Emma Jones1, Holger Hummerich1, Emmanuelle Viré1, James Uphill1, Athanasios Dimitriadis1, Helen Speedy1, Tracy Campbell1, Penny Norsworthy1, Liam Quinn1, Jerome Whitfield1, Jacqueline Linehan1, Zane Jaunmuktane2, Sebastian Brandner3, Parmjit Jat1, Akin Nihat4, Tze How Mok4, Parvin Ahmed1, Steven Collins5, Christiane Stehmann5, Shannon Sarros5, Gabor G Kovacs6, Michael D Geschwind7, Aili Golubjatnikov7, Karl Frontzek8, Herbert Budka9, Adriano Aguzzi8, Hata Karamujić-Čomić10, Sven J van der Lee10, Carla A Ibrahim-Verbaas10, Cornelia M van Duijn11, Beata Sikorska12, Ewa Golanska12, Pawel P Liberski12, Miguel Calero13, Olga Calero13, Pascual Sanchez-Juan14, Antonio Salas15, Federico Martinón-Torres16, Elodie Bouaziz-Amar17, Stéphane Haïk18, Jean-Louis Laplanche17, Jean-Phillipe Brandel18, Phillipe Amouyel19, Jean-Charles Lambert19, Piero Parchi20, Anna Bartoletti-Stella21, Sabina Capellari22, Anna Poleggi23, Anna Ladogana23, Maurizio Pocchiari23, Serena Aneli24, Giuseppe Matullo24, Richard Knight25, Saima Zafar26, Inga Zerr27, Stephanie Booth28, Michael B Coulthart29, Gerard H Jansen30, Katie Glisic31, Janis Blevins31, Pierluigi Gambetti31, Jiri Safar31, Brian Appleby31, John Collinge4, Simon Mead32. 1. Medical Research Council Prion Unit, University College London Institute of Prion Diseases, London, UK. 2. 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. 3. 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. 4. 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. 5. Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia. 6. 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. 7. University of California San Francisco Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. 8. Institute of Neuropathology, University of Zurich, Zurich, Switzerland. 9. Institute of Neuropathology, University of Zurich, Zurich, Switzerland; Medical University Vienna, Vienna, Austria. 10. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands. 11. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Nuffield Department of Population Health, University of Oxford, Oxford, UK. 12. Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland. 13. 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. 14. Neurology Service, University Hospital Marqués de Valdecilla, University of Cantabria, CIBERNED and IDIVAL, Santander, Spain. 15. 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. 16. Translational Paediatrics and Infectious Diseases, Department of Paediatrics, Hospital Clínico Universitario de Santiago de Compostela, Galicia, Spain. 17. Department of Biochemistry and Molecular Biology, Lariboisière Hospital, AP-HP, University of Paris, Paris, France. 18. 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. 19. INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, Labex DISTALZ, University of Lille, Lille, France. 20. IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy. 21. IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 22. IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. 23. Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy. 24. Department of Medical Sciences, Università degli studi di Torino, Torino, Italy. 25. National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Edinburgh, UK. 26. 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. 27. 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. 28. Prion Disease Program, Public Health Agency of Canada, Winnipeg, MB, Canada. 29. Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, Ottawa, ON, Canada. 30. Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada. 31. 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. 32. 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.
Abstract
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 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. 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.
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 × 10-15; heterozygous model p=1·01 × 10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. 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.
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