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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 and Bozi, Maria, et al. (2014) In Neurobiology of Aging 35(1). p.5-266
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... (More)

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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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, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Parkinson Disease, Protein-Serine-Threonine Kinases, Risk, Young Adult, alpha-Synuclein, tau Proteins, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
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Neurobiology of Aging
volume
35
issue
1
pages
5 - 266
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Elsevier
external identifiers
  • scopus:84885187895
ISSN
1558-1497
DOI
10.1016/j.neurobiolaging.2013.07.013
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English
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438aa0d6-5feb-4733-96f7-91805bd24ddf
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2017-07-04 15:48:37
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2017-09-12 11:26:57
@article{438aa0d6-5feb-4733-96f7-91805bd24ddf,
  abstract     = {<p>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.</p>},
  author       = {Heckman, Michael G. and Elbaz, Alexis and Soto-Ortolaza, Alexandra I. and Serie, Daniel J and Aasly, Jan O. and Annesi, Grazia and Auburger, Georg and Bacon, Justin A. and Boczarska-Jedynak, Magdalena and Bozi, Maria and Brighina, Laura and Chartier-Harlin, Marie-Christine and Dardiotis, Efthimios and Destée, Alain and Ferrarese, Carlo and Ferraris, Alessandro and Fiske, Brian and Gispert, Suzana and Hadjigeorgiou, Georgios M. and Hattori, Nobutaka and Ioannidis, John P A and Jasinska-Myga, Barbara and Jeon, Beom S. and Kim, Yun Joong and Klein, Christine and Kruger, Rejko and Kyratzi, Elli and Lin, Chin-Hsien and Lohmann, Katja and Loriot, Marie-Anne and Lynch, Timothy and Mellick, George D. and Mutez, Eugénie and Opala, Grzegorz and Park, Sung-Sup and Petrucci, Simona and Quattrone, Aldo and Sharma, Manu and Silburn, Peter A. and Sohn, Young Ho and Stefanis, Leonidas and Tadic, Vera and Tomiyama, Hiroyuki and Uitti, Ryan J. and Valente, Enza Maria and Vassilatis, Demetrios K. and Vilariño-Güell, Carles and White, Linda R. and Wirdefeldt, Karin and Wszolek, Zbigniew K and Wu, Ruey-Meei and Xiromerisiou, Georgia and Maraganore, Demetrius M. and Farrer, Matthew J. and Ross, Owen A. and ,  and Puschmann, Andreas},
  issn         = {1558-1497},
  keyword      = {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,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2,Male,Middle Aged,Parkinson Disease,Protein-Serine-Threonine Kinases,Risk,Young Adult,alpha-Synuclein,tau Proteins,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {5--266},
  publisher    = {Elsevier},
  series       = {Neurobiology of Aging},
  title        = {Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants},
  url          = {http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.013},
  volume       = {35},
  year         = {2014},
}