Abstract
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.
References
Apr 1, 1976·Archives of Neurology·N P RosenthalW J Brown
Jun 1, 1992·Brain : a Journal of Neurology·M PoulterJ Brown
Jun 1, 1992·Brain : a Journal of Neurology·J CollingeR Ridley
Apr 1, 1992·Nature Genetics·S R DlouhyB Ghetti
Jun 15, 1991·Lancet·J CollingeA J Dryden
Jul 25, 1991·Nature·M S PalmerJ Collinge
Nov 16, 1990·Cell·S B PrusinerG A Carlson
Sep 1, 1988·Journal of Adolescence·M Loftus
Jan 1, 1982·Journal of Neurology, Neurosurgery, and Psychiatry·J AdamE Spokes
Jul 2, 1993·Cell·H BüelerC Weissmann
Jul 11, 1998·Lancet·C M van DuijnR G Will
Aug 10, 1999·Lancet·J Collinge
Oct 3, 1999·Brain : a Journal of Neurology·G R MallucciJ Collinge
Oct 3, 2000·Genomics·D A StephensonG A Carlson
May 17, 2001·Proceedings of the National Academy of Sciences of the United States of America·S E LloydE M Fisher
Nov 13, 2001·American Journal of Human Genetics·S MeadJ Collinge
Mar 3, 2004·Proceedings of the National Academy of Sciences of the United States of America·Nancy S WexlerUNKNOWN U.S.-Venezuela Collaborative Research Project
Jun 29, 2004·The Journal of Pathology·David A HiltonJames W Ironside
Jun 21, 2005·Journal of Neurology, Neurosurgery, and Psychiatry·J Collinge
Jan 5, 2006·European Journal of Human Genetics : EJHG·Simon Mead
Apr 7, 2006·Brain : a Journal of Neurology·Jonathan D F WadsworthJohn Collinge
Jun 27, 2006·Lancet·John CollingeMichael P Alpers
Aug 23, 2006·Brain : a Journal of Neurology·Simon MeadJohn Collinge
Oct 19, 2006·Journal of Medical Genetics·C VollmertH A Kretzschmar
Dec 13, 2006·Lancet·Stephen J WroeJohn Collinge
Citations
May 28, 2011·Brain : a Journal of Neurology·Diego N KaskiSimon Mead
Jan 3, 2012·Human Molecular Genetics·Simon MeadJohn Collinge
Jul 2, 2009·Genome Medicine·Maurizio PocchiariFranco Cardone
Dec 15, 2010·PloS One·Conrad O IyegbeSteven A Whatley
Aug 17, 2011·Prion·Ana Lukic, Simon Mead
Jun 15, 2013·Prion·Qi ShiXiao-Ping Dong
Sep 21, 2019·Annual Review of Genetics·Simon MeadJohn Collinge
Jun 23, 2020·Neurobiology of Disease·Emma Jones, Simon Mead