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Age of onset and death in inherited prion disease are heritable
Author(s) -
Webb T.E.F.,
Whittaker J.,
Collinge J.,
Mead S.
Publication year - 2008
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.30844
Subject(s) - prnp , biology , bovine spongiform encephalopathy , genetics , disease , phenotype , locus (genetics) , quantitative trait locus , offspring , transmissible spongiform encephalopathy , gene , heritability , genotype , prion protein , scrapie , medicine , pathology , pregnancy
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. © 2008 Wiley‐Liss, Inc.