Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study.

Creutzfeldt-Jakob Syndrome / diagnosis Genetic Loci / genetics Genetic Predisposition to Disease / epidemiology Genome-Wide Association Study / methods Humans Polymorphism, Single Nucleotide / genetics Risk Factors

Journal

The Lancet. Neurology
ISSN: 1474-4465
Titre abrégé: Lancet Neurol
Pays: England
ID NLM: 101139309

Informations de publication

Date de publication:
10 2020
Historique:
received: 13 04 2020
revised: 15 07 2020
accepted: 17 07 2020
pubmed: 20 9 2020
medline: 2 10 2020
entrez: 19 9 2020
Statut: ppublish

Résumé

Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10 We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Sections du résumé

BACKGROUND
Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.
METHODS
We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country.
FINDINGS
Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10
INTERPRETATION
We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.
FUNDING
Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Identifiants

DOI: 10.1016/S1474-4422(20)30273-8 PMID: 32949544 PMC: PMC8220892
pubmed: 32949544
pii: S1474-4422(20)30273-8
doi: 10.1016/S1474-4422(20)30273-8
pmc: PMC8220892
mid: NIHMS1709432
pii:
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

840-848

Subventions

Organisme : Medical Research Council
ID : MC_U123160651
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/9
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG031189
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/2
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG062562
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103848
Pays : United States
Organisme : Medical Research Council
ID : MC_U123160657
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400713
Pays : United Kingdom

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

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Auteurs

Emma Jones (E)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Holger Hummerich (H)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Emmanuelle Viré (E)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

James Uphill (J)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Athanasios Dimitriadis (A)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Helen Speedy (H)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Tracy Campbell (T)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Penny Norsworthy (P)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Liam Quinn (L)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Jerome Whitfield (J)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Jacqueline Linehan (J)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Zane Jaunmuktane (Z)

Division of Neuropathology, University College London Hospitals National Health Service Foundation Trust, London, UK; Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, London, UK.

Sebastian Brandner (S)

Division of Neuropathology, University College London Hospitals National Health Service Foundation Trust, London, UK; Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, UK.

Parmjit Jat (P)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Akin Nihat (A)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK; National Prion Clinic, University College London Hospitals National Health Service Foundation Trust, London, UK.

Tze How Mok (T)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK; National Prion Clinic, University College London Hospitals National Health Service Foundation Trust, London, UK.

Parvin Ahmed (P)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK.

Steven Collins (S)

Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.

Christiane Stehmann (C)

Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.

Shannon Sarros (S)

Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.

Gabor G Kovacs (GG)

Institute of Neurology, Medical University of Vienna, Vienna, Austria; Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.

Michael D Geschwind (MD)

University of California San Francisco Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Aili Golubjatnikov (A)

University of California San Francisco Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Karl Frontzek (K)

Institute of Neuropathology, University of Zurich, Zurich, Switzerland.

Herbert Budka (H)

Institute of Neuropathology, University of Zurich, Zurich, Switzerland; Medical University Vienna, Vienna, Austria.

Adriano Aguzzi (A)

Institute of Neuropathology, University of Zurich, Zurich, Switzerland.

Hata Karamujić-Čomić (H)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands.

Sven J van der Lee (SJ)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands.

Carla A Ibrahim-Verbaas (CA)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands.

Cornelia M van Duijn (CM)

Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Beata Sikorska (B)

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.

Ewa Golanska (E)

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.

Pawel P Liberski (PP)

Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.

Miguel Calero (M)

Chronic Disease Programme (UFIEC-CROSADIS) and Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), and Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Centre, Instituto de Salud Carlos III, Madrid, Spain.

Olga Calero (O)

Chronic Disease Programme (UFIEC-CROSADIS) and Network Centre for Biomedical Research in Neurodegenerative Diseases (CIBERNED), and Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Centre, Instituto de Salud Carlos III, Madrid, Spain.

Pascual Sanchez-Juan (P)

Neurology Service, University Hospital Marqués de Valdecilla, University of Cantabria, CIBERNED and IDIVAL, Santander, Spain.

