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Parkinson Disease: HELP
Articles by Andrew B. Singleton
Based on 103 articles published since 2010
(Why 103 articles?)
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Between 2010 and 2020, A. B. Singleton wrote the following 103 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Review Genetics of Parkinson's disease: An introspection of its journey towards precision medicine. 2020

Bandres-Ciga, Sara / Diez-Fairen, Monica / Kim, Jonggeol Jeff / Singleton, Andrew B. ·Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada 18016, Spain. Electronic address: sara.bandresciga@nih.gov. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA; Fundació Docència i Recerca Mútua Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua Terrassa, Terrassa 08221, Barcelona, Spain. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: singleta@mail.nih.gov. ·Neurobiol Dis · Pubmed #31991247.

ABSTRACT: A substantial proportion of risk for Parkinson's disease (PD) is driven by genetics. Progress in understanding the genetic basis of PD has been significant. So far, highly-penetrant rare genetic alterations in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1 and GBA have been linked with typical familial PD and common genetic variability at 90 loci have been linked to risk for PD. In this review, we outline the journey thus far of PD genetics, highlighting how significant advances have improved our knowledge of the genetic basis of PD risk, onset and progression. Despite remarkable progress, our field has yet to unravel how genetic risk variants disrupt biological pathways and molecular networks underlying the pathobiology of the disease. We highlight that currently identified genetic risk factors only represent a fraction of the likely genetic risk for PD. Identifying the remaining genetic risk will require us to diversify our efforts, performing genetic studies across different ancestral groups. This work will inform us on the varied genetic basis of disease across populations and also aid in fine mapping discovered loci. If we are able to take this course, we foresee that genetic discoveries in PD will directly influence our ability to predict disease and aid in defining etiological subtypes, critical steps for the implementation of precision medicine for PD.

2 Review Finding useful biomarkers for Parkinson's disease. 2018

Chen-Plotkin, Alice S / Albin, Roger / Alcalay, Roy / Babcock, Debra / Bajaj, Vikram / Bowman, Dubois / Buko, Alex / Cedarbaum, Jesse / Chelsky, Daniel / Cookson, Mark R / Dawson, Ted M / Dewey, Richard / Foroud, Tatiana / Frasier, Mark / German, Dwight / Gwinn, Katrina / Huang, Xuemei / Kopil, Catherine / Kremer, Thomas / Lasch, Shirley / Marek, Ken / Marto, Jarrod A / Merchant, Kalpana / Mollenhauer, Brit / Naito, Anna / Potashkin, Judith / Reimer, Alyssa / Rosenthal, Liana S / Saunders-Pullman, Rachel / Scherzer, Clemens R / Sherer, Todd / Singleton, Andrew / Sutherland, Margaret / Thiele, Ines / van der Brug, Marcel / Van Keuren-Jensen, Kendall / Vaillancourt, David / Walt, David / West, Andrew / Zhang, Jing. ·Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. chenplot@pennmedicine.upenn.edu. · Neurology Service and GRECC, VAAHS, Ann Arbor, MI 48105, USA. · Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20824, USA. · Verily/Google Life Sciences, South San Francisco, CA 94080, USA. · Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. · Human Metabolome Technology-America, Boston, MA 02134, USA. · Biogen, Cambridge, MA 02142, USA. · Caprion Biosciences, Montreal, Quebec H2X 3Y7, Canada. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10163, USA. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Neurology, Penn State University-Hershey Medical Center, Hershey, PA 17033, USA. · Pharmaceutical Research and Early Development, NORD Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. · Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA. · Departments of Cancer Biology and Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. · Chaperone Therapeutics, Portland, OR 97229, USA. · Paracelsus-Elena-Klinik, 34128 Kassel, Germany. · University Medical Center, 37075 Goettingen, Germany. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL 60064, USA. · Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY 10003, USA. · Center for Advanced Parkinson's Disease Research and Precision Neurology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. · Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg. · Genentech, San Francisco, CA 94080, USA. · Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. · Department of Applied Physiology, Biomedical Engineering, and Neurology, University of Florida, Gainesville, FL 32611, USA. · Department of Neurology, University of Alabama, Birmingham, AL 35233, USA. · Department of Pathology, University of Washington, Seattle, WA 98195, USA. ·Sci Transl Med · Pubmed #30111645.

