ORCID Profile
0000-0002-0941-3990
Current Organisations
Université Pierre et Marie Curie
,
Université Paris Descartes
,
Unité Mixte de Recherche Inserm U1127, CNRS 7225, SU 1127
,
Institut du cerveau et de la moelle épinière
,
Assistance Publique -Hopitaux De Paris
,
Sorbonne University
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Publications
Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases
Publisher: BMJ
Date: 29-11-2016
Targeted Next-Generation Sequencing of a 12.5 Mb Homozygous Region Reveals ANO10 Mutations in Patients with Autosomal-Recessive Cerebellar Ataxia
Publisher: Elsevier BV
Date: 12-2010
Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy
Publisher: Massachusetts Medical Society
Date: 18-07-2013
Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
Publisher: Public Library of Science (PLoS)
Date: 12-06-2014
Parkinson's disease age at onset genome‐wide association study: Defining heritability, genetic loci, and α‐synuclein mechanisms
Publisher: Wiley
Date: 07-04-2019
DOI: 10.1002/MDS.27659
Large-scale assessment of polyglutamine repeat expansions in Parkinson disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-09-2015
Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy.
Publisher: Elsevier BV
Date: 08-2020
Convergent genetic and expression data implicate immunity in Alzheimer's disease
Publisher: Wiley
Date: 19-12-2014
CXCR4 involvement in neurodegenerative diseases
Publisher: Springer Science and Business Media LLC
Date: 11-04-2018
DOI: 10.1038/S41398-017-0049-7
Abstract: Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12 , TLR2, RALB, and CCR5 . Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT , we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.
Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study
Publisher: Elsevier BV
Date: 10-2015
Immune-related genetic enrichment in frontotemporal dementia
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2017
DOI: 10.1101/157875
Abstract: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed. Using large genome-wide association studies (GWAS) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap leiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with ‘FTD-related disorders’ namely FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS) – and one or more immune-mediated diseases including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis (PSOR). We found up to 270-fold genetic enrichment between FTD and RA and comparable enrichment between FTD and UC, T1D, and CeD. In contrast, we found only modest genetic enrichment between any of the immune-mediated diseases and CBD, PSP or ALS. At a conjunction false discovery rate (FDR) 0.05, we identified numerous FTD-immune pleiotropic SNPs within the human leukocyte antigen ( HLA) region on chromosome 6. By leveraging the immune diseases, we also found novel FTD susceptibility loci within LRRK2 (Leucine Rich Repeat Kinase 2) , TBKBP1 (TANK-binding kinase 1 Binding Protein 1), and PGBD5 (PiggyBac Transposable Element Derived 5). Functionally, we found that expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with frontotemporal dementia and is enriched in microglia compared to other central nervous system (CNS) cell types. We show considerable immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to risk for FTD. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.
Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis
Publisher: Springer Science and Business Media LLC
Date: 12-01-2007
DOI: 10.1007/S10048-006-0072-Y
Abstract: PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative in iduals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2022
DOI: 10.1101/2022.05.23.22275465
Abstract: Parkinson’s disease (PD) is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of PD, particularly in the later stages of the disease. However, the rate of cognitive decline varies widely among PD patients, and the genetic basis for this heterogeneity is incompletely understood. Here, we have analysed 3,964 clinically diagnosed PD cases to explore the genetic factors associated with rate of progression to PD dementia. Genome-wide survival analysis identified the APOE- ε4 allele as a major risk factor for the conversion to PD dementia, as well as three new loci , including the ApoE and APP receptor LRP1B. Biomarker analysis also implicates the amyloid pathway in PD dementia, suggesting that amyloid-targeting therapy may have an important role in preventing PDD.
Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
Publisher: Springer Science and Business Media LLC
Date: 22-07-2020
DOI: 10.1038/S41598-020-68848-9
Abstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies ( n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
More missense in amyloid gene
Publisher: Springer Science and Business Media LLC
Date: 12-1992
DOI: 10.1038/NG1292-255
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1038/NG.3916
Nonsteroidal Anti‐inflammatory Use and LRRK2 Parkinson's Disease Penetrance
Publisher: Wiley
Date: 14-07-2020
DOI: 10.1002/MDS.28189
Genetic correlation between amyotrophic lateral sclerosis and schizophrenia
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/NCOMMS14774
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Genome-wide association study confirms BST1 and suggests a locus on 12q24 as the risk loci for Parkinson's disease in the European population
Publisher: Oxford University Press (OUP)
Date: 17-11-2010
DOI: 10.1093/HMG/DDQ497
Abstract: We performed a three-stage genome-wide association study (GWAS) to identify common Parkinson's disease (PD) risk variants in the European population. The initial genome-wide scan was conducted in a French s le of 1039 cases and 1984 controls, using almost 500 000 single nucleotide polymorphisms (SNPs). Two SNPs at SNCA were found to be associated with PD at the genome-wide significance level (P < 3 × 10(-8)). An additional set of promising and new association signals was identified and submitted for immediate replication in two independent case-control studies of subjects of European descent. We first carried out an in silico replication study using GWAS data from the WTCCC2 PD study s le (1705 cases, 5200 WTCCC controls). Nominally replicated SNPs were further genotyped in a third s le of 1527 cases and 1864 controls from France and Australia. We found converging evidence of association with PD on 12q24 (rs4964469, combined P = 2.4 × 10(-7)) and confirmed the association on 4p15/BST1 (rs4698412, combined P = 1.8 × 10(-6)), previously reported in Japanese data. The 12q24 locus includes RFX4, an isoform of which, named RFX4_v3, encodes brain-specific transcription factors that regulate many genes involved in brain morphogenesis and intracellular calcium homeostasis.
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
Publisher: Springer Science and Business Media LLC
Date: 09-2014
DOI: 10.1038/NG.3043
Association between the LRP1B and APOE loci and the development of Parkinson’s disease dementia
Publisher: Oxford University Press (OUP)
Date: 09-11-2023
Abstract: Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson’s disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson’s disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of in iduals with Parkinson’s disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson’s disease dementia [hazard ratio = 2.41 (1.94–3.00), P = 2.32 × 10−15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17–4.81), P = 7.07 × 10−09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21–3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson’s disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson’s disease dementia compared to Parkinson’s disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson’s disease dementia.
Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study
Publisher: Elsevier BV
Date: 2017
Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non‐Ashkenazi Jewish ancestry
Publisher: Wiley
Date: 22-06-2017
DOI: 10.1002/MDS.27059
Shared genetic contribution to ischemic stroke and Alzheimer's disease
Publisher: Wiley
Date: 30-03-2016
DOI: 10.1002/ANA.24621
Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25
Publisher: Wiley
Date: 07-05-2022
DOI: 10.1002/ANA.26366
Abstract: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus . Whole‐exome and whole‐genome sequencing were performed in families linked to SCA25 , including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 ( PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25 . An additional nonsense variant was detected in an unrelated in idual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1‐domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double‐stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response. This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022 :122–137
Ancestral Origins of the Machado-Joseph Disease Mutation: A Worldwide Haplotype Study
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1086/318184
The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants
Publisher: Elsevier BV
Date: 2014
Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis
Publisher: Wiley
Date: 13-03-2019
DOI: 10.1002/ANA.25431
Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy
Publisher: Springer Science and Business Media LLC
Date: 19-06-2011
DOI: 10.1038/NG.859
A novel Alzheimer disease locus located near the gene encoding tau protein
Publisher: Springer Science and Business Media LLC
Date: 17-03-2015
DOI: 10.1038/MP.2015.23
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2022
DOI: 10.1101/2022.07.07.22277297
