7 research outputs found
GBA variants in REM sleep behavior disorder: A multicenter study
Objective:
To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.
Methods:
A total of 4,147 individuals were included: 1,061 iRBD patients and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk for iRBD, age at onset (AAO) and conversion rates.
Results:
GBA variants were found in 9.5% of iRBD patients compared to 4.1% in controls (odds ratio [OR]=2.45, 95% CI=1.87–3.22, p=1x10-10). The estimated OR for mild p.N370S variant carriers was 3.69, 95% CI=1.90–7.14, p=3.5x10-5, while for severe variant carriers it was 17.55, 95% CI=2.11–145.9, p=0.0015. Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or non-carriers (p=0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% in non-carriers (p=0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be taken with caution.
Conclusions:
GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.</p
LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder
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.</br
Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder
Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus.</p
Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects.
Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention
Local coexistence and genetic isolation of three pollinator species on the same fig tree species
Genetic modifiers of risk and age at onset in GBA associated Parkinson\u27s disease and Lewy body dementia
Investigation of Autosomal Genetic Sex Differences in Parkinson's disease.
OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Males are on average ~ 1.5 times more likely to develop PD compared to females with European ancestry. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total 19 genome-wide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females. This article is protected by copyright. All rights reserved