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 Hattori; John 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

doi: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

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 journal › Article › peer-review

24 Scopus citations

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 language	English (US)
Pages (from-to)	266.e5-266.e14
Journal	Neurobiology of aging
Volume	35
Issue number	1
DOIs	https://doi.org/10.1016/j.neurobiolaging.2013.07.013
State	Published - Jan 2014

Keywords

Genetics
Interaction
LRRK2
MAPT
Parkinson's disease
SNCA

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
General Neuroscience
Developmental Biology

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10.1016/j.neurobiolaging.2013.07.013

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Heckman, M. G., Elbaz, A., Soto-Ortolaza, A. I., Serie, D. J., Aasly, J. O., Annesi, G., Auburger, G., Bacon, J. A., Boczarska-Jedynak, M., Bozi, M., Brighina, L., Chartier-Harlin, M. C., Dardiotis, E., Destée, A., Ferrarese, C., Ferraris, A., Fiske, B., Gispert, S., Hadjigeorgiou, G. M., ... 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), 266.e5-266.e14. https://doi.org/10.1016/j.neurobiolaging.2013.07.013

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, pp. 266.e5-266.e14. https://doi.org/10.1016/j.neurobiolaging.2013.07.013

@article{8cecf318936648d3af5e25ae9e86e403,

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

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.",

keywords = "Genetics, Interaction, LRRK2, MAPT, Parkinson's disease, SNCA",

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

note = "Funding Information: This work was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research (O.A.R., M.J.F.). Original funding for the GEO-PD was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research Edmond J. Safra Global Genetics Consortia program (D.M.M.). The Mayo Clinic Jacksonville is a Morris K. Udall Center of Excellence in Parkinson's Disease Research (grant no. P50 NS072187 ) and was supported by a the gift from the family of Carl Edward Bolch, Jr, and Susan Bass Bolch (R.J.U., Z.K.W., O.A.R.). O.A.R. acknowledges funding support from the National Institutes of Health (grant no. R01 NS078086 ). This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (M.J.F., C.V.G.). Leading Edge Endowment Funds, provided by the Province of British Columbia, LifeLabs, and Genome BC, support the Dr Donald Rix BC Leadership Chair (M.J.F.). D.M.M. acknowledges the National Institutes of Health for funding support (grant no. R01ES10751 ). Studies at individual sites were supported by a number of different funding agencies world-wide including; Italian Ministry of Health (Ricerca Corrente, Ricerca Finalizzata); the Swedish Parkinson Academy ; the Swedish Parkinson Foundation ; the Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134) (R.K.); the NGFNplus (Neuron-Parkinson-subproject 7) (S.G.); CHRU de Lille , University of Lille 2, INSERM; French Ministry PHRCs (1994/, 2002/1918, 2005/1914); Association France Parkinson (2005) ; Fondation de France 2004-013306 ; Fondation de la Recherche M{\'e}dicale (2006) ; PPF (synucl{\'e}oth{\`e}que 2005–2009); the 2 Centres de Ressources Biologiques (IPL-Lille, CHRU-Lille) and its scientific committee (A.D., M.C.C.H., Philippe Amouyel, Florence Pasquier, R{\'e}gis Bordet); funding from France-Parkinson Association and the program “Investissement d'avenir” ANR-10-IAIHU-06; the Swedish Research Council ; the Swedish Society for Medical Research ; the Swedish Society of Medicine ; funds from the Karolinska Institutet and the Parkinson Foundation in Sweden (K.W.); the National Institutes of Health and National Institute of Neurological Disorders and Stroke (grant nos. 1RC2NS070276 , NS057567 , and P50NS072187 ); Mayo Clinic Florida Research Committee CR programs (M.J.F., Z.K.W.); the Geriatric Medical Foundation of Queensland (G.D.M.); a career development award from the Volkswagen Foundation and from the Hermann and Lilly Schilling Foundation (C.K.); the Research Committee of University of Thessaly (code 2845); and Laboratory of Neurogenetics , Biomedicine Department, CERETETH, Larissa, Greece (code 01-04-207) (G.H., E.D.). ",

year = "2014",

month = jan,

doi = "10.1016/j.neurobiolaging.2013.07.013",

language = "English (US)",

volume = "35",

pages = "266.e5--266.e14",

journal = "Neurobiology of aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

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.

N1 - Funding Information: This work was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research (O.A.R., M.J.F.). Original funding for the GEO-PD was supported by a grant from The Michael J. Fox Foundation for Parkinson's Research Edmond J. Safra Global Genetics Consortia program (D.M.M.). The Mayo Clinic Jacksonville is a Morris K. Udall Center of Excellence in Parkinson's Disease Research (grant no. P50 NS072187 ) and was supported by a the gift from the family of Carl Edward Bolch, Jr, and Susan Bass Bolch (R.J.U., Z.K.W., O.A.R.). O.A.R. acknowledges funding support from the National Institutes of Health (grant no. R01 NS078086 ). This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (M.J.F., C.V.G.). Leading Edge Endowment Funds, provided by the Province of British Columbia, LifeLabs, and Genome BC, support the Dr Donald Rix BC Leadership Chair (M.J.F.). D.M.M. acknowledges the National Institutes of Health for funding support (grant no. R01ES10751 ). Studies at individual sites were supported by a number of different funding agencies world-wide including; Italian Ministry of Health (Ricerca Corrente, Ricerca Finalizzata); the Swedish Parkinson Academy ; the Swedish Parkinson Foundation ; the Federal Ministry for Education and Research (BMBF, NGFNplus; 01GS08134) (R.K.); the NGFNplus (Neuron-Parkinson-subproject 7) (S.G.); CHRU de Lille , University of Lille 2, INSERM; French Ministry PHRCs (1994/, 2002/1918, 2005/1914); Association France Parkinson (2005) ; Fondation de France 2004-013306 ; Fondation de la Recherche Médicale (2006) ; PPF (synucléothèque 2005–2009); the 2 Centres de Ressources Biologiques (IPL-Lille, CHRU-Lille) and its scientific committee (A.D., M.C.C.H., Philippe Amouyel, Florence Pasquier, Régis Bordet); funding from France-Parkinson Association and the program “Investissement d'avenir” ANR-10-IAIHU-06; the Swedish Research Council ; the Swedish Society for Medical Research ; the Swedish Society of Medicine ; funds from the Karolinska Institutet and the Parkinson Foundation in Sweden (K.W.); the National Institutes of Health and National Institute of Neurological Disorders and Stroke (grant nos. 1RC2NS070276 , NS057567 , and P50NS072187 ); Mayo Clinic Florida Research Committee CR programs (M.J.F., Z.K.W.); the Geriatric Medical Foundation of Queensland (G.D.M.); a career development award from the Volkswagen Foundation and from the Hermann and Lilly Schilling Foundation (C.K.); the Research Committee of University of Thessaly (code 2845); and Laboratory of Neurogenetics , Biomedicine Department, CERETETH, Larissa, Greece (code 01-04-207) (G.H., E.D.).

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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U2 - 10.1016/j.neurobiolaging.2013.07.013

DO - 10.1016/j.neurobiolaging.2013.07.013

M3 - Article

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AN - SCOPUS:84885187895

SN - 0197-4580

VL - 35

SP - 266.e5-266.e14

JO - Neurobiology of aging

JF - Neurobiology of aging

IS - 1

ER -

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

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