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

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; 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding for the project was provided by the Wellcome Trust and Medical Research Council. Several authors at UCL/UCLH receive funding from the Department of Healths NIHR Biomedical Research Centres funding scheme. Some of this work was supported by the Department of Health funded National Prion Monitoring Cohort study. Funding for the collection of Polish samples for study was partially provided by the EU joint programme JPND and Medical University of Lodz. The Italian national surveillance of Creutzfeldt Jakob disease and related disorders is partially supported by the Ministero della Salute, Italy. The German National Reference Centre for TSE is funded by grants from the Robert Koch Institute. The Dutch National Prion Disease Registry is funded by the National Institute for Public Health and the Environment (RIVM), which is part from the Ministry for Health, Welfare and Sports, The Netherlands. PS J was supported by Instituto de Salud Carlos III [Fondo de Investigacion Sanitaria, PI16/01652] Accion Estrategica en Salud integrated in the Spanish National I+D+i Plan and financed by Instituto de Salud Carlos III (ISCIII) ; Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER ; Una Manera de Hacer Europa).The French National Surveillance Network for Creutzfeldt-Jakob disease is supported by Sante Publique France. MDG (UCSF) receives research support from the NIH/NIA (grant R01 AG031189, R56AG055619, R01AG062562) and the Michael J. Homer Family Fund. The National Prion Disease Pathology Surveillance Center in the U.S. is funded by the Centers for Disease Control and Prevention (NU38CK000486). The Austrian Reference Center for Human Prion diseases (ORPE) is supported by the Austrian Ministy of Health ; Bundesministerium fur Soziales, Gesundheit, Pflege und Konsumentenschutz. The Australian National Creutzfeldt Jakob Disease Registry (ANCJDR) is supported through funding from the Commonwealth Department of Health and Aged Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Health Research Authority (UK) gave ethical approval for this work (05/Q0505/113 ). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Summary statistics are available through the GWAS catalog at NHGRI-EBI via study accession number GCST90295967. Further data available upon request.