Antonio Salas (A)

Unidade de Xenética, Instituto de Ciencias Forenses (INCIFOR), Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigaciones Sanitarias (IDIS), Hospital Clínico Universitario de Santiago (SERGAS), Galicia, Spain.

Federico Martinón-Torres (F)

Translational Paediatrics and Infectious Diseases, Department of Paediatrics, Hospital Clínico Universitario de Santiago de Compostela, Galicia, Spain.

Elodie Bouaziz-Amar (E)

Department of Biochemistry and Molecular Biology, Lariboisière Hospital, AP-HP, University of Paris, Paris, France.

Stéphane Haïk (S)

Sorbonne Université, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Cellule nationale de référence des maladies de Creutzfeldt-Jakob, AP-HP, University Hospital Pitié-Salpêtrière, Paris, France.

Jean-Louis Laplanche (JL)

Department of Biochemistry and Molecular Biology, Lariboisière Hospital, AP-HP, University of Paris, Paris, France.

Jean-Phillipe Brandel (JP)

Sorbonne Université, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, Paris, France; Cellule nationale de référence des maladies de Creutzfeldt-Jakob, AP-HP, University Hospital Pitié-Salpêtrière, Paris, France.

Phillipe Amouyel (P)

INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Labex DISTALZ, University of Lille, Lille, France.

Jean-Charles Lambert (JC)

INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Labex DISTALZ, University of Lille, Lille, France.

Piero Parchi (P)

IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy.

Anna Bartoletti-Stella (A)

IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.

Sabina Capellari (S)

IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Anna Poleggi (A)

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.

Anna Ladogana (A)

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.

Maurizio Pocchiari (M)

Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.

Serena Aneli (S)

Department of Medical Sciences, Università degli studi di Torino, Torino, Italy.

Giuseppe Matullo (G)

Department of Medical Sciences, Università degli studi di Torino, Torino, Italy.

Richard Knight (R)

National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Edinburgh, UK.

Saima Zafar (S)

Department of Neurology, Clinical Dementia Centre and National Reference Centre for Creutzfeldt-Jakob Disease Surveillance, University Medical School, Göttingen, Germany; German Centre for Neurodegenerative Diseases (DZNE), Göttingen, Germany; Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, Islamabad, Pakistan.

Inga Zerr (I)

Department of Neurology, Clinical Dementia Centre and National Reference Centre for Creutzfeldt-Jakob Disease Surveillance, University Medical School, Göttingen, Germany; German Centre for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

Stephanie Booth (S)

Prion Disease Program, Public Health Agency of Canada, Winnipeg, MB, Canada.

Michael B Coulthart (MB)

Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, Ottawa, ON, Canada.

Gerard H Jansen (GH)

Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.

Katie Glisic (K)

Departments of Pathology and Neurology, Case Western Reserve University, Cleveland, OH, USA; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

Janis Blevins (J)

Departments of Pathology and Neurology, Case Western Reserve University, Cleveland, OH, USA; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

Pierluigi Gambetti (P)

Departments of Pathology and Neurology, Case Western Reserve University, Cleveland, OH, USA; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

Jiri Safar (J)

Departments of Pathology and Neurology, Case Western Reserve University, Cleveland, OH, USA; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

Brian Appleby (B)

Departments of Pathology and Neurology, Case Western Reserve University, Cleveland, OH, USA; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

John Collinge (J)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK; National Prion Clinic, University College London Hospitals National Health Service Foundation Trust, London, UK.

Simon Mead (S)

Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK; National Prion Clinic, University College London Hospitals National Health Service Foundation Trust, London, UK. Electronic address: s.mead@prion.ucl.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie de Creutzfeldt-Jakob › Identification of novel risk loci and causal...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Identification of novel risk loci and causal...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Identification of novel risk loci and causal...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Identification of novel risk loci and causal...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of novel risk loci and causal...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Identification of novel risk loci and causal...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Identification of novel risk loci and causal...