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See detailReplication of a Novel Parkinson's Locus in a European Ancestry Population
Grover, Sandeep; Kumar-Sreelatha, Ashwin Ashok; Bobbili, Dheeraj R. et al

in Movement Disorders (2021)

ABSTRACT Background A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. Objectives The objective of this study were to ... [more ▼]

ABSTRACT Background A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17. Objectives The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations. Methods We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled. Results Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10−4, pooled PD P = 1.15 × 10−11). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10−8). Conclusions Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [less ▲]

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See detailGenome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara et al

in Nature Genetics (2021)

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic ... [more ▼]

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition. [less ▲]

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See detailPathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Dewan, Ramita; Chia, Ruth; Ding, Jinhui et al

in Neuron (2021), 109(3), 448-460

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients ... [more ▼]

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. [less ▲]

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See detailAnalysis and visualisation of tremor dynamics in deep brain stimulation patients
Bremm, René Peter UL; Koch, Klaus Peter; Krüger, Rejko UL et al

in Current Directions in Biomedical Engineering (2020), 6(3), 4

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See detailA rule-based expert system for real-time feedback-control in deep brain stimulation
Bremm, René Peter UL; Koch, Klaus Peter; Krüger, Rejko UL et al

in Current Directions in Biomedical Engineering (2020), 6(3), 4

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See detailCommon diseases alter the physiological age-related blood microRNA profile.
Fehlmann, Tobias; Lehallier, Benoit; Schaum, Nicholas et al

in Nature communications (2020), 11(1), 5958

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in ... [more ▼]

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5' mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers. [less ▲]

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See detailMitochondria interaction networks show altered topological patterns in Parkinson's disease.
Zanin, Massimiliano; Santos, Bruno F. R.; Antony, Paul UL et al

in NPJ systems biology and applications (2020), 6(1), 38

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact ... [more ▼]

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation. [less ▲]

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See detailMitochondrial and Clearance Impairment in p.D620N VPS35 Patient-Derived Neurons
Hanss, Zoé UL; Larsen, Simone UL; Antony, Paul UL et al

in Movement Disorders (2020)

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation ... [more ▼]

Background: VPS35 is part of the retromer complex and is responsible for the trafficking and recycling of proteins implicated in autophagy and lysosomal degradation, but also takes part in the degradation of mitochondrial proteins via mitochondria-derived vesicles. The p.D620N mutation of VPS35 causes an autosomal-dominant form of Parkinson’s disease (PD), clinically representing typical PD. Objective: Most of the studies on p.D620N VPS35 were performed on human tumor cell lines, rodent models overexpressing mutant VPS35, or in patient-derived fibroblasts. Here, based on identified target proteins, we investigated the implication of mutant VPS35 in autophagy, lysosomal degradation, and mitochondrial function in induced pluripotent stem cell-derived neurons from a patient harboring the p.D620N mutation. Methods: We reprogrammed fibroblasts from a PD patient carrying the p.D620N mutation in the VPS35 gene and from two healthy donors in induced pluripotent stem cells. These were subsequently differentiated into neuronal precursor cells to finally generate midbrain dopaminergic neurons. Results: We observed a decreased autophagic flux and lysosomal mass associated with an accumulation of α-synuclein in patient-derived neurons compared to controls. Moreover, patient-derived neurons presented a mitochondrial dysfunction with decreased membrane potential, impaired mitochondrial respiration, and increased production of reactive oxygen species associated with a defect in mitochondrial quality control via mitophagy. Conclusion: We describe for the first time the impact of the p.D620N VPS35 mutation on autophago-lysosome pathway and mitochondrial function in stem cell-derived neurons from an affected p.D620N carrier and define neuronal phenotypes for future pharmacological interventions [less ▲]

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See detailHaploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy
Neumann, Marie Anne-Catherine UL; Grossmann, Dajana UL; Schimpf-Linzenbold, Simone et al

in Scientific Reports (2020)

ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of ... [more ▼]

ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy. [less ▲]

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See detailGeneration of two iPS cell lines (HIHDNDi001-A and HIHDNDi001-B) from a Parkinson's disease patient carrying the heterozygous p.A30P mutation in SNCA.
Barbuti, Peter; Santos, Bruno; Dording, Claire UL et al

in Stem cell research (2020), 48

Dermal fibroblasts from a patient carrying a heterozygous c.88G > C mutation in the SNCA gene that encodes alpha-synuclein were reprogrammed to pluripotency by retroviruses. This pathogenic mutation ... [more ▼]

