Prion disease

Implications of new genetic risk factors in prion disease

A genome-wide association study has identified the first risk factors for sporadic prion disease other than mutations of PRNP, which encodes prion protein. These hits could open up new fronts in prion biology, risk prediction, and drug development.

Refers to Jones, E. et al. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study. Lancet Neurol. 19, 840–848 (2020).

Prion disease is unique for its three different aetiologies. Infamously, this fatal neurodegenerative disease can be acquired through transmission, although this route is rare. Approximately 15% of cases are genetic, resulting from pathogenic variants in PRNP, which encodes prion protein (PrP). The remaining 85% of cases arise spontaneously and are referred to as sporadic prion disease. Regardless of aetiology, all prion disease shares a core molecular mechanism, in which conformationally corrupted PrP molecules act as templates for further PrP misfolding. What differs between aetiologies is the trigger of this cascade, and it is in sporadic prion disease that the nature of this trigger poses the greatest mystery. Common polymorphisms within PRNP affect the risk and progression of sporadic prion disease but, to date, genome-wide association studies (GWASs) have been limited in power and, consequently, unable to shed light on what causes spontaneous prion formation in the absence of a pathogenic mutation or exogenous challenge. A new study by Jones et al.1 offers our first glimpse of the genetic factors beyond PRNP that influence the risk of sporadic prion disease.

This large, international study included 5,208 individuals with prion disease. Given the rarity of prion disease, this number might be approaching the limit of ancestry-matched patients for whom the diagnosis is definite, research consent has been obtained and DNA samples are available. The study revealed two novel loci — 1q25.3 and 22q12.2 — associated with prion disease. These hits seem to be robust: both exceed the genome-wide significance threshold (P = 9.7 × 10−9 and 8.6 × 10−10, for the lead SNPs at 1q25.3 and 22q12.2, respectively), and the linkage disequilibrium peaks for each look reasonable. In the meantime, the genomic inflation factor, which measures how well matched cases are to controls, is 1.026, rendering population stratification an unlikely confounder. By combining variant-to-gene algorithms with co-localization and expression data, the investigators convincingly map these loci to a variant that controls expression of the gene STX6 (1q25.3) and a pair of missense variants in GAL3ST1 (22q12.2). Identification of risk variants in these genes has implications for how we understand, predict and treat prion disease (Table 1).

Table 1 Implications of the new genome-wide association study in prion disease

Most immediately, these findings highlight frontiers of interest in understanding prion biology. STX6 encodes syntaxin 6, a component of the t-SNARE complex involved in endosomal transport. Jones et al.1 provide evidence that increased expression of STX6 mRNA correlates with an increased risk of prion disease. GAL3ST1 encodes galactose-3-O-sulfotransferase 1, an enzyme involved in sphingolipid metabolism. Endocytic recycling and lipid interactions are both believed to play important roles in prion biology1. Therefore, present knowledge enables hypotheses to be formed as to the relevance of both of these novel gene associations to the disease process, but dissecting exactly how the identified variants contribute to the risk of prion disease offers hope of illuminating the mechanism of prion formation, and could reveal surprises. In Huntington disease, for example, a GWAS uncovered a previously unappreciated role for DNA repair, implicating mechanisms that are shared across trinucleotide repeat disorders2.

“these findings highlight frontiers of interest in understanding prion biology”

Beyond basic biology, GWAS findings can, in principle, improve risk prediction, although the baseline rarity of prion disease, which kills ~1 in 6,000 people, poses a challenge. The novel associations identified are modest, as expected for GWAS hits, with odds ratios of 1.14 and 1.11 in an allelic model, meaning that someone who is homozygous for both risk alleles still has a lifetime risk of just 1 in 3,000 — too low to be clinically meaningful. Polygenic risk scores enable prediction of individual disease risk on the basis of genome-wide information without being limited to genome-wide significant loci. However, in the new study1, the heritability of sporadic prion disease risk is estimated at only ~25%, making clinically actionable identification of high-risk individuals from the general population by use of polygenic risk scores unlikely. Evidence from other diseases that can occur in Mendelian or idiopathic forms3 suggests that polygenic risk scores could aid prediction of the age of onset in people who carry highly penetrant PRNP mutations, or help to predict which people who carry PRNP mutations with low penetrance4 will develop disease. These possibilities merit investigation, although precise individualized risk prediction remains unlikely: among individuals with genetic prion disease, even the specific PRNP mutation that an individual has explains only a small fraction of variability in the age of onset5.

Finally, GWASs can identify new drug targets. The novel associations identified are unlikely to rewrite prion disease drug discovery overnight. As confirmed by Jones et al.1, prion disease already has a genetically validated drug target — PrP — that is known to be central to the disease process. Targeting of PrP has been de-risked through decades-long investigation of its mechanistic role in disease, the desired direction of effect, its relevance to different disease stages, and drug activity biomarkers. Much work remains to establish a similar drug development framework for new targets that are only now being identified. Nevertheless, the findings provide exciting opportunities, as targets that are backed up by human genetic evidence are more likely to yield approved drugs than targets for which human genetic validation is lacking6. GAL3ST1 encodes an enzyme, a class of protein that could in theory prove more amenable to small-molecule drug discovery than PrP has, though the direction of effect required and other critical details remain to be established. The risk allele identified in STX6 seems to be shared between prion disease and the tauopathy progressive supranuclear palsy, thereby uniting two neurodegenerative diseases caused by misfolding of two distinct proteins. This overlap could offer mechanistic insights and the possibility of united drug development efforts.

Intriguingly, the novel risk alleles do not seem to affect the duration of prion disease, and STX6 knockdown did not affect prion replication in a cell culture model. These findings suggest the possibility that one or both genes might influence only the initial prion seed formation and not subsequent replication or neurotoxicity. This observation echoes findings from GWASs in Alzheimer disease, which have revealed imperfect overlap between genetic risk factors that affect initiation of the pathological cascade and those that affect subsequent progression7.

“The novel associations identified are unlikely to rewrite prion disease drug discovery overnight”

This dichotomy should prompt consideration of which clinical development paths could best support advancement of drugs against targets identified in human genetic studies. For example, the only randomized, placebo-controlled clinical trials conducted in prion disease to date have involved symptomatic patients, in whom modulation of initial prion seed formation would not be expected to be beneficial. In pre-symptomatic individuals who are at risk of genetic prion disease, PrP-lowering drugs8 could be tested with cerebrospinal fluid levels of PrP as a readout9, but a preventive drug with a different mechanism of action would require a different clinical paradigm, which might rely on biomarkers that are still under investigation or yet to be developed10. As GWASs continue to identify potential upstream drug targets across the field of neurodegeneration, the development of tools that enable rigorous clinical testing in early and preventive paradigms will be more important than ever.


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Correspondence to Eric Vallabh Minikel.

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Competing interests

S.M.V. has received speaking fees from Biogen and Illumina, and has received research support in the form of unrestricted charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals. E.V.M. has received consulting fees from Deerfield Management and Guidepoint, and has received research support in the form of unrestricted charitable contributions from Charles River Laboratories and Ionis Pharmaceuticals.

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Vallabh, S.M., Minikel, E.V. Implications of new genetic risk factors in prion disease. Nat Rev Neurol 17, 5–6 (2021).

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