Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Abstract

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms.Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. FindingsSamples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1•23 [95% CI 1•17-1•30], p=2•68 × 10 -¹⁵; heterozygous model p=1•01 × 10 -¹³⁵), STX6 (rs3747957; OR 1•16 [1•10-1•22], p=9•74 × 10 -⁹), and GAL3ST1 (rs2267161; OR 1•18 [1•12-1•25], p=8•60 × 10 -¹⁰). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions.Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders.

Novel regulators of PrPC biosynthesis revealed by genome-wide RNA interference

“…This sobering situation was a primary driver of the present study, as the assessment of every individual protein-coding gene may plausibly highlight factors undetectable by human genetics. In addition, we did not find evidence of a genetic association between screen hits and sCJD susceptibility using gene-based analysis from a recent GWAS (Jones et al, 2020). Similarly, in the GWAS, PrP brain expression quantitative trait loci near to PRNP showed no evidence of association with sCJD.…”

“…Role for genes that regulate PrPC expression in sporadic Creutzfeldt-Jakob disease (sCJD) susceptibility We tested for a role of genes identified in the primary screen (n=743) or after hit validation (n=9) in genetic susceptibility to sCJD using data from a recent collaborative genome-wide association study (Jones et al, 2020). Gene based tests, such as those implemented with MAGMA and VEGAS packages (de Leeuw et al, 2015; Mishra and Macgregor, 2015), aggregate single nucleotide variants within entire genes into a single statistical test, whilst accounting for linkage disequilibrium and other confounders like gene size.…”

“…However, in the case of prion diseases these strategies have been largely unsuccessful. Although genome-wide association studies (GWAS) have identified two potential risk loci (Jones et al, 2020), the only strong genetic risk factor for Creutzfeldt-Jakob disease has remained PRNP itself (Hsiao et al, 1989). This sobering situation was a primary driver of the present study, as the assessment of every individual protein-coding gene may plausibly highlight factors undetectable by human genetics.…”

Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion

“…The extremely low penetrance of close to 0%, with upper bounds of 95% CIs of below 2%, suggest that 2-OPRI is, at most, a very low-risk variant. There may also be non- PRNP genetic variants that affect penetrance [ 42 ]. Predictive clinical genetic testing for asymptomatic blood relatives is not likely to be justified, given the extremely modest increased lifetime risk.…”

Infection outcome needs two to tango: human host and the pathogen

“…In Sporadic Creutzfeldt–Jakob disease (CJD), increased expression of STX6 in multiple brain regions was associated with the risk of disease contraction. The SNPs rs12754041, rs10797664 and rs6425657, each in strong linkage disequilibrium with the SNP rs3747957, showed a high probability of being causal [ 145 ]. The advancement in genomic tools has made it possible to identify and find associated elements with gene expression levels.…”