Dermal fibroblasts from a patient carrying a heterozygous c.88G > C mutation in the SNCA gene that encodes alpha-synuclein were reprogrammed to pluripotency by retroviruses. This pathogenic mutation generates the p.A30P form of the alpha-synuclein protein leading to autosomal dominantly inherited Parkinson's disease (PD). Two clonal iPS cell lines were generated (A30P-3 and A30P-4) and characterised by validating the silencing of viral transgenes, the expression of endogenous pluripotency genes, directed differentiation into three germ layers in-vitro and a stable molecular genotype. These iPSC lines will serve as a valuable resource in determining the role of the p.A30P SNCA mutation in PD pathogenesis. [less ▲]

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See detailBidirectional Relation Between Parkinson’s Disease and Glioblastoma Multiforme
Mencke, Pauline UL; Hanss, Zoé; Boussaad, Ibrahim UL et al

in Frontiers in Neurology (2020)

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See detailGenome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into the complex genetic architecture
Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara et al

E-print/Working paper (2020)

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic ... [more ▼]

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Competing Interest StatementThomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests. [less ▲]

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See detailGenetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research.
Rajan, Roopa; Divya, K. P.; Kandadai, Rukmini Mridula et al

in Frontiers in neurology (2020), 11

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability ... [more ▼]

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our "hub-spoke" model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD. [less ▲]

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See detailParkinson’s disease-associated alterations of the gut microbiome predict diseaserelevant changes in metabolic functions
Krüger, Rejko UL; Baldini, Federico UL; Thiele, Ines UL et al

in BMC Biology (2020)

Background: 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 ... [more ▼]

Background: 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 samples from the Luxembourg Parkinson’s Study (n = 147 typical PD cases, n = 162 controls). Results: All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals 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. Conclusion: Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype. [less ▲]

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See detailDeep sncRNA-seq of the PPMI cohort to study Parkinson’s disease progression
Kern, Fabian; Fehlmann, Tobias; Violich, Ivo et al

E-print/Working paper (2020)

Coding and non-coding RNAs have diagnostic and prognostic importance in Parkinson’s diseases (PD). We studied circulating small non-coding RNAs (sncRNAs) in 7, 003 samples from two longitudinal PD cohorts ... [more ▼]

Coding and non-coding RNAs have diagnostic and prognostic importance in Parkinson’s diseases (PD). We studied circulating small non-coding RNAs (sncRNAs) in 7, 003 samples from two longitudinal PD cohorts (Parkinson’s Progression Marker Initiative (PPMI) and Luxembourg Parkinson’s Study (NCER-PD)) and modelled their influence on the transcriptome. First, we sequenced sncRNAs in 5, 450 blood samples of 1, 614 individuals in PPMI. The majority of 323 billion reads (59 million reads per sample) mapped to miRNAs. Other covered RNA classes include piRNAs, rRNAs, snoRNAs, tRNAs, scaRNAs, and snRNAs. De-regulated miRNAs were associated with the disease and disease progression and occur in two distinct waves in the third and seventh decade of live. Originating mostly from a characteristic set of immune cells they resemble a systemic inflammation response and mitochondrial dysfunction, two hallmarks of PD. By profiling 1, 553 samples from 1, 024 individuals in the NCER-PD cohort using an independent technology, we validate relevant findings from the sequencing study. Finally, network analysis of sncRNAs and transcriptome sequencing of the original cohort identified regulatory modules emerging in progressing PD patients.Competing Interest StatementThe authors have declared no competing interest. [less ▲]

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See detailEmerging concepts for precision medicine in Parkinson's disease with focus on genetics
Krüger, Rejko UL; Stute, Lara UL

in Fortschritte der Neurologie-Psychiatrie (2020)

The diverse and highly individual presentations of Parkinson's disease (PD) as a complex combination of motor and non-motor symptoms are being increasingly well characterised not least through large ... [more ▼]

The diverse and highly individual presentations of Parkinson's disease (PD) as a complex combination of motor and non-motor symptoms are being increasingly well characterised not least through large patient cohorts applying deep phenotyping. However, in terms of treatment of PD, the approach is uniform and purely symptomatic. Better stratification strategies with better precision medicine approaches offer opportunities to improve symptomatic treatment, define first causative therapies and provide more patient-centred care. Insight from targeted therapies for monogenic forms of PD aiming at neuroprotection may pave the way for new mechanism-based interventions also for the more common idiopathic PD. Improved stratification of patients may support symptomatic treatments by predicting treatment efficacy and long-term benefit of current pharmacological or neuromodulatory therapies, e.g. in the context of emerging pharmacogenomic knowledge. Based on asymptomatic carriers with monogenic PD or patients with REM sleep behaviour disorder (RBD), first options for applying preventive treatments emerge. The implications of these treatment strategies in relation to disease progression, and the prospects of their implementation in clinical practice need to be addressed. [less ▲]

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See detailPrevalence of SARS-CoV-2 infection in the Luxembourgish population: the CON-VINCE study.
Snoeck, Chantal J.; Vaillant, Michel; Abdelrahman, Tamir et al

