Publications by authors named "Jose M Bras"

15 Publications

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Coding variation in GBA explains the majority of the SYT11-GBA Parkinson's disease GWAS locus.

Mov Disord 2018 11 9;33(11):1821-1823. Epub 2018 Oct 9.

Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1002/mds.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379910PMC
November 2018

Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population.

Neurobiol Aging 2017 02 11;50:167.e11-167.e13. Epub 2016 Oct 11.

Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address:

Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812479PMC
February 2017

CHCHD2 and Parkinson's disease.

Lancet Neurol 2015 Jul;14(7):678-9

Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Silcherstraße 5, 70276, Germany. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(15)00094-0DOI Listing
July 2015

EIF4G1 mutations do not cause Parkinson's disease.

Neurobiol Aging 2015 Aug 9;36(8):2444.e1-4. Epub 2015 May 9.

Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. Electronic address:

EIF4G1 mutations were previously reported as a cause of Parkinson's disease (PD). As a result of this finding, considerable work has been performed to test this idea and to examine the functional role of eukaryotic translation initiation factor 4-gamma in the pathogenic process underlying PD. Here, we show that the originally described mutation is likely a rare benign variant. We tested this variant in a very large series of subjects and show that it is more frequent in controls than cases. We argue here that this infers that EIF4G1 mutations are not related to PD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464946PMC
August 2015

H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?

Mov Disord 2015 May 27;30(6):828-33. Epub 2014 Dec 27.

Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom.

Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.
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http://dx.doi.org/10.1002/mds.26129DOI Listing
May 2015

Atypical Parkinsonism-Dystonia Syndrome Caused by a Novel DJ1 Mutation.

Mov Disord Clin Pract 2014 Apr 10;1(1):45-49. Epub 2014 Apr 10.

Departmentof Neurology University of Kiel Kiel Germany.

We describe a sporadic case of atypical parkinsonism-dystonia of subacute onset at the age of 16 years in a male from a consanguineous family. He showed marked orofacial dystonia, levodopa-induced dyskinesia, and a stereotyped bilateral eye-pressing movement disorder. We combined Sanger sequencing of candidate genes, homozygosity mapping, and whole-exome sequencing. A homozygous mutation was identified disrupting a splice site in exon 5 of the DJ1 (PARK7) gene. Clinical details and a video are provided. DJ1 mutations are a rare cause of atypical complex parkinsonism. Exome sequencing is efficacious in identifying the causal gene variant.
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http://dx.doi.org/10.1002/mdc3.12008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182985PMC
April 2014

Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

JAMA Neurol 2013 Oct;70(10):1268-76

Importance: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders.

Objective: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD.

Design: Combined GWA analysis.

Setting: Data sets from the United Kingdom, Germany, France, and the United States.

Participants: Thousands of patients with AD or PD and their controls.

Main Outcomes And Measures: Meta-analysis of GWA studies of AD and PD.

Methods: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD.

Results: Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD.

Conclusions And Relevance: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
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http://dx.doi.org/10.1001/jamaneurol.2013.448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978422PMC
October 2013

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism.

J Neurol Neurosurg Psychiatry 2013 Jun 13;84(6):666-73. Epub 2013 Feb 13.

Centre d'Investigation Clinique, Institut du Cerveau et de la Moelle épinière, Hôpital de la Pitié-Salpêtrière, 47 boulevard de l'Hôpital, Paris 75651 Cedex 13, France.

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
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http://dx.doi.org/10.1136/jnnp-2012-304475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646288PMC
June 2013

A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.

Hum Mol Genet 2013 Mar 7;22(5):1039-49. Epub 2012 Dec 7.

Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
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http://dx.doi.org/10.1093/hmg/dds492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561909PMC
March 2013

Tau acts as an independent genetic risk factor in pathologically proven PD.

Neurobiol Aging 2012 Apr 4;33(4):838.e7-11. Epub 2012 Jan 4.

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.

MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.
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http://dx.doi.org/10.1016/j.neurobiolaging.2011.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629571PMC
April 2012

Exome sequencing in Parkinson's disease.

Clin Genet 2011 Aug 16;80(2):104-9. Epub 2011 Jun 16.

Department of Molecular Neuroscience, Institute of Neurology, University College of London, London, UK.

Exome sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review, we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson's disease, but also what are the known caveats of this approach.
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http://dx.doi.org/10.1111/j.1399-0004.2011.01722.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135730PMC
August 2011

Sequencing analysis of the ITPR1 gene in a pure autosomal dominant spinocerebellar ataxia series.

Mov Disord 2010 Apr;25(6):771-3

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

Spinocerebellar ataxia type 15 and 16 (SCA15/16) are autosomal dominant cerebellar ataxias that are slowly progressive with a predominantly pure ataxia phenotype (ADCA III). The locus for SCA15 was first mapped to 3p24.2-3pter and subsequently full or partial deletions in the inositol 1,4,5-triphosphate receptor type 1 (ITPR1) gene were identified in several ADCA III families that segregated with the disease. A single missense coding variant has been described, but the pathogenicity of this change has not been proven. We sequenced the entire coding region and flanking regions of ITPR1 in unrelated ADCA III families (n = 38) that were negative for large deletions on whole genome arrays, and for which SCAs 1, 2, 3, 6, 7, 8, 11, 12, 14, 17 and the Friedreich's ataxia expansion were excluded in all probands. Mutation at SCA5, 10, and 27 was also excluded in some families. A number of coding and noncoding polymorphisms were identified but no ITPR1 mutations were found. The results indicate that point mutations in ITPR1 are at best a rare cause of ADCA III.
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http://dx.doi.org/10.1002/mds.22970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864955PMC
April 2010

Genome-wide association study reveals genetic risk underlying Parkinson's disease.

Nat Genet 2009 Dec 15;41(12):1308-12. Epub 2009 Nov 15.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding alpha-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 x 10(-16)) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 x 10(-16)). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 x 10(-8)) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 x 10(-5)). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.
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http://dx.doi.org/10.1038/ng.487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787725PMC
December 2009

Genotype, haplotype and copy-number variation in worldwide human populations.

Nature 2008 Feb;451(7181):998-1003

Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.
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http://dx.doi.org/10.1038/nature06742DOI Listing
February 2008

Association of HFE common mutations with Parkinson's disease, Alzheimer's disease and mild cognitive impairment in a Portuguese cohort.

BMC Neurol 2006 Jul 6;6:24. Epub 2006 Jul 6.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, USA.

Background: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.

Methods: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened.

Results: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease.

Conclusion: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.
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http://dx.doi.org/10.1186/1471-2377-6-24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1534050PMC
July 2006