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Age of onset and death in inherited prion disease are heritable

T E F Webb1, J Whittaker, J Collinge

  • 1MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics
|August 30, 2008
PubMed

Insights

Genetic factors influence prion disease progression beyond the prion protein gene (PRNP). This study found significant heritability for inherited prion disease phenotypes, suggesting other human prion disease modifier genes exist.

Area of Science:

  • Neuroscience
  • Genetics
  • Epidemiology

Background:

  • The prion protein gene (PRNP) codon 129 polymorphism impacts prion disease susceptibility and presentation.
  • Mouse studies indicate genetic modifiers of prion disease incubation time exist outside the Prnp gene.
  • Direct evidence for human prion disease modifiers, independent of PRNP, has been limited.

Purpose of the Study:

  • To investigate the heritability of phenotypic variability in human prion diseases.
  • To explore the potential existence of genetic modifiers for prion diseases in humans, similar to those found in mice.
  • To provide evidence supporting the search for novel human prion disease modifier genes.

Main Methods:

  • Analysis of parent-offspring age at onset and death (composite Z score) in three large UK inherited prion disease kindreds.
  • Statistical assessment of heritability for the composite phenotype.
  • Consideration of PRNP-linked modifiers and their potential impact on overall heritability estimates.

Main Results:

  • A significant heritability estimate of 0.55 (95% CI 0.35-0.75) for the composite prion disease phenotype was observed.
  • This heritability suggests a substantial genetic contribution to phenotypic variation in inherited prion diseases.
  • The analysis indicates that PRNP-linked modifiers may not account for all genetic influences on prion disease phenotypes.

Conclusions:

  • These findings provide evidence for a significant heritable component influencing phenotypic variability in human prion diseases.
  • The results support the ongoing search for human prion disease modifier genes.
  • Identifying these modifiers is crucial for understanding the epidemiology of variant Creutzfeldt-Jakob disease (vCJD) and prion disease in general.

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