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Parkinson Disease: HELP
Articles by Iris E. Jansen
Based on 9 articles published since 2008
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Between 2008 and 2019, Iris Jansen wrote the following 9 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Article Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. 2017

Robak, Laurie A / Jansen, Iris E / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Jankovic, Joseph / Anonymous821082 / Heutink, Peter / Shulman, Joshua M. ·Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX USA. · Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston TX USA. · German Center for Neurodegenerative Diseases (DZNE) and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany. · Department of Clinical Genetics, VU University Medical Center, Amsterdam 1081HZ, The Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, The Netherlands. · Department of Neurology, Erasmus MC, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. ·Brain · Pubmed #29140481.

ABSTRACT: Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility.

2 Article Establishing the role of rare coding variants in known Parkinson's disease risk loci. 2017

Jansen, Iris E / Gibbs, J Raphael / Nalls, Mike A / Price, T Ryan / Lubbe, Steven / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Williams, Nigel M / Brice, Alexis / Hardy, John / Wood, Nicholas W / Morris, Huw R / Gasser, Thomas / Singleton, Andrew B / Heutink, Peter / Sharma, Manu / Anonymous1560918. ·Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA. · University California Irvine, Irvine, CA, USA. · Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales, UK. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Reta Lila Weston Institute, University College London, London, UK. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. Electronic address: manu.sharma@uni-tuebingen.de. ·Neurobiol Aging · Pubmed #28867149.

ABSTRACT: Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks.

3 Article Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. 2017

Liu, Ganqiang / Locascio, Joseph J / Corvol, Jean-Christophe / Boot, Brendon / Liao, Zhixiang / Page, Kara / Franco, Daly / Burke, Kyle / Jansen, Iris E / Trisini-Lipsanopoulos, Ana / Winder-Rhodes, Sophie / Tanner, Caroline M / Lang, Anthony E / Eberly, Shirley / Elbaz, Alexis / Brice, Alexis / Mangone, Graziella / Ravina, Bernard / Shoulson, Ira / Cormier-Dequaire, Florence / Heutink, Peter / van Hilten, Jacobus J / Barker, Roger A / Williams-Gray, Caroline H / Marinus, Johan / Scherzer, Clemens R / Anonymous3720910 / Anonymous3730910 / Anonymous3740910 / Anonymous3750910 / Anonymous3760910 / Anonymous3770910 / Anonymous3780910. ·Neurogenomics Laboratory and Parkinson Personalized Medicine Program of Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA. · Neurogenomics Laboratory and Parkinson Personalized Medicine Program of Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. · Université Pierre et Marie Curie Paris 06 UMR S 1127, Sorbonne Université, Institut du Cerveau et de la Moelle Epinière, Paris, France; U 1127 and Centre d'Investigation Clinique 1422, Institut National de Santé et en Recherche Médicale, Paris, France; U 7225, Centre National de Recherche Scientifique, Paris, France; Département de Neurologie et de Génétique, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France. · Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA, USA. · Neurogenomics Laboratory and Parkinson Personalized Medicine Program of Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA, USA. · Department of Medical Genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, HZ, Netherlands; German Center for Neurodegenerative diseases, Tübingen, Germany. · John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. · San Francisco Veterans Affairs Medical Center and Department of Neurology, UCSF School of Medicine, San Francisco, CA, USA. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital and the University of Toronto, Toronto, ON, Canada. · Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA. · INSERM, Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of ageing and age related diseases, University Paris-Sud, UMRS 1018, Villejuif, France. · Voyager Therapeutics, Cambridge, MA, USA. · Program for Regulatory Science and Medicine, Department of Neurology, Georgetown University, Washington, DC, USA. · Department of Neurology, Leiden University Medical Center, Leiden, Netherlands. · Neurogenomics Laboratory and Parkinson Personalized Medicine Program of Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA, USA. Electronic address: cscherzer@rics.bwh.harvard.edu. ·Lancet Neurol · Pubmed #28629879.

ABSTRACT: BACKGROUND: Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. METHODS: In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. FINDINGS: 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets. INTERPRETATION: Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. FUNDING: National Institutes of Health, US Department of Defense.

