Quantifying prion disease penetrance using large population control cohorts

Eric Vallabh Minikel, Sonia M. Vallabh, Monkol Lek, Karol Estrada, Kaitlin E. Samocha, J. Fah Sathirapongsasuti, Cory Y. McLean, Joyce Y. Tung, Linda P.C. Yu, Pierluigi Gambetti, Janis Blevins, Shulin Zhang, Yvonne Cohen, Wei Chen, Masahito Yamada, Tsuyoshi Hamaguchi, Nobuo Sanjo, Hidehiro Mizusawa, Yosikazu Nakamura, Tetsuyuki KitamotoSteven J. Collins, Alison Boyd, Robert G. Will, Richard Knight, Claudia Ponto, Inga Zerr, Theo F.J. Kraus, Sabina Eigenbrod, Armin Giese, Miguel Calero, Jesús De Pedro-Cuesta, Stéphane Haïk, Jean Louis Laplanche, Elodie Bouaziz-Amar, Jean Philippe Brandel, Sabina Capellari, Piero Parchi, Anna Poleggi, Anna Ladogana, Anne H. O'Donnell-Luria, Konrad J. Karczewski, Jamie L. Marshall, Michael Boehnke, Markku Laakso, Karen L. Mohlke, Anna Kähler, Kimberly Chambert, Steven McCarroll, Patrick F. Sullivan, Christina M. Hultman, Shaun M. Purcell, Pamela Sklar, Sven J. Van Der Lee, Annemieke Rozemuller, Casper Jansen, Albert Hofman, Robert Kraaij, Jeroen G.J. Van Rooij, M. Arfan Ikram, André G. Uitterlinden, Cornelia M. van Duijn, Mark J. Daly, Daniel G MacArthur

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247 Citations (Scopus)


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.

Original languageEnglish
Article number322ra9
JournalScience Translational Medicine
Issue number322
Publication statusPublished - 20 Jan 2016

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