Abstract: There are 90 genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10 -10 ). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10 -8 ). We also report 4 independent loci associated with motor progression: the top locus within MORN1 (HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10 -9 ), the second most significant locus near ASNS , the third most significant locus near PDE5A , and a fourth locus within XPO1 . We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. We report six novel loci associated with PD motor progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release, and phosphodiesterase inhibition may represent new candidates for disease modification in PD. Parkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority
Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases
Publisher: Oxford University Press (OUP)
Date: 03-05-2012
DOI: 10.1093/HMG/DDS161
Author Correction: Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS
Publisher: Springer Science and Business Media LLC
Date: 14-05-2018
DOI: 10.1038/S41598-018-21308-X
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS
Publisher: Springer Science and Business Media LLC
Date: 21-08-2017
DOI: 10.1038/S41598-017-09320-Z
Abstract: Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting the frontal and temporal lobes. Genome-wide association studies (GWAS) on FTD identified only a few risk loci. One of the possible explanations is that FTD is clinically, pathologically, and genetically heterogeneous. An important open question is to what extent epigenetic factors contribute to FTD and whether these factors vary between FTD clinical subgroup. We compared the DNA-methylation levels of FTD cases (n = 128), and of FTD cases with Amyotrophic Lateral Sclerosis (FTD-ALS n = 7) to those of unaffected controls (n = 193), which resulted in 14 and 224 candidate genes, respectively. Cluster analysis revealed significant class separation of FTD-ALS from controls. We could further specify genes with increased susceptibility for abnormal gene-transcript behavior by jointly analyzing DNA-methylation levels with the presence of mutations in a GWAS FTD-cohort. For FTD-ALS, this resulted in 9 potential candidate genes, whereas for FTD we detected 1 candidate gene ( ELP2 ). Independent validation-sets confirmed the genes DLG1, METTL7A, KIAA1147, IGHMBP2, PCNX, UBTD2, WDR35 , and ELP2/SLC39A6 among others. We could furthermore demonstrate that genes harboring mutations and/or displaying differential DNA-methylation, are involved in common pathways, and may therefore be critical for neurodegeneration in both FTD and FTD-ALS.
Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability
Publisher: Springer Science and Business Media LLC
Date: 17-04-2019
DOI: 10.1038/S41531-019-0076-6
Abstract: Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or in idual brain regions, but rather in global cellular processes detectable across several cell types.
Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance
Publisher: Springer Science and Business Media LLC
Date: 27-02-2017
DOI: 10.1038/NG.3794
Mutations in the GIGYF2 (TNRC15) Gene at the PARK11 Locus in Familial Parkinson Disease
Publisher: Elsevier BV
Date: 04-2008
Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study
Publisher: Elsevier BV
Date: 07-2008
No mutation in codon 713 of the amyloid precursor gene in schizophrenic patients
Publisher: Oxford University Press (OUP)
Date: 1993
DOI: 10.1093/HMG/2.3.321
Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2019
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Publisher: Springer Science and Business Media LLC
Date: 03-07-2202
DOI: 10.1038/NG.803
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
Publisher: Springer Science and Business Media LLC
Date: 27-10-2013
DOI: 10.1038/NG.2802
Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-10-2014
Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
Publisher: Springer Science and Business Media LLC
Date: 18-01-2020
DOI: 10.1007/S00401-019-02107-8
Abstract: The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.
Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies
Publisher: Public Library of Science (PLoS)
Date: 09-01-2018
Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia
Publisher: Oxford University Press (OUP)
Date: 05-04-2017
DOI: 10.1093/BRAIN/AWX066
Abstract: Genome-wide association studies in frontotemporal dementia showed limited success in identifying associated loci. This is possibly due to small s le size, allelic heterogeneity, small effect sizes of single genetic variants, and the necessity to statistically correct for testing millions of genetic variants. To overcome these issues, we performed gene-based association studies on 3348 clinically identified frontotemporal dementia cases and 9390 controls (discovery, replication and joint-cohort analyses). We report association of APOE and TOMM40 with behavioural variant frontotemporal dementia, and ARHGAP35 and SERPINA1 with progressive non-fluent aphasia. Further, we found the ɛ2 and ɛ4 alleles of APOE harbouring protective and risk increasing effects, respectively, in clinical subtypes of frontotemporal dementia against neurologically normal controls. The APOE-locus association with behavioural variant frontotemporal dementia indicates its potential risk-increasing role across different neurodegenerative diseases, whereas the novel genetic associations of ARHGAP35 and SERPINA1 with progressive non-fluent aphasia point towards a potential role of the stress-signalling pathway in its pathophysiology.
Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2018
DOI: 10.1101/294629
Abstract: Late-onset Alzheimer’s disease (LOAD, onset age 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 in iduals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.
Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Publisher: Elsevier BV
Date: 03-2018
Molecular characterisation of ILRUN, a novel inhibitor of proinflammatory and antimicrobial cytokines
Publisher: Elsevier BV
Date: 06-2020
Homologous DNA Exchanges in Humans Can Be Explained by the Yeast Double-Strand Break Repair Model: A Study of 17p11.2 Rearrangements Associated with CMT1A and HNPP
Publisher: Oxford University Press (OUP)
Date: 11-1999
Abstract: Rearrangements in 17p11.2, responsible for the 1.5 Mb duplications and deletions associated, respectively, with autosomal dominant Charcot-Marie-Tooth type 1A disease (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are a suitable model for studying human recombination. Rearrangements in 17p11.2 are caused by unequal crossing-over between two homologous 24 kb sequences, the CMT1A-REPs, that flank the disease locus and occur in most cases within a 1.7 kb hotspot. We sequenced this hotspot in 28 de novo patients (25 CMT1A and three HNPP), in order to localize precisely, at the DNA sequence level, the crossing-overs. We show that some chimeric CMT1A-REPs in de novo patients (10/28) present conversion of DNA segments associated with the crossing-over. These rearrangements can be explained by the double-strand break (DSB) repair model described in yeast. Fine mapping of the de novo rearrangements provided evidence that the successive steps of this model, heteroduplex DNA formation, mismatch correction and gene conversion, occurred in patients. Furthermore, the model explains 17p11.2 recombinations between chromosome homologues as well as between sister chromatids. In addition, defective mismatch repair of the heteroduplex DNA, observed in two patients, resulted in two heterozygous chimeric CMT1A-REPs which can be explained, as in yeast, by post-meiotic segregation. This work supports the hypothesis that the DSB repair model of DNA exchange may apply universally from yeasts to humans.
Dominant partial epilepsies: A clinical, electrophysiological and genetic study of 19 European families
Publisher: Oxford University Press (OUP)
Date: 06-2000
Abstract: Nineteen families with autosomal dominant partial epilepsy were analysed clinically and electrophysiologically in detail. Seventy-one patients were studied as well as 33 non-epileptic at-risk family members. We sub ided the families into those with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) (n = 8), familial temporal lobe epilepsy (n = 7) and autosomal dominant partial epilepsy with variable foci (n = 4). However, the application of this nosology to certain families was difficult in cases of non-specific or conflicting clinical and electrophysiological evidence. This was underscored by the observation by depth electrode recordings in one patient that a so-called ADNFLE may originate in an extrafrontal area. The evolution of familial partial epilepsies, which exhibit great intrafamilial variability, is not always benign. The level of pharmacoresistance may reach 30%, close to that seen in classical cryptogenic partial epilepsies. The familial character of a partial epilepsy may be unrecognized in small families as some affected members may have only EEG abnormalities and are clinically asymptomatic, which reflects incomplete clinical penetrance. In view of the recent discoveries of mutations in the alpha4 nicotinic acetylcholine receptor subunit in a few families with ADNFLE, this genetic study focused on genes encoding nicotinic receptor subunits and a candidate region on chromosome 10q. No mutation was detected in the alpha4 and 012 nicotinic acetylcholine receptor subunits. Positive but not significant lod scores were obtained in four families with markers from the candidate region on chromosome 10q.
Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease
Publisher: Elsevier BV
Date: 12-2016
Prediction of cognition in Parkinson's disease with a clinical–genetic score: a longitudinal analysis of nine cohorts
Publisher: Elsevier BV
Date: 08-2017
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
DOI: 10.1038/NG.3622
Genetic variability and potential effects on clinical trial outcomes: perspectives in Parkinson’s disease
Publisher: BMJ
Date: 29-11-2019
DOI: 10.1136/JMEDGENET-2019-106283
Abstract: Classical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes. 5851 patients with Parkinson’s disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were res led at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms. 5851 patients with Parkinson’s disease (mean (SD) age, 61.02 (12.61) years 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in in idual risk SNPs between each trial arm. Approximately 5%–6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of −0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives. Our data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.
Related Organisations
Unité Mixte De Recherche Inserm U1127, CNRS 7225, SU 1127
Location: France
Related Funding Activities
No related grants have been discovered for Alexis Brice.