Age of onset and death in inherited prion disease are heritable.

The common polymorphism at codon 129 of the prion protein gene (PRNP) is known to affect prion disease susceptibility, incubation period and phenotype. Mouse quantitative trait locus (QTL) studies demonstrate multiple modifiers of incubation time unlinked to Prnp, suggesting the existence of homologous human prion disease modifiers, but direct evidence of these has been lacking. We investigated the correlation of age at onset and death, expressed as a composite Z score, between parents and offspring in three large UK inherited prion disease kindreds. Our analysis suggests that overall heritability of the composite phenotype is 0.55 (95% CI 0.35-0.75). This measure may be an underestimate of the total genetic contribution to phenotypic heterogeneity as the analysis does not incorporate the effect of PRNP-linked modifiers. Although the confidence intervals are wide, these data suggest a significant heritable component to phenotypic variability and support attempts to identify human prion disease modifier genes which would be important in understanding the epidemiology of variant Creutzfeldt-Jakob disease (vCJD) in populations with significant exposure to bovine spongiform encephalopathy (BSE) prions.