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

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; 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.

Multiomic Analyses Direct Hypotheses for Creutzfeldt-Jakob Disease Risk Genes

“…Syntaxin-6 is a member of the SNARE protein family 10 , which mediate the final step of membrane fusion during vesicle transport, and thus its identification in GWAS implicated intracellular trafficking as a causal disease mechanism. However, although STX6 appears to modify disease susceptibility 8 , in more recent work we have shown there is no association with age of onset or disease progression 45 , and knockout of Stx6 expression in mouse has no, or modest effects, on prion disease incubation time 46 . In this work, we show increased STX6 expression was significantly linked to risk of sCJD across multiple reference panels both for TWAS and PWAS, along with e/pQTL-GWAS colocalization, whereas evidence was limited for other genes (including KIAA1614) at the same locus.…”