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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e0304528 |
| Tidsskrift | PLoS ONE |
| Vol/bind | 19 |
| Udgave nummer | 7 |
| Antal sider | 18 |
| ISSN | 1932-6203 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:This work was supported by the MRC (UK) core grant to the MRC Prion Unit at UCL (code MC_UU_00024/1). Several authors at UCL/ UCLH receive funding from the Department of Health\u2019s 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 Investigaci\u00F3n 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) \u2013 Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER \u2013 \u201CUna Manera de Hacer Europa\u201D). The French National Surveillance Network for Creutzfeldt-Jakob disease is supported by Sant\u00E9 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 (\u00D6RPE) is supported by the Austrian Ministy of Health \u2013 Bundesministerium f\u00FCr Soziales, Gesundheit, Pflege und Konsumentenschutz. The ANCJDR is supported through funding from the Commonwealth Department of Health and Aged Care. We thank Richard Newton for support with images and UCL Genomics who did the array processing. For UK samples we would like to thank patients, their families and carers, UK neurologists and other referring physicians, co-workers at the National Prion Clinic, our colleagues at the National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Edinburgh. We thank Dr. Maria Styczynska from Mossakowski Medical Research Centre; Polish Academy of Sciences; Warsaw, for kindly providing control DNA samples for the Polish cohort. We thank In\u00E9s Santiuste and the Valdecilla Biobank (PT17/0015/0019), integrated in the Spanish Biobank Network, for their support and collaboration in sample collection and management. We thank Megan Casey for assistance with sample collection and management. The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) would like to thank all patients and their families for supporting surveillance activities that have allowed participation in the study, as well as their managing physicians. The Italian Creutzfeldt-Jakob Registry would like to thank Dr.Clara Salciccia for the collaboration in DNA sample collection and management, Cinzia Gasparrini for administrative assistance and all patients, their families, neurologists, and referring physicians.
Publisher Copyright:
© 2024 Hummerich et al.
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