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; Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium; Karen Morrison

doi:10.1016/j.neurobiolaging.2013.07.013

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, Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium, Karen Morrison

Clinical Sciences

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24 Citations (Scopus)

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
Pages (from-to)	266.e5-14
Journal	Neurobiology of Aging
Volume	35
Issue number	1
DOIs	https://doi.org/10.1016/j.neurobiolaging.2013.07.013
Publication status	Published - Jan 2014

Bibliographical note

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Asian Continental Ancestry Group
European Continental Ancestry Group
Female
Genetic Predisposition to Disease
Genetic Variation
Genotype
Haplotypes
Humans
Male
Middle Aged
Parkinson Disease
Protein-Serine-Threonine Kinases
Risk
Young Adult
alpha-Synuclein
tau Proteins

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10.1016/j.neurobiolaging.2013.07.013

Cite this

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., ... Morrison, K. (2014). 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.e5-14. https://doi.org/10.1016/j.neurobiolaging.2013.07.013

@article{745f46872aae45959968b2a1478a0ede,

title = "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 = "Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Haplotypes, Humans, Male, Middle Aged, Parkinson Disease, Protein-Serine-Threonine Kinases, Risk, Young Adult, alpha-Synuclein, tau Proteins",

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 Marie-Christine Chartier-Harlin 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 Chin-Hsien Lin and Katja Lohmann and Marie-Anne Loriot 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 {Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium} and Karen Morrison",

year = "2014",

month = jan,

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

language = "English",

volume = "35",

pages = "266.e5--14",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier",

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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, M-C, 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, C-H, Lohmann, K, Loriot, M-A, 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, Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium & Morrison, K 2014, '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.e5-14. https://doi.org/10.1016/j.neurobiolaging.2013.07.013

TY - JOUR

T1 - 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 - Genetic Epidemiology Of Parkinson's Disease (GEO-PD) Consortium

AU - Morrison, Karen

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 - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Asian Continental Ancestry Group

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genotype

KW - Haplotypes

KW - Humans

KW - Male

KW - Middle Aged

KW - Parkinson Disease

KW - Protein-Serine-Threonine Kinases

KW - Risk

KW - Young Adult

KW - alpha-Synuclein

KW - tau Proteins

U2 - 10.1016/j.neurobiolaging.2013.07.013

DO - 10.1016/j.neurobiolaging.2013.07.013

M3 - Article

C2 - 23962496

SN - 0197-4580

VL - 35

SP - 266.e5-14

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

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