4 Article Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. 2017

Witoelar, Aree / Jansen, Iris E / Wang, Yunpeng / Desikan, Rahul S / Gibbs, J Raphael / Blauwendraat, Cornelis / Thompson, Wesley K / Hernandez, Dena G / Djurovic, Srdjan / Schork, Andrew J / Bettella, Francesco / Ellinghaus, David / Franke, Andre / Lie, Benedicte A / McEvoy, Linda K / Karlsen, Tom H / Lesage, Suzanne / Morris, Huw R / Brice, Alexis / Wood, Nicholas W / Heutink, Peter / Hardy, John / Singleton, Andrew B / Dale, Anders M / Gasser, Thomas / Andreassen, Ole A / Sharma, Manu / Anonymous4711037. ·Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo2Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. · Department of Clinical Genetics, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands4German Center for Neurodegenerative Diseases (DZNE), Tübingen. · Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo5Multimodal Imaging Laboratory, University of California at San Diego, La Jolla. · Multimodal Imaging Laboratory, University of California at San Diego, La Jolla6Department of Radiology and Biomedical Imaging, University of California, San Francisco. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland. · German Center for Neurodegenerative Diseases (DZNE), Tübingen. · Department of Psychiatry, University of California at San Diego, La Jolla9Department of Psychiatry, University of Copenhagen, Copenhagen, Denmark. · Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo10Department of Medical Genetics, University of Oslo, Oslo, Norway11Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. · Multimodal Imaging Laboratory, University of California at San Diego, La Jolla12Sciences Graduate Program, University of California at San Diego, La Jolla13Department of Neurosciences, University of California at San Diego, La Jolla. · Norwegian Centre for Mental Disorders Research (NORMENT), K. G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo. · Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany. · Department of Medical Genetics, University of Oslo, Oslo, Norway11Department of Medical Genetics, Oslo University Hospital, Oslo, Norway15K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway16Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway17Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. · Multimodal Imaging Laboratory, University of California at San Diego, La Jolla15K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway. · K. G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo, Norway16Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway18Division of Gastroenterology, Institute of Medicine, University of Bergen, Bergen, Norway19Norwegian Primary Sclerosing Cholangitis (PSC) Research Center, Department of Transplantation Medicine, Oslo. · Sorbonne Universités, Université Pierre-et-Marie Curie (UPMC) Paris 06, UM 1127, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France21Institut National de la Santé et de la Récherche Médicale (INSERM), Unité 1127, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France22Centre National de la Recherche Scientifique (CNRS) UMR 7225, Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France23Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France24Assistance Publique-Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Department of Clinical Neuroscience, National Hospital for Neurology and Neurosurgery (NHNN), University College London, London, England. · Department of Molecular Neurosciences, Institute of Neurology, University College London, London, England. · Department of Clinical Genetics, Vrije Universiteit (VU) University Medical Center, Amsterdam, the Netherlands4German Center for Neurodegenerative Diseases (DZNE), Tübingen27Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Rita Lila Weston Institute, University College London, London, England. · Multimodal Imaging Laboratory, University of California at San Diego, La Jolla8Department of Psychiatry, University of California at San Diego, La Jolla13Department of Neurosciences, University of California at San Diego, La Jolla29Department of Radiology, University of California at San Diego, La Jolla. · German Center for Neurodegenerative Diseases (DZNE), Tübingen27Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany30Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. ·JAMA Neurol · Pubmed #28586827.

ABSTRACT: Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

5 Article Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. 2017

Jansen, Iris E / Ye, Hui / Heetveld, Sasja / Lechler, Marie C / Michels, Helen / Seinstra, Renée I / Lubbe, Steven J / Drouet, Valérie / Lesage, Suzanne / Majounie, Elisa / Gibbs, J Raphael / Nalls, Mike A / Ryten, Mina / Botia, Juan A / Vandrovcova, Jana / Simon-Sanchez, Javier / Castillo-Lizardo, Melissa / Rizzu, Patrizia / Blauwendraat, Cornelis / Chouhan, Amit K / Li, Yarong / Yogi, Puja / Amin, Najaf / van Duijn, Cornelia M / Anonymous1171027 / Morris, Huw R / Brice, Alexis / Singleton, Andrew B / David, Della C / Nollen, Ellen A / Jain, Shushant / Shulman, Joshua M / Heutink, Peter. ·German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Graduate School of Cellular & Molecular Neuroscience, Tübingen, 72074, Germany. · European Research Institute for the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, 9700AD, The Netherlands. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Northwestern University Feinberg School of Medicine, Ken and Ruth Davee Department of Neurology, Chicago, IL, USA. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Medical & Molecular Genetics, King's College London, London, UK. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Assistance Publique Hôpitaux de Paris, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA. Joshua.Shulman@bcm.edu. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund St., N.1150, Houston, TX, 77030, USA. Joshua.Shulman@bcm.edu. · German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller-Str. 23, Tübingen, 72076, Germany. Peter.Heutink@dzne.de. · Department of Clinical Genetics, VU University Medical Center, Amsterdam, 1081HZ, The Netherlands. Peter.Heutink@dzne.de. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Peter.Heutink@dzne.de. ·Genome Biol · Pubmed #28137300.

ABSTRACT: BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.

