. 2024 Jul 26;19(7):e0304528.

doi: 10.1371/journal.pone.0304528. eCollection 2024.

Genome wide association study of clinical duration and age at onset of sporadic CJD

Holger Hummerich¹, Helen Speedy¹, Tracy Campbell¹, Lee Darwent¹, Elizabeth Hill¹, Steven Collins², Christiane Stehmann², Gabor G Kovacs^{3

4

5}, Michael D Geschwind⁶, Karl Frontzek⁷, Herbert Budka⁵, Ellen Gelpi⁵, Adriano Aguzzi⁷, Sven J van der Lee^{8

9

10}, Cornelia M van Duijn^{11

12}, Pawel P Liberski¹³, Miguel Calero¹⁴, Pascual Sanchez-Juan¹⁵, Elodie Bouaziz-Amar¹⁶, Jean-Louis Laplanche¹⁶, Stéphane Haïk^{17

18}, Jean-Phillipe Brandel^{17

18}, Angela Mammana¹⁹, Sabina Capellari^{19

20}, Anna Poleggi²¹, Anna Ladogana²¹, Maurizio Pocchiari²¹, Saima Zafar^{22

23}, Stephanie Booth²⁴, Gerard H Jansen²⁵, Aušrinė Areškevičiūtė²⁶, Eva Løbner Lund^{26

27}, Katie Glisic²⁸, Piero Parchi^{19

20}, Peter Hermann^{22

29}, Inga Zerr^{22

29}, Brian S Appleby²⁸, Jiri Safar³⁰, Pierluigi Gambetti³⁰, John Collinge¹, Simon Mead¹

Affiliations

¹ MRC Prion Unit at University College London (UCL), Institute of Prion Diseases, UCL, London, United Kingdom.
² Australian National Creutzfeldt-Jakob Disease Registry, The Florey, Department of Medicine (RMH), The University of Melbourne, Victoria, Australia.
³ Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Ontario, Toronto, Canada.
⁴ Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁵ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna and Austrian Reference Center for Human Prion Diseases (ÖRPE), Vienna, Austria.
⁶ UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, United States of America.
⁷ Institute of Neuropathology, University of Zürich, Zürich, Switzerland.
⁸ Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
⁹ Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
¹⁰ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
¹¹ Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
¹² Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
¹³ Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
¹⁴ Chronic Disease Programme (UFIEC-CROSADIS) and Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁵ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Research Platforms, Madrid, Spain.
¹⁶ Department of Biochemistry and Molecular Biology, Lariboisière Hospital, GHU AP-HP Nord, University of Paris Cité, Paris, France.
¹⁷ Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.
¹⁸ Assistance Publique-Hôpitaux de Paris (AP-HP), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
¹⁹ IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁰ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
²¹ Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
²² Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.
²³ Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, Islamabad, Pakistan.
²⁴ Prion Disease Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
²⁵ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.
²⁶ Danish Reference Center for Prion Diseases, Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
²⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁸ National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, United States of America.
²⁹ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
³⁰ Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America.

PMID: 39079175
PMCID: PMC11280162
DOI: 10.1371/journal.pone.0304528

Genome wide association study of clinical duration and age at onset of sporadic CJD

Holger Hummerich et al. PLoS One. 2024.

. 2024 Jul 26;19(7):e0304528.

doi: 10.1371/journal.pone.0304528. eCollection 2024.

Authors

Affiliations

¹ MRC Prion Unit at University College London (UCL), Institute of Prion Diseases, UCL, London, United Kingdom.
² Australian National Creutzfeldt-Jakob Disease Registry, The Florey, Department of Medicine (RMH), The University of Melbourne, Victoria, Australia.
³ Department of Laboratory Medicine and Pathobiology and Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Ontario, Toronto, Canada.
⁴ Laboratory Medicine Program & Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada.
⁵ Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna and Austrian Reference Center for Human Prion Diseases (ÖRPE), Vienna, Austria.
⁶ UCSF Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, United States of America.
⁷ Institute of Neuropathology, University of Zürich, Zürich, Switzerland.
⁸ Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
⁹ Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
¹⁰ Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands.
¹¹ Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
¹² Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
¹³ Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
¹⁴ Chronic Disease Programme (UFIEC-CROSADIS) and Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
¹⁵ Alzheimer's Centre Reina Sofia-CIEN Foundation-ISCIII, Research Platforms, Madrid, Spain.
¹⁶ Department of Biochemistry and Molecular Biology, Lariboisière Hospital, GHU AP-HP Nord, University of Paris Cité, Paris, France.
¹⁷ Paris Brain Institute (Institut du Cerveau, ICM), INSERM, CNRS, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.
¹⁸ Assistance Publique-Hôpitaux de Paris (AP-HP), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
¹⁹ IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
²⁰ Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
²¹ Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
²² Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.
²³ Biomedical Engineering and Sciences Department, School of Mechanical and Manufacturing Engineering, National University of Sciences and Technology, Islamabad, Pakistan.
²⁴ Prion Disease Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Canada.
²⁵ Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.
²⁶ Danish Reference Center for Prion Diseases, Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
²⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²⁸ National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, United States of America.
²⁹ German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
³⁰ Departments of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, United States of America.

