37 research outputs found
Analysis of common and rare VPS13C variants in late-onset Parkinson disease
Objective
We aimed to study the role of coding VPS13C variants in a large cohort of patients with lateonset Parkinson disease (PD) (LOPD).
Methods
VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare
potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression
adjusted for age and sex in each of the cohorts, followed by a meta-analysis.
Results
No biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of
compound heterozygous variants were found in 2 controls. There was no statistically significant
burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C
variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q
variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP
p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28â0.82, p = 0.0052]). This haplotype
was not in linkage disequilibrium with the known genome-wide association study top hit.
Conclusions
Our results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD.
Additional genetic replication and functional studies are needed to examine the role of the
haplotype identified here associated with reduced risk for PD
GBA mutations are associated with Rapid eye movement sleep behavior disorder
Rapid eye movement sleep behavior disorder and GBA mutations are both
associated with Parkinsonâs disease. The GBA gene was sequenced in idiopathic
rapid eye movement sleep behavior disorder patients (n = 265), and compared
to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinsonâs disease cohort (n = 120).
GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among
Parkinsonâs disease patients, the OR for mutation carriers to have probable
rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results
demonstrate that rapid eye movement sleep behavior disorder is associated with
GBA mutations, and that combining genetic and prodromal data may assist in
identifying individuals susceptible to Parkinsonâs disease
The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder
The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was
sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551),
rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of
European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with
frequency>0.01. None of the common variants was associated with PD or RBD in the different
regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was
associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant
heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant
association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants
had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and
no cumulative effect of carrying more than one MC1R variant was found. The current study does
not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD
The dementia-associated APOE Δ4 allele is not associated with rapid eye movement sleep behavior disorder
The present study aimed to examine whether the APOE Δ4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n = 480) and in controls (n = 823). APOE Δ4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR = 1.11, 95% CI: 0.88-1.40, p = 0.41). APOE Δ4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p = 1.0). The APOE Δ4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies
GBA variants in REM sleep behavior disorder: a multicenter study
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
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
HLA in isolated REM sleep behavior disorder and Lewy body dementia
peer reviewedSynucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (ORâ=â1.57, 95 CIâ=â1.27â1.93, pâ=â2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (ORâ=â1.26, 95\%CIâ=â1.12â1.41, pâ=â8.76e-05), 70Q (ORâ=â0.81, 95\%CIâ=â0.72â0.91, pâ=â3.65e-04) and 71R (ORâ=â1.21, 95\%CIâ=â1.08â1.35, pâ=â1.35e-03). Position 71 (pomnibusâ=â0.00102) and 70 (pomnibusâ=â0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies
Common variants in P2RY11 are associated with narcolepsy.
l e t t e r s Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genomewide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3âČ untranslated region of P2RY11, the purinergic receptor subtype P2Y 11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 Ă 10 â10 , odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The diseaseassociated allele is correlated with reduced expression of P2RY11 in CD8 + T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases
Common variants in P2RY11 are associated with narcolepsy.
Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Yââ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 Ă 10â»Âčâ°, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.journal articleresearch support, n.i.h., extramuralresearch support, non-u.s. gov'tresearch support, u.s. gov't, p.h.s.2011 Jan2010 12 19importedErratum in : Nat Genet. 2011 Oct;43(10):1040