ABSTRACT: The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

3 Review Genetic risk factors in Parkinson's disease. 2018

Billingsley, K J / Bandres-Ciga, S / Saez-Atienzar, S / Singleton, A B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD, 20892, USA. · Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, L69 3BX, Liverpool, UK. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD, 20892, USA. singleta@mail.nih.gov. ·Cell Tissue Res · Pubmed #29536161.

ABSTRACT: Over the last two decades, we have witnessed a revolution in the field of Parkinson's disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.

4 Review Make dopamine neurons great again: An exciting new therapeutic option in parkinson's disease. 2017

Bonet-Ponce, Luis / Singleton, Andrew B. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland, USA. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland, USA. ·Mov Disord · Pubmed #28631854.

ABSTRACT: -- No abstract --

5 Review The Birth of the Modern Era of Parkinson's Disease Genetics. 2017

Singleton, Andrew B / Hardy, John A / Gasser, Thomas. ·Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. ·J Parkinsons Dis · Pubmed #28282818.

ABSTRACT: -- No abstract --

6 Review The Evolution of Genetics: Alzheimer's and Parkinson's Diseases. 2016

Singleton, Andrew / Hardy, John. ·Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. Electronic address: singleta@mail.nih.gov. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. ·Neuron · Pubmed #27311081.

ABSTRACT: Genetic discoveries underlie the majority of the current thinking in neurodegenerative disease. This work has been driven by the significant gains made in identifying causal mutations; however, the translation of genetic causes of disease into pathobiological understanding remains a challenge. The application of a second generation of genetics methods allows the dissection of moderate and mild genetic risk factors for disease. This requires new thinking in two key areas: what constitutes proof of pathogenicity, and how do we translate these findings to biological understanding. Here we describe the progress and ongoing evolution in genetics. We describe a view that rejects the tradition that genetic proof has to be absolute before functional characterization and centers on a multi-dimensional approach integrating genetics, reference data, and functional work. We also argue that these challenges cannot be efficiently met by traditional hypothesis-driven methods but that high content system-wide efforts are required.

7 Review Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. 2016

Hernandez, Dena G / Reed, Xylena / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. · German Center for Neurodegenerative Diseases (DZNE)-Tübingen, Tübingen, Germany. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. singleta@mail.nih.gov. ·J Neurochem · Pubmed #27090875.

ABSTRACT: Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

8 Review Targeting α-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. 2015

Dehay, Benjamin / Bourdenx, Mathieu / Gorry, Philippe / Przedborski, Serge / Vila, Miquel / Hunot, Stephane / Singleton, Andrew / Olanow, C Warren / Merchant, Kalpana M / Bezard, Erwan / Petsko, Gregory A / Meissner, Wassilios G. ·Institute of Neurodegenerative Diseases, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France. · Research Unit of Theoretical & Applied Economics, University of Bordeaux, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5113, 33608 Pessac, France. · Departments of Neurology, Pathology and Cell Biology, and the Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, 08035 Barcelona, Spain. · Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08193 Bellaterra, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain. · ICM, Paris, France; Sorbonne Universités. · UPMC Université Paris 06, UM 75, ICM, Paris, France. · CNRS, UMR 7225, ICM, Paris, France. · Inserm, U 1127, ICM, Paris, France. · Molecular Genetics Section and Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD20892, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10032, USA. · TransThera Consulting Co., Zionsville, IN, 46077, USA. · Department of Neurology and Feil Family Brain and Mind research Institute, Weill Cornell Medical College, New York NY 10021, USA. ·Lancet Neurol · Pubmed #26050140.

ABSTRACT: Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes α-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of α-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of α-synuclein toxicity. We critically assess the potential of experimental therapies targeting α-synuclein, and discuss steps that need to be taken for target validation and drug development.

9 Review Multiple system atrophy: the application of genetics in understanding etiology. 2015

Federoff, Monica / Schottlaender, Lucia V / Houlden, Henry / Singleton, Andrew. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. ·Clin Auton Res · Pubmed #25687905.

ABSTRACT: Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism, and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA's clinical presentation exhibits several overlapping features with other members including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome-wide association study is underway for MSA to further clarify the role of associated genetic loci and single-nucleotide polymorphisms, several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic-based therapies.

