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BMC Neurology

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Open Access 01-12-2018 | Research article

Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson’s disease: a genetic association study

Authors: Kari Anne Bjørnarå, Lasse Pihlstrøm, Espen Dietrichs, Mathias Toft

Published in: BMC Neurology | Issue 1/2018

Abstract

Background

Parkinson’s disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, including Parkinson’s disease. We hypothesized that SNCA variants conferring risk of Parkinson’s disease would also predispose to an RBD phenotype.

Methods

We assessed possible RBD (pRBD) status using the RBD screening questionnaire and investigated known susceptibility variants for Parkinson’s disease located in the α-synuclein (SNCA) and tau (MAPT) gene loci in 325 Parkinson’s disease patients. Associations between genetic risk variants and RBD were investigated by logistic regression, and an independent dataset of 382 patients from the Parkinson’s Progression Marker Initiative (PPMI) study was used for replication.

Results

pRBD was associated with rs3756063 located in the 5’ region of SNCA (two-sided p = 0.018, odds ratio 1.44). We replicated this finding in the PPMI dataset (one-sided p = 0.036, odds ratio 1.35) and meta-analyzed the results (two-sided p = 0.0032, odds ratio 1.40). The Parkinson’s disease risk variant in the 3′ region of SNCA and the MAPT variant showed no association with pRBD.

Conclusions

Our findings provide proof of principle that a largely stable, dichotomous clinical feature of Parkinson’s disease can be linked to a specific genetic susceptibility profile. Indirectly, it also supports the hypothesis of RBD as relevant marker for a distinct subtype of the disorder.

Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med. 2013;14(8):744–8.CrossRefPubMed

Postuma RB, Bertrand JA, Montplaisir J, Desjardins C, Vendette M, Rios Romenets S, Panisset M, Gagnon JF. Rapid eye movement sleep behavior disorder and risk of dementia in Parkinson's disease: a prospective study. Mov Disord. 2012;27(6):720–6.CrossRefPubMed

Romenets SR, Gagnon JF, Latreille V, Panniset M, Chouinard S, Montplaisir J, Postuma RB. Rapid eye movement sleep behavior disorder and subtypes of Parkinson's disease. Mov Disord. 2012;27(8):996–1003.CrossRefPubMed

Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 2006;5(5):424–32.CrossRefPubMed

Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, Saad M, DeStefano AL, Kara E, Bras J, Sharma M, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46(9):989–93.CrossRefPubMedPubMedCentral

Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry. 1988;51(6):745–52.CrossRefPubMedPubMedCentral

Nomura T, Inoue Y, Kagimura T, Uemura Y, Nakashima K. Utility of the REM sleep behavior disorder screening questionnaire (RBDSQ) in Parkinson's disease patients. Sleep Med. 2011;12(7):711–3.CrossRefPubMed

International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium. A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet. 2011;7(6):e1002142.CrossRef

Lill CM, Roehr JT, McQueen MB, Kavvoura FK, Bagade S, Schjeide BM, Schjeide LM, Meissner E, Zauft U, Allen NC, et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: the PDGene database. PLoS Genet. 2012;8(3):e1002548.CrossRefPubMedPubMedCentral

10.

Spencer CC, Plagnol V, Strange A, Gardner M, Paisan-Ruiz C, Band G, Barker RA, Bellenguez C, Bhatia K, Blackburn H, et al. Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Hum Mol Genet. 2011;20(2):345–53.CrossRefPubMed

11.

Loh PR, Danecek P, Palamara PF, Fuchsberger C, A Reshef Y, K Finucane H, Schoenherr S, Forer L, McCarthy S, Abecasis GR, et al. Reference-based phasing using the haplotype reference consortium panel. Nat Genet. 2016;48(11):1443–8.CrossRefPubMedPubMedCentral

12.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.CrossRefPubMedPubMedCentral

13.

Gan-Or Z, Girard SL, Noreau A, Leblond CS, Gagnon JF, Arnulf I, Mirarchi C, Dauvilliers Y, Desautels A, Mitterling T, et al. Parkinson's disease genetic loci in rapid eye movement sleep behavior disorder. J Mol Neurosci. 2015;56(3):617–22.CrossRefPubMed

14.

Ritz B, Rhodes SL, Bordelon Y, Bronstein J. Alpha-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease. PLoS One. 2012;7(5):e36199.CrossRefPubMedPubMedCentral

15.

Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM, Ritz B, Rausch R, Rhodes SL, Factor SA, et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 2014;71(11):1405–12.CrossRefPubMedPubMedCentral

16.

Cooper CA, Jain N, Gallagher MD, Weintraub D, Xie SX, Berlyand Y, Espay AJ, Quinn J, Edwards KL, Montine T, et al. Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. Ann Clin Transl Neurol. 2017;4(1):15–25.CrossRefPubMed

17.

Nombela C, Rowe JB, Winder-Rhodes SE, Hampshire A, Owen AM, Breen DP, Duncan GW, Khoo TK, Yarnall AJ, Firbank MJ, et al. Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain. 2014;137(Pt 10):2743–58.CrossRefPubMedPubMedCentral

18.

Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiol Aging. 2016;37:209. e201-207CrossRefPubMed

19.

Pihlstrom L, Morset KR, Grimstad E, Vitelli V, Toft M. A cumulative genetic risk score predicts progression in Parkinson's disease. Mov Disord. 2016;31(4):487–90.CrossRefPubMed

20.

Ko Y, Ament SA, Eddy JA, Caballero J, Earls JC, Hood L, Price ND. Cell type-specific genes show striking and distinct patterns of spatial expression in the mouse brain. Proc Natl Acad Sci U S A. 2013;110(8):3095–100.CrossRefPubMedPubMedCentral

21.

Ramasamy A, Trabzuni D, Guelfi S, Varghese V, Smith C, Walker R, De T, Coin L, de Silva R, Cookson MR, et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci. 2014;17(10):1418–28.CrossRefPubMedPubMedCentral

22.

Bjornara KA, Dietrichs E, Toft M. Longitudinal assessment of probable rapid eye movement sleep behaviour disorder in Parkinson's disease. Eur J Neurol. 2015;22(8):1242–4.CrossRefPubMed

23.

Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology. 2011;77(11):1048–54.CrossRefPubMed

24.

Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, Parisi JE, Benarroch EE, Ahlskog JE, Smith GE, Caselli RC, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain. 2007;130(Pt 11):2770–88.CrossRefPubMed

Title: Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson’s disease: a genetic association study
Authors: Kari Anne Bjørnarå
Lasse Pihlstrøm
Espen Dietrichs
Mathias Toft
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2018
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-018-1023-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson’s disease: a genetic association study

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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