title: Ascertainment bias causes false signal of anticipation in genetic prion disease.
abstract: Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.
authors.affiliation: Prion Alliance, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: eric.minikel@prionalliance.org.
authors.forename: Eric Vallabh
authors.initials: EV
authors.lastname: Minikel
authors.affiliation: National Reference Center for TSE, Georg-August University, 37073 Goettingen, Germany; German Center for Neurodegenerative Disease (DZNE), 37073 Goettingen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia 3010.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.affiliation: National Reference Center for TSE, Georg-August University, 37073 Goettingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ponto
authors.affiliation: Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia 3010.
authors.forename: Alison
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia 3010.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Klug
authors.affiliation: National Reference Center for TSE, Georg-August University, 37073 Goettingen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Karch
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, and NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Trust, Queen Square, WC1N 3BG London, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kenny
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, and NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Trust, Queen Square, WC1N 3BG London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Leonel T
authors.initials: LT
authors.lastname: Takada
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Forner
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Fong
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, and NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Trust, Queen Square, WC1N 3BG London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020132:Anticipation, Genetic / Q000235:genetics*; D015982:Bias; D002648:Child; D003198:Computer Simulation; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics*; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions