ORCID Profile
0000-0001-7325-0199
Current Organisations
Sorbonne Université Campus Pierre et Marie Curie
,
Pierre and Marie Curie University
,
Université Pierre et Marie Curie
,
Hôpital Pitié-Salpêtrière
,
Institut du cerveau et de la moelle épinière
,
INSERM
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Publications
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
Self-reported physical activity levels and clinical progression in early Parkinson's disease
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.PARKRELDIS.2018.11.006
Abstract: This study investigates longitudinal changes in self-reported physical activity, measured by Physical Activity Scale of the Elderly (PASE), in early Parkinson's disease (PD) and matched healthy control (HC) participants in the Parkinson's Progression Marker Initiative (PPMI) and evaluates associations between physical activity and PD progression. PPMI is a prospective, longitudinal study evaluating markers of progression in PD participants who are unmedicated at enrollment. PASE, a self-reported measure of physical activity, was administered to early PD (N = 380) and HC (N = 174). PASE was introduced after study launch and therefore administered at years 2, 3, and 4. PASE scores for PD and HC were compared with t-tests and changes over time were evaluated with generalized estimating equations. There were no differences in activity levels between PD and HC at any time point. However, PD participants had a longitudinal decrease in PASE from years two to four (p = 0.034), while HC did not (p = 0.89). In exploratory analyses controlling for age, sex, and disease duration, higher self-reported activity at year 2 were associated with slower progression of motor symptoms (p = 0.018), ADL performance (p < 0.0001), depression (p = 0.001), anxiety (p = 0.002), and cognitive decline (p = 0.016) over two years. These findings remained significant after adjusting for disease severity. There are no differences in self-reported physical activity between HC and early PD, but activity levels decline longitudinally in PD. Exploratory analyses show that higher self-reported physical activity is associated with less disease progression. Therefore, interventions to increase physical activity in early PD could potentially modify the disease course.
Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria
Publisher: Wiley
Date: 03-05-2017
DOI: 10.1002/MDS.26987
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
Familial occurrence and heritable connective tissue disorders in cervical artery dissection
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-10-2014
Dairy Intake and Parkinson's Disease: A Mendelian Randomization Study
Publisher: Wiley
Date: 08-01-2022
DOI: 10.1002/MDS.28902
Abstract: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding. The aim is to examine the association between genetically predicted dairy intake and PD using two‐s le Mendelian randomization (MR). We genotyped a well‐established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage‐PD consortium (23 studies 9823 patients and 8376 controls of European ancestry). Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12–2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37–4.56], P = 0.003 P ‐difference with women = 0.029). Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society
European Academy of Neurology/Movement Disorder Society‐European Section Guideline on the Treatment of Parkinson's Disease: I. Invasive Therapies
Publisher: Wiley
Date: 07-2022
DOI: 10.1002/MDS.29066
Abstract: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist should know the therapies and their place in the treatment pathway. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging–guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health‐related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high‐class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN‐DBS is the best‐studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi‐DBS can also be offered. For early PD with early fluctuations, STN‐DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment‐resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication‐resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Baseline genetic associations in the Parkinson's Progression Markers Initiative (PPMI)
Publisher: Wiley
Date: 13-08-2015
DOI: 10.1002/MDS.26374
Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study
Publisher: Elsevier BV
Date: 10-2015
Association of genetic variation at the GJA5/ACP6 locus with motor progression in Parkinson’s
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.
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.
Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI)
Publisher: Elsevier BV
Date: 05-2019
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.
The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease
Publisher: Informa UK Limited
Date: 02-03-2017
DOI: 10.1080/03007995.2017.1294054
Abstract: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.
Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study
Publisher: Elsevier BV
Date: 2020
Migraine in cervical artery dissection and ischemic stroke patients
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-04-2012
The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort
Publisher: Wiley
Date: 31-10-2018
DOI: 10.1002/ACN3.644
Phosphoproteomic screening identifies Rab GTP ases as novel downstream targets of PINK 1
Publisher: EMBO
Date: 16-10-2015
Abstract: Mutations in the PTEN ‐induced kinase 1 ( PINK 1) are causative of autosomal recessive Parkinson's disease ( PD ). We have previously reported that PINK 1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser 65 ) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK 1‐dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub‐family of Rab GTP ases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser 111 ) in response to PINK 1 activation. Using phospho‐specific antibodies raised against Ser 111 of each of the Rabs, we demonstrate that Rab Ser 111 phosphorylation occurs specifically in response to PINK 1 activation and is abolished in HeLa PINK 1 knockout cells and mutant PINK 1 PD patient‐derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTP ase Ser 111 phosphorylation is not directly regulated by PINK 1 in vitro and demonstrate in cells the time course of Ser 111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser 65 . We further show mechanistically that phosphorylation at Ser 111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor ( GEF ), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK 1 is able to regulate the phosphorylation of Rab GTP ases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser 111 may represent novel biomarkers of PINK 1 activity in vivo . Our findings also suggest that disruption of Rab GTP ase‐mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.
The Interaction between HLA‐DRB1 and Smoking in Parkinson's Disease Revisited
Publisher: Wiley
Date: 10-07-2022
DOI: 10.1002/MDS.29133
Abstract: Two studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. To perform a large‐scale independent replication of the HLA‐DRB1 × smoking interaction. We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA‐DRB1 . At the amino acid level, a valine at position 11 (V11) in HLA‐DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, P Interaction = 0.028). In silico predictions of the influence of V11 and smoking‐induced modifications of α‐synuclein on binding affinity showed findings consistent with this interaction pattern. Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Which ante mortem clinical features predict progressive supranuclear palsy pathology?
Publisher: Wiley
Date: 13-05-2017
DOI: 10.1002/MDS.27034
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.
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
Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers
Publisher: Wiley
Date: 14-02-2023
DOI: 10.1002/MDS.29337
Abstract: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. We used results from genome‐wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. We used in idual data for participants of European ancestry from the Courage‐PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium PD, N = 482,730), Melanoma Meta‐Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross‐phenotypes polygenic risk score (PRS) analyses. We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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
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 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
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.
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