10 Review LRRK2: cause, risk, and mechanism. 2013

Paisán-Ruiz, Coro / Lewis, Patrick A / Singleton, Andrew B. ·Department of Neurology, Psychiatry, and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, NY, USA. ·J Parkinsons Dis · Pubmed #23938341.

ABSTRACT: In 2004 it was first shown that mutations in LRRK2 can cause Parkinson's disease. This initial discovery was quickly followed by the observation that a single particular mutation is a relatively common cause of Parkinson's disease across varied populations. Further genetic investigation has revealed a variety of genetic ties to Parkinson's disease across this gene. These include common alleles with quite broad effects on risk, likely through both alterations at the protein sequence level, and in the context of expression. A great deal of functional characterization of LRRK2 and disease-causing mutations in this protein has occurred over the last 9 years, and considerable progress has been made. Particular attention has been paid to the kinase activity of LRRK2 as a therapeutic target, and while it is no means certain that this is viable target it is likely that this hypothesis will be tested in clinical trials sooner rather than later. We believe that the future goals for LRRK2 research are, while challenging, relatively clear and that the next 10 years of research promises to be perhaps more exciting than the last.

11 Review The genetics of Parkinson's disease: progress and therapeutic implications. 2013

Singleton, Andrew B / Farrer, Matthew J / Bonifati, Vincenzo. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. singleta@mail.nih.gov ·Mov Disord · Pubmed #23389780.

ABSTRACT: The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson's disease (PD). Notably, whereas most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2 has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date, approximately 16 such loci exist; notably, some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise, second-generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease, and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics, notably by the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting, productive time for PD genetics and, furthermore, that genetics will continue to drive the etiologic understanding and etiology-based therapeutic approaches in this disease.

12 Review The genetics and neuropathology of Parkinson's disease. 2012

Houlden, Henry / Singleton, Andrew B. ·Molecular Neuroscience Department, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, Queen Square, London, UK. ·Acta Neuropathol · Pubmed #22806825.

ABSTRACT: There has been tremendous progress toward understanding the genetic basis of Parkinson's disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA, LRRK2, ATXN2, ATXN3, MAPT, GCH1, DCTN1 and VPS35. We then discuss the identification of mutations in PARK2, PARK7, PINK1, ATP13A2, FBXO7, PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

13 Review Parkinson's disease and α-synuclein expression. 2011

Devine, Michael J / Gwinn, Katrina / Singleton, Andrew / Hardy, John. ·Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. m.devine@ion.ucl.ac.uk ·Mov Disord · Pubmed #21887711.

ABSTRACT: Genetic studies of Parkinson's disease over the last decade or more have revolutionized our understanding of this condition. α-Synuclein was the first gene to be linked to Parkinson's disease, and is arguably the most important: the protein is the principal constituent of Lewy bodies, and variation at its locus is the major genetic risk factor for sporadic disease. Intriguingly, duplications and triplications of the locus, as well as point mutations, cause familial disease. Therefore, subtle alterations of α-synuclein expression can manifest with a dramatic phenotype. We outline the clinical impact of α-synuclein locus multiplications, and the implications that this has for Parkinson's disease pathogenesis. Finally, we discuss potential strategies for disease-modifying therapies for this currently incurable disorder.

14 Review Exome sequencing in Parkinson's disease. 2011

Bras, Jose M / Singleton, A B. ·Department of Molecular Neuroscience, Institute of Neurology, University College of London, London, UK. j.bras@ion.ucl.ac.uk ·Clin Genet · Pubmed #21651510.

ABSTRACT: Exome sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review, we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson's disease, but also what are the known caveats of this approach.

15 Article Comprehensive assessment of PINK1 variants in Parkinson's disease. 2020

Krohn, Lynne / Grenn, Francis P / Makarious, Mary B / Kim, Jonggeol Jeffrey / Bandres-Ciga, Sara / Roosen, Dorien A / Gan-Or, Ziv / Nalls, Mike A / Singleton, Andrew B / Blauwendraat, Cornelis / Anonymous7001201. ·Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: cornelis.blauwendraat@nih.gov. ·Neurobiol Aging · Pubmed #32249012.

ABSTRACT: Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early-onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here, we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large data sets totalling 376,558 individuals including 13,708 cases with Parkinson's disease and 362,850 control subjects. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a robust risk factor for Parkinson's disease.

