Research in context
Evidence before this study
The rarity of sporadic Creutzfeldt-Jakob disease (sCJD) has been limiting in previous genome-wide association studies (GWAS) for disease risk. We searched PubMed on April 9, 2020, with the terms (“prion” OR “creutzfeldt*”) AND (“genome wide association” OR “GWAS”), without language or date restrictions, and identified four relevant publications, including two directly investigating sCJD risk through genome-wide analyses. However, the sample sizes in these studies were not sufficient to identify statistically significant associations outside of the known risk at the prion protein gene (PRNP). Further studies into genetic risk factors for sCJD have primarily utilised targeted replication of putative risk variants or candidate gene studies to propose association.
Added value of this study
Through international collaboration of sample resources, this study is, to our knowledge, the first GWAS to identify genetic variants associated with sCJD risk outside of PRNP, at genome-wide significance. Two of these variants (within STX6 and GAL3ST1) were statistically robust to replication in an independent cohort, with 5208 patients with sCJD in total included in the two-stage study design. Through statistical fine-mapping and analysis of exome sequencing and gene expression data, we propose genes that are likely to be causal, and mechanisms for both novel associations. We used patient brain samples and cell-based assays to further investigate the biological implications of these associations in relevant systems. Two further loci at PDIA4 and BMERB1 were also associated with sCJD risk in gene-based tests.
Implications of all the available evidence
Identification of two novel non-PRNP loci conferring sCJD risk will provide further avenues for research, with increased evidence to support a role of modified intracellular trafficking and sphingolipid metabolism within sCJD biology, providing the potential to inform new therapeutic approaches. With the shared genetic risk of variants within STX6 and those previously identified for the tauopathy progressive supranuclear palsy, this study also supports the notion of a common so-called prion-like causal mechanism for related neurodegenerative disorders and thus potential for shared treatments.