E-print/Working paper (2020)

BACKGROUND: After the World Health Organization declared the outbreak of coronavirus disease to be a public health emergency of international concern on January 30, 2020, the first SARS-CoV-2 infection ... [more ▼]

BACKGROUND: After the World Health Organization declared the outbreak of coronavirus disease to be a public health emergency of international concern on January 30, 2020, the first SARS-CoV-2 infection was detected in Luxembourg on February 29, 2020. Representative population-based data, including asymptomatic individuals for assessing the viral spread and immune response were, however, lacking worldwide. METHODS: Using a panel-based method, we implemented a representative sample of the Luxembourgish population based on age, gender and residency for testing for SARS-CoV-2 infection and antibody status in order to define prevalence irrespective of clinical symptoms. Participants were contacted via email to fill an online questionnaire before biosampling at local laboratories. All participants provided information related to clinical symptoms, epidemiology, socioeconomic and psychological assessments and underwent biosampling, rRT-PCR testing and serology for SARS-CoV-2. RESULTS: We included a total of 1862 individuals in our representative sample of the general Luxembourgish population. Of these, 5 individuals had a current positive result for infection with SARS-CoV-2 based on rRT-PCR. Four of these individuals were oligosymptomatic and one was asymptomatic. Overall we found a positive IgG antibody status in 35 individuals (1.97%), of which 11 reported to be tested positive by rRT-PCR for SARS-CoV-2 previously and showed in addition their IgG positive status also a positive status for IgA. Our data indicate a prevalence of 0.3% for active SARS-CoV-2 infection and an infection rate of 2.15% in the Luxembourgish population between 18 and 79 years of age. CONCLUSIONS: Luxembourgish residents show a low rate of acute infections after 7 weeks of confinement and present with an antibody profile indicative of a more recent immune response to SARS-CoV-2. All infected individuals were oligo- or asymptomatic. Bi-weekly follow-up visits over the next 2 months will inform about the viral spread by a- and oligosymptomatic carriers and the individual changes in the immune profile.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialNCT04379297Funding StatementThe CON-VINCE Study is funded by the Research Fund Luxembourg (FNR; CON-VINCE) and the André Losch Foundation (Luxembourg).Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesDue to ethical concerns, supporting data cannot be made openly available. [less ▲]

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See detailInduced pluripotent stem cell line (LCSBi001-A) derived from a patient with Parkinson's disease carrying the p.D620N mutation in VPS35
Larsen, Simone UL; Hanss, Zoé UL; Cruciani, Gérald UL et al

in Stem Cell Research (2020)

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were ... [more ▼]

Fibroblasts were obtained from a 76 year-old man diagnosed with Parkinson's disease (PD). The disease is caused by a heterozygous p.D620N mutation in VPS35. Induced pluripotent stem cells (iPSCs) were generated using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Thermo Fisher Scientific). The presence of the c.1858G > A base exchange in exon 15 of VPS35 was confirmed by Sanger sequencing. The iPSCs are free of genomically integrated reprogramming genes, express pluripotency markers, display in vitro differentiation potential to the three germ layers and have karyotypic integrity. Our iPSC line will be useful for studying the impact of the p.D620N mutation in VPS35 in vitro. [less ▲]

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See detailMissing heritability in Parkinson’s disease: the emerging role of non‑coding genetic variation
Ohnmacht, Jochen UL; May, Patrick UL; Sinkkonen, Lasse UL et al

in Journal of Neural Transmission (2020)

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical ... [more ▼]

Parkinson's disease (PD) is a neurodegenerative disorder caused by a complex interplay of genetic and environmental factors. For the stratification of PD patients and the development of advanced clinical trials, including causative treatments, a better understanding of the underlying genetic architecture of PD is required. Despite substantial efforts, genome-wide association studies have not been able to explain most of the observed heritability. The majority of PD-associated genetic variants are located in non-coding regions of the genome. A systematic assessment of their functional role is hampered by our incomplete understanding of genotype-phenotype correlations, for example through differential regulation of gene expression. Here, the recent progress and remaining challenges for the elucidation of the role of non-coding genetic variants is reviewed with a focus on PD as a complex disease with multifactorial origins. The function of gene regulatory elements and the impact of non-coding variants on them, and the means to map these elements on a genome-wide level, will be delineated. Moreover, examples of how the integration of functional genomic annotations can serve to identify disease-associated pathways and to prioritize disease- and cell type-specific regulatory variants will be given. Finally, strategies for functional validation and considerations for suitable model systems are outlined. Together this emphasizes the contribution of rare and common genetic variants to the complex pathogenesis of PD and points to remaining challenges for the dissection of genetic complexity that may allow for better stratification, improved diagnostics and more targeted treatments for PD in the future. [less ▲]

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