PMID: 39079175
PMCID: PMC11280162
DOI: 10.1371/journal.pone.0304528

Abstract

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.

Copyright: © 2024 Hummerich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Conflict of interest statement

Stéphane Haik reports grants from Santé Publique France, during the conduct of the study; grants from LFB Biomedicaments, grants from Institut de Recherche Servier, grants from MedDay Pharmaceuticals, outside the submitted work; In addition, Stéphane Haik has a patent Method for treating prion diseases (PCT/EP2019/070457) pending. Brian Appleby has received funding from CDC, NIH, CJD Foundation, Alector, and Ionis. He has served as a consultant for Ionis, Sangamo, and Gate Biosciences. He has received royalties from Wolter Kluwers. Karl Fronztek reports grants from Ono Pharmaceuticals outside the submitted work. Simon Mead reports grants from Medical Research Council (UK) and grants from National Institute of Health Research’s Biomedical Research Centre at University College London Hospitals NHS Foundation Trust during the conduct of the study. Gabor G Kovacs reports personal fees from Biogen, outside the submitted work. John Collinge reports grants from Medical Research Council, grants from NIHR UCLH Biomedical Research Centre, during the conduct of the study; and is a Director and shareholder of D-Gen Limited, an academic spinout in the field of prion disease diagnostics, decontamination and therapeutics. Inga Zerr reports grants from the Bundesministerium für Gesundheit via Robert Koch institute, JPND and personal fees (not related to the content of the manuscript) from Ferring Pharmaceuticals and IONIS, speaking honoraria for medical lectures from Lilly, Biogen, Medfora, DGLN (German Society for cerebrospinal fluid diagnostics in Neurology). Maurizio Pocchiari reports personal fees from Ferring Pharmaceuticals, personal fees from CNCCS (Collection of National Chemical Compounds and Screening Center), non-financial support from Fondazione Cellule Staminali, outside the submitted work. Michael D Geschwind has consulted for3D Communications, Adept Field Consulting, Advanced Medical Inc., Best Doctors Inc., Second Opinion Inc., Gerson Lehrman Group Inc., Guidepoint Global LLC, InThought Consulting Inc., Market Plus, Trinity Partners LLC, Biohaven Pharmaceuticals, Quest Diagnostics and various medical-legal consulting. He has received speaking honoraria for various medical center lectures and from Oakstone publishing. He has received past research support from Alliance Biosecure, CurePSP, the Tau Consortium, and Quest Diagnostics. Michael D Geschwind serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility and on the editorial board of Dementia & Neuropsychologia.

Figures

**Fig 1**
Histograms for phenotypes duration before (A) and after (B) Box-Cox transformation and age before (C) and after (D) Box-Cox transformation.

**Fig 2**
Quantile-Quantile plots for phenotypes duration before (A) and after (B) Box-Cox transformation and age before (C) and after (D) Box-Cox transformation.

**Fig 3. Quantile-Quantile plot with duration as phenotype.**

**Fig 4. Quantile-Quantile plot with age as phenotype.**

**Fig 5. Manhattan plot with clinical duration as phenotype.**
(red line indicating genome-wide significance of 5x10^-8; blue line indicating suggestive genome-wide significance (5x10^-8 > pvalue < 1x10^-5)).

**Fig 6. Regional association plot at *PRNP* locus with clinical duration as phenotype (additive model).**

**Fig 7. Regional association plot at *PRNP* locus with clinical duration as phenotype (heterozygous model).**

**Fig 8. Regional association plot at *PRNP* locus for conditional analysis on SNP rs1799990 with clinical duration as phenotype (additive model).**

**Fig 9. Manhattan plot with age at onset as phenotype.**
(red line indicating genome-wide significance of 5x10^-8; blue line indicating suggestive genome-wide significance (5x10^-8 > pvalue < 1x10^-).

See this image and copyright information in PMC

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Genome wide association study of clinical duration and age at onset of sporadic CJD

Affiliations

Genome wide association study of clinical duration and age at onset of sporadic CJD

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Conflict of interest statement

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