TY - JOUR
T1 - LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder
AU - Ouled Amar Bencheikh, Bouchra
AU - Ruskey, Jennifer A.
AU - Arnulf, Isabelle
AU - Dauvilliers, Yves
AU - Monaca, Christelle Charley
AU - De Cock, Valérie Cochen
AU - Gagnon, Jean François
AU - Spiegelman, Dan
AU - Hu, Michele T.M.
AU - Högl, Birgit
AU - Stefani, Ambra
AU - Ferini-Strambi, Luigi
AU - Plazzi, Giuseppe
AU - Antelmi, Elena
AU - Young, Peter
AU - Heidbreder, Anna
AU - Mollenhauer, Brit
AU - Sixel-Döring, Friederike
AU - Trenkwalder, Claudia
AU - Oertel, Wolfgang
AU - Montplaisir, Jacques Y.
AU - Postuma, Ronald B.
AU - Rouleau, Guy A.
AU - Gan-Or, Ziv
N1 - Ricercatori distaccati presso IRCCS a seguito Convenzione esclusiva con Università di Bologna (Plazzi Giuseppe, Antelmi Elena).
La Dr.ssa E. Antelmi ha pubblicato anche lavori con affiliazione straniera che descrivono i risultati del progetto di ricerca svolto al “Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London” nel corso dei 3 anni della sua permanenza precedente presso l’Istituto (2014-2016).
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.
AB - Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.
KW - Genetics
KW - LRRK2
KW - Parkinson disease
KW - REM sleep behavior disorder
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U2 - 10.1016/j.parkreldis.2018.03.019
DO - 10.1016/j.parkreldis.2018.03.019
M3 - Article
C2 - 29576439
AN - SCOPUS:85044258033
VL - 52
SP - 98
EP - 101
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
SN - 1353-8020
ER -