16 Article Clinical and Dopamine Transporter Imaging Characteristics of Leucine Rich Repeat Kinase 2 (LRRK2) and Glucosylceramidase Beta (GBA) Parkinson's Disease Participants in the Parkinson's Progression Markers Initiative: A Cross-Sectional Study. 2020

Simuni, Tanya / Brumm, Michael C / Uribe, Liz / Caspell-Garcia, Chelsea / Coffey, Christopher S / Siderowf, Andrew / Alcalay, Roy N / Trojanowski, John Q / Shaw, Leslie M / Seibyl, John / Singleton, Andrew / Toga, Arthur W / Galasko, Doug / Foroud, Tatiana / Nudelman, Kelly / Tosun-Turgut, Duygu / Poston, Kathleen / Weintraub, Daniel / Mollenhauer, Brit / Tanner, Caroline M / Kieburtz, Karl / Chahine, Lana M / Reimer, Alyssa / Hutten, Samantha / Bressman, Susan / Marek, Kenneth / Anonymous6481201. ·Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · Departments of Neurology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Neurology, The Taub Institite for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA. · Departments of Pathology and Laboratory Medicine Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, Maryland, USA. · Laboratory of Neuroimaging (LONI), University of Southern California, Los Angeles, California, USA. · Department of Neurology, University of California, San Diego, California, USA. · Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA. · Department of Neurology, University of California San Francisco, San Francisco, California, USA. · Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA. · Departments of Psychiatry and Neurology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Neurology, University Medical Center Goettingen, Goettingen, Germany and Paracelsus-Elena-Klinik, Kassel, Germany. · Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Icahn School of Medicine, Mount Sinai, New York, New York, USA. ·Mov Disord · Pubmed #32073681.

ABSTRACT: BACKGROUND: There are limited data on the phenotypic and dopamine transporter (DAT) imaging characterization of the Parkinson's disease (PD) patients with leucine rich kinase 2 (LRRK2) and glucosylceramidase beta (GBA) mutations. OBJECTIVE: The objective of this study was to examine baseline clinical and DAT imaging characteristics in GBA and LRRK2 mutation carriers with early PD compared with sporadic PD. METHODS: The Parkinson's Progression Markers Initiative is an ongoing observational longitudinal study that enrolled participants with sporadic PD, LRRK2 and GBA PD carriers from 33 sites worldwide. All participants are assessed annually with a battery of motor and nonmotor scales, 123-I Ioflupane DAT imaging, and biologic variables. RESULTS: We assessed 158 LRRK2 (89% G2019S), 80 GBA (89 %N370S), and 361 sporadic PD participants with the mean (standard deviation) disease duration of 2.9 (1.9), 3.1 (2.0), and 2.6 (0.6) years, respectively. When compared with sporadic PD, the GBA PD patients had no difference in any motor, cognitive, or autonomic features. The LRRK2 PD patients had less motor disability and lower rapid eye movement behavior disorder questionnaire scores, but no meaningful difference in cognitive or autonomic features. Both genetic cohorts had a higher score on the impulse control disorders scale when compared with sporadic PD, but no difference in other psychiatric features. Both genetic PD cohorts had less loss of dopamine transporter on DAT imaging when compared with sporadic PD. CONCLUSIONS: We confirm previous reports of milder phenotype associated with LRRK2-PD. A previously reported more aggressive phenotype in GBA-PD is not evident early in the disease in N370s carriers. This observation identifies a window for potential disease-modifying interventions. Longitudinal data will be essential to define the slope of progression for both genetic cohorts. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01141023). © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

17 Article Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score. 2020

Iwaki, Hirotaka / Blauwendraat, Cornelis / Makarious, Mary B / Bandrés-Ciga, Sara / Leonard, Hampton L / Gibbs, J Raphael / Hernandez, Dena G / Scholz, Sonja W / Faghri, Faraz / Anonymous6161201 / Nalls, Mike A / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #31958187.

ABSTRACT: BACKGROUND: Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. OBJECTIVES: To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers. METHODS: We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS. RESULTS: After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008). CONCLUSIONS: Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society.

