ORCID Profile
0000-0001-6382-5841
Current Organisations
University of Oxford
,
Kings College London
,
Royal College of Physicians
,
University of London
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Publisher: Wiley
Date: 06-01-2014
DOI: 10.1002/MDS.25748
Publisher: Elsevier BV
Date: 03-2016
Publisher: Elsevier BV
Date: 08-2015
Publisher: Springer Science and Business Media LLC
Date: 24-01-2017
DOI: 10.1038/SREP41188
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population over 65 years characterized clinically by both motor and non-motor symptoms accompanied by the preferential loss of dopamine neurons in the substantia nigra pars compacta. Here, we sequenced the exomes of 244 Parkinson’s patients selected from the Oxford Parkinson’s Disease Centre Discovery Cohort and, after quality control, 228 exomes were available for analyses. The PD patient exomes were compared to 884 control exomes selected from the UK10K datasets. No single non-synonymous (NS) single nucleotide variant (SNV) nor any gene carrying a higher burden of NS SNVs was significantly associated with PD status after multiple-testing correction. However, significant enrichments of genes whose proteins have roles in the extracellular matrix were amongst the top 300 genes with the most significantly associated NS SNVs, while regions associated with PD by a recent Genome Wide Association (GWA) study were enriched in genes containing PD-associated NS SNVs. By examining genes within GWA regions possessing rare PD-associated SNVs, we identified RAD51B . The protein-product of RAD51B interacts with that of its paralogue RAD51 , which is associated with congenital mirror movements phenotypes, a phenotype also comorbid with PD.
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
Publisher: Springer Science and Business Media LLC
Date: 09-06-2020
DOI: 10.1186/S12915-020-00775-7
Abstract: Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool s les from the Luxembourg Parkinson’s Study ( n = 147 typical PD cases, n = 162 controls). All in iduals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool s les from these in iduals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms. Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype.
Publisher: Elsevier BV
Date: 2019
Publisher: BMJ
Date: 22-06-2022
Abstract: To explore the genetics of four Parkinson’s disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer’s disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no in idual variants met genome wide significance ( ×10e-8) although four variants require further follow-up, meeting a threshold of ×10e-6. We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.
Publisher: Oxford University Press (OUP)
Date: 17-01-2017
DOI: 10.1093/HMG/DDW412
Publisher: Wiley
Date: 28-10-2021
DOI: 10.1002/MDS.28342
Publisher: BMJ
Date: 05-2021
DOI: 10.1136/BMJOPEN-2020-047993
Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder with substantial morbidity. No disease-modifying treatments currently exist. The glucagon like peptide-1 receptor agonist exenatide has been associated in single-centre studies with reduced motor deterioration over 1 year. The aim of this multicentre UK trial is to confirm whether these previous positive results are maintained in a larger number of participants over 2 years and if effects accumulate with prolonged drug exposure. This is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial of exenatide at a dose of 2 mg weekly in 200 participants with mild to moderate PD. Treatment duration is 96 weeks. Randomisation is 1:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48, 60, 72, 84 and 96 weeks. The primary outcome is the comparison of Movement Disorders Society Unified Parkinson’s Disease Rating Scale part 3 motor subscore in the practically defined OFF medication state at 96 weeks between participants according to treatment allocation. Secondary outcomes will compare the change between groups among other motor, non-motor and cognitive scores. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups using a mixed model, adjusting for baseline scores. Secondary outcomes will be summarised between treatment groups using summary statistics and appropriate statistical tests to assess for significant differences. This trial has been approved by the South Central-Berkshire Research Ethics Committee and the Health Research Authority. Results will be disseminated in peer-reviewed journals, presented at scientific meetings and to patients in lay-summary format. NCT04232969 , ISRCTN14552789 .
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.
Publisher: Cold Spring Harbor Laboratory
Date: 11-2022
DOI: 10.1101/2022.10.28.22281645
Abstract: There is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets. To identify genomic variation associated with PD motor presentation and early stage progression. GWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments. Multicentre 3572 unrelated European ancestry in iduals diagnosed with PD from 6 studies. Linear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model. We identified an association between the PD axial rate of progression and variation at the GJA5 locus at 1q12 (Beta = -0.25, SE = 0.04, P = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression of ACP6 , a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: 10 −8 in eQTLGen and 10 −7 in PsychEncode). In addition, we found a nominal association between axial motor presentation and the MAD1L1 gene at 7q21.11 (Beta = 0.54, SE = 0.11, P = 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNA LINC00511 at 17q21.31 (Beta = -0.62, SE = 0.11, P = 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation of MAD1L1 expression. Variants at LINC00511 may cause a disruption of a distal epigenetic regulation of SOX9 through an anchored chromatin loop. Our large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2020
DOI: 10.1007/S10654-020-00633-4
Abstract: The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 in iduals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure ‘lab’ using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 in idual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
Publisher: Wiley
Date: 16-07-2013
DOI: 10.1002/HBM.22282
Publisher: Springer Science and Business Media LLC
Date: 07-10-2014
DOI: 10.1038/MP.2014.107
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.
Publisher: Oxford University Press (OUP)
Date: 24-07-2016
DOI: 10.1093/BRAIN/AWW188
Publisher: Springer Science and Business Media LLC
Date: 08-06-2021
DOI: 10.1038/S41531-021-00174-X
Abstract: To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable “QoL responders”/“non-responders”. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as “QoL non-responders”. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as ‘difficulties experiencing pleasure’ and ‘problems sustaining concentration’. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting in iduals for DBS therapy.
Publisher: Elsevier BV
Date: 02-2021
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Michele Hu.