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oai:repisalud.isciii.es:20.500.12105/263612025-12-18T13:00:42Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617

00925njm 22002777a 4500 dc Hummerich, Holger author Speedy, Helen author Campbell, Tracy author Darwent, Lee author Hill, Elizabeth author Collins, Steven author Stehmann, Christiane author Kovacs, Gabor G author Geschwind, Michael D author Frontzek, Karl author Budka, Herbert author Gelpi, Ellen author Aguzzi, Adriano author van der Lee, Sven J author van Duijn, Cornelia M author Liberski, Pawel P author Calero, Miguel author Sánchez-Juan, Pascual author Bouaziz-Amar, Elodie author Laplanche, Jean-Louis author Haïk, Stéphane author Brandel, Jean-Philippe author Mammana, Angela author Capellari, Sabina author Poleggi, Anna author Ladogana, Anna author Pocchiari, Maurizio author Zafar, Saima author Booth, Stephanie author Jansen, Gerard H author Areškevičiūtė, Aušrinė author Løbner Lund, Eva author Glisic, Katie author Parchi, Piero author Hermann, Peter author Zerr, Inga author Appleby, Brian S author Safar, Jiri author Gambetti, Pierluigi author Collinge, John author Mead, Simon author 2024 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. Hummerich H, Speedy H, Campbell T, Darwent L, Hill E, Collins S, Stehmann C, Kovacs GG, Geschwind MD, Frontzek K, Budka H, Gelpi E, Aguzzi A, van der Lee SJ, van Duijn CM, Liberski PP, Calero M, Sanchez-Juan P, Bouaziz-Amar E, Laplanche JL, Haïk S, Brandel JP, Mammana A, Capellari S, Poleggi A, Ladogana A, Pocchiari M, Zafar S, Booth S, Jansen GH, Areškevičiūtė A, Løbner Lund E, Glisic K, Parchi P, Hermann P, Zerr I, Appleby BS, Safar J, Gambetti P, Collinge J, Mead S. Genome wide association study of clinical duration and age at onset of sporadic CJD. PLoS One. 2024 Jul 26;19(7):e0304528. 10.1371/journal.pone.0304528 1932-6203 PloS one 39079175 https://hdl.handle.net/20.500.12105/26361 Genome wide association study of clinical duration and age at onset of sporadic CJD