18 Article Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. 2020

Blauwendraat, Cornelis / Reed, Xylena / Krohn, Lynne / Heilbron, Karl / Bandres-Ciga, Sara / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Kumaran, Ravindran / Langston, Rebekah / Bonet-Ponce, Luis / Alcalay, Roy N / Hassin-Baer, Sharon / Greenbaum, Lior / Iwaki, Hirotaka / Leonard, Hampton L / Grenn, Francis P / Ruskey, Jennifer A / Sabir, Marya / Ahmed, Sarah / Makarious, Mary B / Pihlstrøm, Lasse / Toft, Mathias / van Hilten, Jacobus J / Marinus, Johan / Schulte, Claudia / Brockmann, Kathrin / Sharma, Manu / Siitonen, Ari / Majamaa, Kari / Eerola-Rautio, Johanna / Tienari, Pentti J / Anonymous2491178 / Pantelyat, Alexander / Hillis, Argye E / Dawson, Ted M / Rosenthal, Liana S / Albert, Marilyn S / Resnick, Susan M / Ferrucci, Luigi / Morris, Christopher M / Pletnikova, Olga / Troncoso, Juan / Grosset, Donald / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / Noyce, Alastair J / Masliah, Eliezer / Wood, Nick / Hardy, John / Shulman, Lisa M / Jankovic, Joseph / Shulman, Joshua M / Heutink, Peter / Gasser, Thomas / Cannon, Paul / Scholz, Sonja W / Morris, Huw / Cookson, Mark R / Nalls, Mike A / Gan-Or, Ziv / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · 23andMe, Inc., Mountain View, CA, USA. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel. · Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel. · The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel. · The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Neuroregeneration and Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. · Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA. · Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Pathology (Neuropathology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of Neurology, Baylor College of Medicine, Houston, USA. · Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, USA. · Data Tecnica International, Glen Echo, MD, USA. · Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. ·Brain · Pubmed #31755958.

ABSTRACT: Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

19 Article The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. 2019

Bandres-Ciga, Sara / Ahmed, Sarah / Sabir, Marya S / Blauwendraat, Cornelis / Adarmes-Gómez, Astrid D / Bernal-Bernal, Inmaculada / Bonilla-Toribio, Marta / Buiza-Rueda, Dolores / Carrillo, Fátima / Carrión-Claro, Mario / Gómez-Garre, Pilar / Jesús, Silvia / Labrador-Espinosa, Miguel A / Macias, Daniel / Méndez-Del-Barrio, Carlota / Periñán-Tocino, Teresa / Tejera-Parrado, Cristina / Vargas-González, Laura / Diez-Fairen, Monica / Alvarez, Ignacio / Tartari, Juan Pablo / Buongiorno, Mariateresa / Aguilar, Miquel / Gorostidi, Ana / Bergareche, Jesús Alberto / Mondragon, Elisabet / Vinagre-Aragon, Ana / Croitoru, Ioana / Ruiz-Martínez, Javier / Dols-Icardo, Oriol / Kulisevsky, Jaime / Marín-Lahoz, Juan / Pagonabarraga, Javier / Pascual-Sedano, Berta / Ezquerra, Mario / Cámara, Ana / Compta, Yaroslau / Fernández, Manel / Fernández-Santiago, Rubén / Muñoz, Esteban / Tolosa, Eduard / Valldeoriola, Francesc / Gonzalez-Aramburu, Isabel / Sanchez Rodriguez, Antonio / Sierra, María / Menéndez-González, Manuel / Blazquez, Marta / Garcia, Ciara / Suarez-San Martin, Esther / García-Ruiz, Pedro / Martínez-Castrillo, Juan Carlos / Vela-Desojo, Lydia / Ruz, Clara / Barrero, Francisco Javier / Escamilla-Sevilla, Francisco / Mínguez-Castellanos, Adolfo / Cerdan, Debora / Tabernero, Cesar / Gomez Heredia, Maria Jose / Perez Errazquin, Francisco / Romero-Acebal, Manolo / Feliz, Cici / Lopez-Sendon, Jose Luis / Mata, Marina / Martínez Torres, Irene / Kim, Jonggeol Jeffrey / Dalgard, Clifton L / Anonymous1451065 / Brooks, Janet / Saez-Atienzar, Sara / Gibbs, J Raphael / Jorda, Rafael / Botia, Juan A / Bonet-Ponce, Luis / Morrison, Karen E / Clarke, Carl / Tan, Manuela / Morris, Huw / Edsall, Connor / Hernandez, Dena / Simon-Sanchez, Javier / Nalls, Mike A / Scholz, Sonja W / Jimenez-Escrig, Adriano / Duarte, Jacinto / Vives, Francisco / Duran, Raquel / Hoenicka, Janet / Alvarez, Victoria / Infante, Jon / Marti, Maria José / Clarimón, Jordi / López de Munain, Adolfo / Pastor, Pau / Mir, Pablo / Singleton, Andrew / Anonymous1461065. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Seville, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. · Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain. · Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastián, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Plataforma de Genomica, Instituto de Investigacion Biodonostia, San Sebastián, Spain. · Unidad de Trastornos de Movimiento, Departamento de Neurologia, Hospital Universitario de Donostia, San Sebastián, Spain. · Genetics of Neurodegenerative Disorders Unit, IIB Sant Pau, and Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Lab. of Parkinson disease and Other Neurodegenerative Movement Disorders, IDIBAPS-Institut d'Investigacions Biomèdiques, Barcelona, Catalonia, Spain. · Unitat de Parkinson i Trastorns del Moviment. Servicio de Neurologia, Hospital Clínic de Barcelona and Institut de Neurociencies de la Universitat de Barcelona (Maria de Maetzu Center), Catalonia, Spain. · Servicio de Neurología, Hospital Universitario Marqués de Valdecilla (IDIVAL) and Universidad de Cantabria, Santander, Spain. · Servicio de Neurología, Hospital Universitario Central de Asturias, Asturias, Spain. · Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. · Departamento de Neurologia, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Servicio de Neurologia, Hospital Universitario Fundación Alcorcón, Madrid, Spain. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Servicio de Neurología, Hospital Universitario San Cecilio, Granada, Universidad de Granada, Spain. · Servicio de Neurología, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Servicio de Neurología, Hospital General de Segovia, Segovia, Spain. · Servicio de Neurología, Hospital Universitario Virgen de la Victoria, Malaga, Spain. · Departamento de Neurologia, Hospital Universitario Infanta Sofía, Madrid, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain. · Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. · Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom. · Department of Neurology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. · University of Birmingham, Birmingham, United Kingdom. · Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. · Department of Clinical Neuroscience, University College London, London, United Kingdom. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · Data Tecnica International, Glen Echo, Maryland, USA. · Department of Neurology, Johns Hopkins Medical Center, Baltimore, Maryland, USA. · Laboratorio de Neurogenética y Medicina Molecular, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. · Laboratorio de Genética, Hospital Universitario Central de Asturias, Asturias, Spain. · Departamento de Neurociencias. UPV-EHU, Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Spain. ·Mov Disord · Pubmed #31660654.

