Vacic V.,Columbia University |
Vacic V.,New York Genome Center |
Ozelius L.J.,Mount Sinai School of Medicine |
Clark L.N.,Columbia University |
And 32 more authors.
Human Molecular Genetics | Year: 2014
The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial geneticcomponent.Tofurther investigate the genetic landscape of PD, weperformed agenome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-bydescent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments.Weobserved significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR 5 12.05, P 5 1.23 3 10-56), MAPT(OR 5 0.62, P 5 1.78 3 10-11) and GBA (multiple distinct haplotypes, OR > 8.28, P 5 1.13 3 10-11 and OR 5 2.50, P 5 1.22 3 10-9). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR 5 22.58, P 5 1.21 3 10-10) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts. © The Author 2014. Published by Oxford University Press. All rights reserved.
Siri C.,Parkinson Institute |
Duerr S.,Innsbruck Medical University |
Canesi M.,Parkinson Institute |
Delazer M.,Innsbruck Medical University |
And 20 more authors.
Journal of Neural Transmission | Year: 2013
Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group (http://www.emsa-sg.org), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies. © 2013 Springer-Verlag Wien.
Kedmi M.,Genetic Institute |
Bar-Shira A.,Genetic Institute |
Gurevich T.,Movement Disorders Unit and Parkinson Center |
Gurevich T.,Tel Aviv University |
And 4 more authors.
Molecular Neurodegeneration | Year: 2011
Background: Parkinson's disease (PD) is a complex disorder caused by genetic, environmental and age-related factors, and it is more prevalent in men. We aimed to identify differentially expressed genes in peripheral blood leukocytes (PBLs) that might be involved in PD pathogenesis. Transcriptomes of 30 female PD-patients and 29 age- and sex-matched controls were profiled using GeneChip Human Exon 1.0 ST Arrays. Samples were from unrelated Ashkenazi individuals, non-carriers of LRRK2 G2019S or GBA founder mutations. Results: Differential expression was detected in 115 genes (206 exons), with over-representation of immune response annotations. Thirty genes were related to B cell functions, including the uniquely B cell-expressed IGHM and IGHD, the B cell surface molecules CD19, CD22 and CD79A, and the B cell gene regulator, PAX5. Quantitative-RT-PCR confirmation of these 6 genes in 79 individuals demonstrated decreased expression, mainly in women patients, independent of PD-pharmacotherapy status. Conclusions: Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD. © 2011 Kedmi et al; licensee BioMed Central Ltd.