNeurobiology of Aging
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Microtubule-Associated Proteins
Leucine
Parkinson Disease
Phosphotransferases
Genotype
Haplotypes
Synucleins
Genes
Population

Keywords

  • Genetics
  • Interaction
  • LRRK2
  • MAPT
  • Parkinson's disease
  • SNCA

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., ... Ross, O. A. (2014). The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiology of Aging, 35(1). https://doi.org/10.1016/j.neurobiolaging.2013.07.013

The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. / Heckman, Michael G.; Elbaz, Alexis; Soto-Ortolaza, Alexandra I.; Serie, Daniel J.; Aasly, Jan O.; Annesi, Grazia; Auburger, Georg; Bacon, Justin A.; Boczarska-Jedynak, Magdalena; Bozi, Maria; Brighina, Laura; Chartier-Harlin, Marie Christine; Dardiotis, Efthimios; Destée, Alain; Ferrarese, Carlo; Ferraris, Alessandro; Fiske, Brian; Gispert, Suzana; Hadjigeorgiou, Georgios M.; Hattori, Nobutaka; Ioannidis, John P A; Jasinska-Myga, Barbara; Jeon, Beom S.; Kim, Yun Joong; Klein, Christine; Kruger, Rejko; Kyratzi, Elli; Lin, Chin Hsien; Lohmann, Katja; Loriot, Marie Anne; Lynch, Timothy; Mellick, George D.; Mutez, Eugénie; Opala, Grzegorz; Park, Sung Sup; Petrucci, Simona; Quattrone, Aldo; Sharma, Manu; Silburn, Peter A.; Sohn, Young Ho; Stefanis, Leonidas; Tadic, Vera; Tomiyama, Hiroyuki; Uitti, Ryan J.; Valente, Enza Maria; Vassilatis, Demetrios K.; Vilariño-Güell, Carles; White, Linda R.; Wirdefeldt, Karin; Wszolek, Zbigniew K.; Wu, Ruey Meei; Xiromerisiou, Georgia; Maraganore, Demetrius M.; Farrer, Matthew J.; Ross, Owen A.

In: Neurobiology of Aging, Vol. 35, No. 1, 01.2014.

Research output: Contribution to journalArticle

Heckman, MG, Elbaz, A, Soto-Ortolaza, AI, Serie, DJ, Aasly, JO, Annesi, G, Auburger, G, Bacon, JA, Boczarska-Jedynak, M, Bozi, M, Brighina, L, Chartier-Harlin, MC, Dardiotis, E, Destée, A, Ferrarese, C, Ferraris, A, Fiske, B, Gispert, S, Hadjigeorgiou, GM, Hattori, N, Ioannidis, JPA, Jasinska-Myga, B, Jeon, BS, Kim, YJ, Klein, C, Kruger, R, Kyratzi, E, Lin, CH, Lohmann, K, Loriot, MA, Lynch, T, Mellick, GD, Mutez, E, Opala, G, Park, SS, Petrucci, S, Quattrone, A, Sharma, M, Silburn, PA, Sohn, YH, Stefanis, L, Tadic, V, Tomiyama, H, Uitti, RJ, Valente, EM, Vassilatis, DK, Vilariño-Güell, C, White, LR, Wirdefeldt, K, Wszolek, ZK, Wu, RM, Xiromerisiou, G, Maraganore, DM, Farrer, MJ & Ross, OA 2014, 'The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants', Neurobiology of Aging, vol. 35, no. 1. https://doi.org/10.1016/j.neurobiolaging.2013.07.013
Heckman, Michael G. ; Elbaz, Alexis ; Soto-Ortolaza, Alexandra I. ; Serie, Daniel J. ; Aasly, Jan O. ; Annesi, Grazia ; Auburger, Georg ; Bacon, Justin A. ; Boczarska-Jedynak, Magdalena ; Bozi, Maria ; Brighina, Laura ; Chartier-Harlin, Marie Christine ; Dardiotis, Efthimios ; Destée, Alain ; Ferrarese, Carlo ; Ferraris, Alessandro ; Fiske, Brian ; Gispert, Suzana ; Hadjigeorgiou, Georgios M. ; Hattori, Nobutaka ; Ioannidis, John P A ; Jasinska-Myga, Barbara ; Jeon, Beom S. ; Kim, Yun Joong ; Klein, Christine ; Kruger, Rejko ; Kyratzi, Elli ; Lin, Chin Hsien ; Lohmann, Katja ; Loriot, Marie Anne ; Lynch, Timothy ; Mellick, George D. ; Mutez, Eugénie ; Opala, Grzegorz ; Park, Sung Sup ; Petrucci, Simona ; Quattrone, Aldo ; Sharma, Manu ; Silburn, Peter A. ; Sohn, Young Ho ; Stefanis, Leonidas ; Tadic, Vera ; Tomiyama, Hiroyuki ; Uitti, Ryan J. ; Valente, Enza Maria ; Vassilatis, Demetrios K. ; Vilariño-Güell, Carles ; White, Linda R. ; Wirdefeldt, Karin ; Wszolek, Zbigniew K. ; Wu, Ruey Meei ; Xiromerisiou, Georgia ; Maraganore, Demetrius M. ; Farrer, Matthew J. ; Ross, Owen A. / The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. In: Neurobiology of Aging. 2014 ; Vol. 35, No. 1.
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abstract = "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.",
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T1 - The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

AU - Heckman, Michael G.

AU - Elbaz, Alexis

AU - Soto-Ortolaza, Alexandra I.

AU - Serie, Daniel J.

AU - Aasly, Jan O.

AU - Annesi, Grazia

AU - Auburger, Georg

AU - Bacon, Justin A.

AU - Boczarska-Jedynak, Magdalena

AU - Bozi, Maria

AU - Brighina, Laura

AU - Chartier-Harlin, Marie Christine

AU - Dardiotis, Efthimios

AU - Destée, Alain

AU - Ferrarese, Carlo

AU - Ferraris, Alessandro

AU - Fiske, Brian

AU - Gispert, Suzana

AU - Hadjigeorgiou, Georgios M.

AU - Hattori, Nobutaka

AU - Ioannidis, John P A

AU - Jasinska-Myga, Barbara

AU - Jeon, Beom S.

AU - Kim, Yun Joong

AU - Klein, Christine

AU - Kruger, Rejko

AU - Kyratzi, Elli

AU - Lin, Chin Hsien

AU - Lohmann, Katja

AU - Loriot, Marie Anne

AU - Lynch, Timothy

AU - Mellick, George D.

AU - Mutez, Eugénie

AU - Opala, Grzegorz

AU - Park, Sung Sup

AU - Petrucci, Simona

AU - Quattrone, Aldo

AU - Sharma, Manu

AU - Silburn, Peter A.

AU - Sohn, Young Ho

AU - Stefanis, Leonidas

AU - Tadic, Vera

AU - Tomiyama, Hiroyuki

AU - Uitti, Ryan J.

AU - Valente, Enza Maria

AU - Vassilatis, Demetrios K.

AU - Vilariño-Güell, Carles

AU - White, Linda R.

AU - Wirdefeldt, Karin

AU - Wszolek, Zbigniew K.

AU - Wu, Ruey Meei

AU - Xiromerisiou, Georgia

AU - Maraganore, Demetrius M.

AU - Farrer, Matthew J.

AU - Ross, Owen A.

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

KW - Genetics

KW - Interaction

KW - LRRK2

KW - MAPT

KW - Parkinson's disease

KW - SNCA

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