ABSTRACT: BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

20 Article The Parkinson's Disease Mendelian Randomization Research Portal. 2019

Noyce, Alastair J / Bandres-Ciga, Sara / Kim, Jonggeol / Heilbron, Karl / Kia, Demis / Hemani, Gibran / Xue, Angli / Lawlor, Debbie A / Smith, George Davey / Duran, Raquel / Gan-Or, Ziv / Blauwendraat, Cornelis / Gibbs, J Raphael / Anonymous7311119 / Hinds, David A / Yang, Jian / Visscher, Peter / Cuzick, Jack / Morris, Huw / Hardy, John / Wood, Nicholas W / Nalls, Mike A / Singleton, Andrew B. ·Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, University College London, Institute of Neurology, London, United Kingdom. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · 23andMe, Inc., Mountain View, California, USA. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. · Population Health Science, Bristol Medical School, University of Bristol, Bristol, United Kingdom. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Institute for Advanced Research, Wenzhou Medical University, Wenzhou, Zhejiang, China. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #31659794.

ABSTRACT: BACKGROUND: Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

21 Article Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts. 2019

Iwaki, Hirotaka / Blauwendraat, Cornelis / Leonard, Hampton L / Kim, Jonggeol J / Liu, Ganqiang / Maple-Grødem, Jodi / Corvol, Jean-Christophe / Pihlstrøm, Lasse / van Nimwegen, Marlies / Hutten, Samantha J / Nguyen, Khanh-Dung H / Rick, Jacqueline / Eberly, Shirley / Faghri, Faraz / Auinger, Peggy / Scott, Kirsten M / Wijeyekoon, Ruwani / Van Deerlin, Vivianna M / Hernandez, Dena G / Gibbs, J Raphael / Anonymous20211124 / Chitrala, Kumaraswamy Naidu / Day-Williams, Aaron G / Brice, Alexis / Alves, Guido / Noyce, Alastair J / Tysnes, Ole-Bjørn / Evans, Jonathan R / Breen, David P / Estrada, Karol / Wegel, Claire E / Danjou, Fabrice / Simon, David K / Andreassen, Ole / Ravina, Bernard / Toft, Mathias / Heutink, Peter / Bloem, Bastiaan R / Weintraub, Daniel / Barker, Roger A / Williams-Gray, Caroline H / van de Warrenburg, Bart P / Van Hilten, Jacobus J / Scherzer, Clemens R / Singleton, Andrew B / Nalls, Mike A. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Data Tecnica International, Glen Echo, Maryland, USA. · School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. · Advanced Center for Parkinson's Disease Research, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Precision Neurology Program, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA. · The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway. · Department of Chemistry, Bioscience and Environmental Engineering, University in Stavanger, Stavanger, Norway. · Assistance-Publique Hôpitaux de Paris, ICM, INSERM UMRS 1127, CNRS 7225, ICM, Department of Neurology and CIC Neurosciences, Pitié-Salpêtrière Hospital, Paris, France. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour; Department of Neurology, Nijmegen, The Netherlands. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Translational Genome Sciences, Biogen, Cambridge, Massachusetts, USA. · Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA. · Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, Illinois, USA. · Department of Neurology, Center for Health + Technology, University of Rochester, Rochester, New York, USA. · Department of Clinical Neurosciences, University of Cambridge, John van Geest Centre for Brain Repair, Cambridge, United Kingdom. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Parelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. · Flagship Labs 60 Inc, Cambridge, Massachusetts, USA. · Statistical Genetics, Biogen, Cambridge, Massachusetts, USA. · Institut du cerveau et de la moelle épinière ICM, Paris, France. · Sorbonne Université SU, Paris, France. · INSERM UMR1127, Paris, France. · Department of Neurology, Stavanger University Hospital, Stavanger, Norway. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, United Kingdom. · Department of Neurology, Haukeland University Hospital, Bergen, Norway. · University of Bergen, Bergen, Norway. · Department of Neurology, Nottingham University NHS Trust, Nottingham, United Kingdom. · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland. · Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, Scotland. · Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland. · Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA. · Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway, Norway. · Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway, Norway. · Voyager Therapeutics, Cambridge, Massachusetts, USA. · Department of Neurology, University of Rochester School of Medicine, Rochester, New York, USA. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · German Center for Neurodegenerative Diseases-Tubingen, Tuebingen, Germany. · HIH Tuebingen, Tubingen, Tuebingen, Germany. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · Department of Veterans Affairs, Philadelphia, Pennsylvania, USA. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. ·Mov Disord · Pubmed #31505070.

ABSTRACT: BACKGROUND: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

22 Article Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease. 2019

Mollenhauer, Brit / Caspell-Garcia, Chelsea J / Coffey, Christopher S / Taylor, Peggy / Singleton, Andy / Shaw, Leslie M / Trojanowski, John Q / Frasier, Mark / Simuni, Tanya / Iranzo, Alex / Oertel, Wolfgang / Siderowf, Andrew / Weintraub, Daniel / Seibyl, John / Toga, Arthur W / Tanner, Caroline M / Kieburtz, Karl / Chahine, Lana M / Marek, Kenneth / Galasko, Douglas / Anonymous7711143. ·Department of Neurology, University Medical Center Goettingen, Göttingen, Germany; and Paracelsus-Elena Klinik, Kassel, Germany. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · BioLegend Inc., San Diego, California, USA. · Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Parkinson's Disease and Movement Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. · Neurological Service, Hospital Clinic de Barcelona, Barcelona, Spain. · Department of Neurology, Philipps University Marburg, Marburg, Germany. · Department of Neurology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · University of Southern California, Laboratory of Neuro Imaging, Los Angeles, California, USA. · Department of Neurology, University of California San Francisco, San Francisco, California, USA. · Clinical Trials Coordination Center, University of Rochester Medical Center, Rochester, New York, USA. · Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Department of Neurosciences, University of California, San Diego, San Diego, California, USA. ·Mov Disord · Pubmed #31361367.

