title: Quantifying prion disease penetrance using large population control cohorts.
abstract: More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA. Prion Alliance, Cambridge, MA 02139, USA. eminikel@broadinstitute.org macarthur@atgu.mgh.harvard.edu.
authors.forename: Eric Vallabh
authors.initials: EV
authors.lastname: Minikel
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA. Prion Alliance, Cambridge, MA 02139, USA.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Vallabh
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Research, 23andMe Inc., Mountain View, CA 94041, USA.
authors.forename: J Fah
authors.initials: JF
authors.lastname: Sathirapongsasuti
authors.affiliation: Research, 23andMe Inc., Mountain View, CA 94041, USA.
authors.forename: Cory Y
authors.initials: CY
authors.lastname: McLean
authors.affiliation: Research, 23andMe Inc., Mountain View, CA 94041, USA.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: Research, 23andMe Inc., Mountain View, CA 94041, USA.
authors.forename: Linda P C
authors.initials: LP
authors.lastname: Yu
authors.affiliation: National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, USA.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, USA.
authors.forename: Janis
authors.initials: J
authors.lastname: Blevins
authors.affiliation: University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan.
authors.forename: Tsuyoshi
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authors.lastname: Hamaguchi
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors.forename: Nobuo
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authors.affiliation: National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
authors.forename: Hidehiro
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authors.lastname: Mizusawa
authors.affiliation: Department of Public Health, Jichi Medical University, Shimotsuke 329-0498, Japan.
authors.forename: Yosikazu
authors.initials: Y
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authors.affiliation: Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Tetsuyuki
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authors.affiliation: Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
authors.affiliation: Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Alison
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authors.affiliation: National Creutzfeldt-Jakob Disease Research & Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Robert G
authors.initials: RG
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authors.affiliation: National Creutzfeldt-Jakob Disease Research & Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Richard
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authors.affiliation: National Reference Center for the Surveillance of Human Transmissible Spongiform Encephalopathies, Georg-August-University, Goettingen 37073, Germany.
authors.forename: Claudia
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authors.affiliation: National Reference Center for the Surveillance of Human Transmissible Spongiform Encephalopathies, Georg-August-University, Goettingen 37073, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Theo F J
authors.initials: TF
authors.lastname: Kraus
authors.affiliation: Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Sabina
authors.initials: S
authors.lastname: Eigenbrod
authors.affiliation: Center for Neuropathology and Prion Research (ZNP), Ludwig-Maximilians-University, Munich 81377, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid 28031, Spain.
authors.forename: Miguel
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authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid 28031, Spain.
authors.forename: Jesús
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authors.lastname: de Pedro-Cuesta
authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Pierre and Marie Curie University Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France. Assistance Publique-Hôpitaux de Paris (AP-HP), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Stéphane
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authors.affiliation: AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, 75010 Paris, France.
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authors.affiliation: AP-HP, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, 75010 Paris, France.
authors.forename: Elodie
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authors.affiliation: INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Pierre and Marie Curie University Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France. Assistance Publique-Hôpitaux de Paris (AP-HP), Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brandel
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Neurological Sciences, Bologna 40123, Italy. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40126, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Capellari
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico, Institute of Neurological Sciences, Bologna 40123, Italy. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40126, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome 00161, Italy.
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authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome 00161, Italy.
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authors.initials: A
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
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authors.initials: AH
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.initials: JL
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authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
authors.forename: Michael
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authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio 70210, Finland.
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authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
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authors.affiliation: Karolinska Institutet, Stockholm SE-171 77, Sweden.
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authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. Karolinska Institutet, Stockholm SE-171 77, Sweden.
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authors.affiliation: Karolinska Institutet, Stockholm SE-171 77, Sweden.
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authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam 3000 CA, Netherlands.
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authors.affiliation: Dutch Surveillance Centre for Prion Diseases, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands.
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authors.affiliation: Dutch Surveillance Centre for Prion Diseases, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands.
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam 3000 CA, Netherlands.
authors.forename: Albert
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authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, Netherlands.
authors.forename: Robert
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authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, Netherlands.
authors.forename: Jeroen G J
authors.initials: JG
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam 3000 CA, Netherlands.
authors.forename: M Arfan
authors.initials: MA
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam 3000 CA, Netherlands. Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, Netherlands.
authors.forename: André G
authors.initials: AG
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authors.affiliation: Department of Epidemiology, Erasmus Medical Center (MC), Rotterdam 3000 CA, Netherlands.
authors.forename: Cornelia M
authors.initials: CM
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
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authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. eminikel@broadinstitute.org macarthur@atgu.mgh.harvard.edu.
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mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics; D019683:Penetrance; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000235:genetics; D012307:Risk Factors
chemical_list: D011328:Prions