6 Article Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. 2017

Giri, Anamika / Mok, Kin Y / Jansen, Iris / Sharma, Manu / Tesson, Christelle / Mangone, Graziella / Lesage, Suzanne / Bras, José M / Shulman, Joshua M / Sheerin, Una-Marie / Anonymous6860886 / Díez-Fairen, Mónica / Pastor, Pau / Martí, María José / Ezquerra, Mario / Tolosa, Eduardo / Correia-Guedes, Leonor / Ferreira, Joaquim / Amin, Najaf / van Duijn, Cornelia M / van Rooij, Jeroen / Uitterlinden, André G / Kraaij, Robert / Nalls, Michael / Simón-Sánchez, Javier. ·Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France. · Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. · Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain. · Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain; Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal. · Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Neurosciences, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing (NCHA), Rotterdam, the Netherlands. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Electronic address: javier.simon-sanchez@dzne.de. ·Neurobiol Aging · Pubmed #27818000.

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

7 Article Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance. 2016

Lubbe, Steven J / Escott-Price, Valentina / Gibbs, J Raphael / Nalls, Mike A / Bras, Jose / Price, T Ryan / Nicolas, Aude / Jansen, Iris E / Mok, Kin Y / Pittman, Alan M / Tomkins, James E / Lewis, Patrick A / Noyce, Alastair J / Lesage, Suzanne / Sharma, Manu / Schiff, Elena R / Levine, Adam P / Brice, Alexis / Gasser, Thomas / Hardy, John / Heutink, Peter / Wood, Nicholas W / Singleton, Andrew B / Williams, Nigel M / Morris, Huw R / Anonymous1450886. ·Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK. · Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. · Department of Clinical Genetics, VU University Medical Center (VUmc), Amsterdam, The Netherlands. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, People's Republic of China. · School of Pharmacy, University of Reading, Whiteknights, Reading, UK. · Centre for Integrated Neuroscience and Neurodynamics, University of Reading, Whiteknights, Reading, UK. · Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK. · Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. · Division of Medicine, University College London, London, UK and 15UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK. ·Hum Mol Genet · Pubmed #27798102.

ABSTRACT: Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.

8 Article Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. 2016

Liu, Ganqiang / Boot, Brendon / Locascio, Joseph J / Jansen, Iris E / Winder-Rhodes, Sophie / Eberly, Shirley / Elbaz, Alexis / Brice, Alexis / Ravina, Bernard / van Hilten, Jacobus J / Cormier-Dequaire, Florence / Corvol, Jean-Christophe / Barker, Roger A / Heutink, Peter / Marinus, Johan / Williams-Gray, Caroline H / Scherzer, Clemens R / Anonymous14660883. ·Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham & Women's Hospital, Cambridge, MA. · Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA. · Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA. · Department of Neurology, Brigham and Women's Hospital, Boston, MA. · Department of Neurology, Massachusetts General Hospital, Boston, MA. · Department of Medical Genomics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, HZ, The Netherlands. · German Center for Neurodegenerative diseases (DZNE), Tübingen, Germany. · John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. · Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY. · INSERM, Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of ageing and age related diseases, Villejuif, France. · University Paris-Sud, UMRS 1018, Villejuif, France. · Sorbonne Université, Université Pierre et Marie Curie Paris 06 UMR S 1127, Institut National de Santé et en Recherche Médicale U 1127 and Centre d'Investigation Clinique 1422, Centre National de Recherche Scientifique U 7225, Institut du Cerveau et de la Moelle Epinière, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France. · Voyager Therapeutics, Clinical Development, Cambridge, MA. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. ·Ann Neurol · Pubmed #27717005.

ABSTRACT: OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.

9 Article EIF4G1 mutations do not cause Parkinson's disease. 2015

Nichols, Noah / Bras, Jose M / Hernandez, Dena G / Jansen, Iris E / Lesage, Suzanne / Lubbe, Steven / Singleton, Andrew B / Anonymous5320831. ·Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Clinical Genetics, VU University Medical Center (VUmc), Amsterdam, the Netherlands; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Sorbonne Universités, UPMC (Paris 6), UMR S 1127, Inserm U 1127, CNRS UMR 7225, and ICM, Paris, France. · Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. Electronic address: singleta@mail.nih.gov. ·Neurobiol Aging · Pubmed #26022768.

ABSTRACT: EIF4G1 mutations were previously reported as a cause of Parkinson's disease (PD). As a result of this finding, considerable work has been performed to test this idea and to examine the functional role of eukaryotic translation initiation factor 4-gamma in the pathogenic process underlying PD. Here, we show that the originally described mutation is likely a rare benign variant. We tested this variant in a very large series of subjects and show that it is more frequent in controls than cases. We argue here that this infers that EIF4G1 mutations are not related to PD.