ABSTRACT: BACKGROUND: Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression. OBJECTIVES: To analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative. METHODS: Over up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed. RESULTS: The inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. CONCLUSIONS: CSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.

23 Article Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. 2019

Jinn, Sarah / Blauwendraat, Cornelis / Toolan, Dawn / Gretzula, Cheryl A / Drolet, Robert E / Smith, Sean / Nalls, Mike A / Marcus, Jacob / Singleton, Andrew B / Stone, David J. ·Merck & Co., Inc., West Point, PA 19486, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Data Tecnica International, Glen Echo, MD, USA. ·Hum Mol Genet · Pubmed #31261387.

ABSTRACT: Multiple genome-wide association studies (GWAS) in Parkinson disease (PD) have identified a signal at chromosome 4p16.3; however, the causal variant has not been established for this locus. Deep investigation of the region resulted in one identified variant, the rs34311866 missense SNP (p.M393T) in TMEM175, which is 20 orders of magnitude more significant than any other SNP in the region. Because TMEM175 is a lysosomal gene that has been shown to influence α-synuclein phosphorylation and autophagy, the p.M393T variant is an attractive candidate, and we have examined its effect on TMEM175 protein and PD-related biology. After knocking down each of the genes located under the GWAS peak via multiple shRNAs, only TMEM175 was found to consistently influence accumulation of phosphorylated α-synuclein (p-α-syn). Examination of the p.M393T variant showed effects on TMEM175 function that were intermediate between the wild-type (WT) and knockout phenotypes, with reduced regulation of lysosomal pH in response to starvation and minor changes in clearance of autophagy substrates, reduced lysosomal localization, and increased accumulation of p-α-syn. Finally, overexpression of WT TMEM175 protein reduced p-α-syn, while overexpression of the p.M393T variant resulted in no change in α-synuclein phosphorylation. These results suggest that the main signal in the chromosome 4p16.3 PD risk locus is driven by the TMEM175 p.M393T variant. Modulation of TMEM175 may impact α-synuclein biology and therefore may be a rational therapeutic strategy for PD.

24 Article SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. 2019

Fernández-Santiago, Rubén / Martín-Flores, Núria / Antonelli, Francesca / Cerquera, Catalina / Moreno, Verónica / Bandres-Ciga, Sara / Manduchi, Elisabetta / Tolosa, Eduard / Singleton, Andrew B / Moore, Jason H / Anonymous3481045 / Martí, María-Josep / Ezquerra, Mario / Malagelada, Cristina. ·Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain. · Neurology Service, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain. · Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. · Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Barcelona, Catalonia, Spain. · Institute of Neurosciences, University of Barcelona, Barcelona, Catalonia, Spain. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain. · The Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Mov Disord · Pubmed #31234232.

ABSTRACT: BACKGROUND: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. OBJECTIVES: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. METHODS: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. RESULTS: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. CONCLUSIONS: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.

25 Article Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. 2019

Blauwendraat, Cornelis / Heilbron, Karl / Vallerga, Costanza L / Bandres-Ciga, Sara / von Coelln, Rainer / Pihlstrøm, Lasse / Simón-Sánchez, Javier / Schulte, Claudia / Sharma, Manu / Krohn, Lynne / Siitonen, Ari / Iwaki, Hirotaka / Leonard, Hampton / Noyce, Alastair J / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Scholz, Sonja W / Jankovic, Joseph / Shulman, Lisa M / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / van Hilten, Jacobus J / Marinus, Johan / Anonymous861129 / Eerola-Rautio, Johanna / Tienari, Pentti / Majamaa, Kari / Toft, Mathias / Grosset, Donald G / Gasser, Thomas / Heutink, Peter / Shulman, Joshua M / Wood, Nicolas / Hardy, John / Morris, Huw R / Hinds, David A / Gratten, Jacob / Visscher, Peter M / Gan-Or, Ziv / Nalls, Mike A / Singleton, Andrew B / Anonymous871129. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · 23andMe, Inc., Mountain View, California, USA. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · The Michael J Fox Foundation for Parkinson's Research, New York, New York, USA. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. · Departments of Molecular & Human Genetics and Neuroscience, Baylor College of Medicine, Houston, Texas, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. · Mater Research, Translational Research Institute, Brisbane, Queensland, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Australia. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #30957308.

ABSTRACT: BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

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