TY - JOUR
T1 - Quantifying prion disease penetrance using large population control cohorts
AU - Minikel, Eric Vallabh
AU - Vallabh, Sonia M.
AU - Lek, Monkol
AU - Estrada, Karol
AU - Samocha, Kaitlin E.
AU - Sathirapongsasuti, J. Fah
AU - McLean, Cory Y.
AU - Tung, Joyce Y.
AU - Yu, Linda P.C.
AU - Gambetti, Pierluigi
AU - Blevins, Janis
AU - Zhang, Shulin
AU - Cohen, Yvonne
AU - Chen, Wei
AU - Yamada, Masahito
AU - Hamaguchi, Tsuyoshi
AU - Sanjo, Nobuo
AU - Mizusawa, Hidehiro
AU - Nakamura, Yosikazu
AU - Kitamoto, Tetsuyuki
AU - Collins, Steven J.
AU - Boyd, Alison
AU - Will, Robert G.
AU - Knight, Richard
AU - Ponto, Claudia
AU - Zerr, Inga
AU - Kraus, Theo F.J.
AU - Eigenbrod, Sabina
AU - Giese, Armin
AU - Calero, Miguel
AU - De Pedro-Cuesta, Jesús
AU - Haïk, Stéphane
AU - Laplanche, Jean Louis
AU - Bouaziz-Amar, Elodie
AU - Brandel, Jean Philippe
AU - Capellari, Sabina
AU - Parchi, Piero
AU - Poleggi, Anna
AU - Ladogana, Anna
AU - O'Donnell-Luria, Anne H.
AU - Karczewski, Konrad J.
AU - Marshall, Jamie L.
AU - Boehnke, Michael
AU - Laakso, Markku
AU - Mohlke, Karen L.
AU - Kähler, Anna
AU - Chambert, Kimberly
AU - McCarroll, Steven
AU - Sullivan, Patrick F.
AU - Hultman, Christina M.
AU - Purcell, Shaun M.
AU - Sklar, Pamela
AU - Van Der Lee, Sven J.
AU - Rozemuller, Annemieke
AU - Jansen, Casper
AU - Hofman, Albert
AU - Kraaij, Robert
AU - Van Rooij, Jeroen G.J.
AU - Ikram, M. Arfan
AU - Uitterlinden, André G.
AU - Van Duijn, Cornelia M.
AU - Daly, Mark J.
AU - MacArthur, Daniel G.
N1 - Funding Information:
We thank the customers of 23andMe, ExAC research participants, and prion disease patients and families who participated in this research. Research reported in this publication was partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of General Medical Sciences of the NIH (awards U54DK105566 and R01GM104371), by Broad Institute NextGen funds, and by Prion Alliance sundry funds. S.M.V. is supported by the National Science Foundation Graduate Research Fellowship Program (grant 2015214731). U.S. prion surveillance work was conducted under Centers for Disease Control and Prevention (contract UR8/CCU515004). Japanese prion surveillance work was supported by a grant-in-aid from the Research Committee of Prion Disease and Slow Virus Infection and the Research Committee of Surveillance and Infection Control of Prion Disease of the Ministry of Health, Labour and Welfare of Japan. The French prion surveillance network is supported by the Institut National de veille Sanitaire. The German prion surveillance work was supported by Robert Koch Institute/Federal Ministry of Health (grant 1369-341). The UK National Creutzfeldt Jakob Disease Research and Surveillance Unit is supported by the Department of Health and the Scottish Executive. The Australian National Creutzfeldt-Jakob Disease Registry is funded by the Commonwealth Department of Health. S.J.C. is supported by a National Health and Medical Research Council Practitioner Fellowship (identification number APP1005816). Contributions at Erasmus Medical Center (MC) were supported by Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research–sponsored Netherlands Consortium for Healthy Aging (project 050-060-810); by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (www.bbmri.nl; project number CP2010-41); and by Erasmus MC and Erasmus University, Rotterdam, Netherlands Organisation for Health Research and Development (ZonMw Middelgroot #91111025), Netherlands Organization for the Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (Directorate-General for Science, Research and Development), and the Municipality of Rotterdam.
Publisher Copyright:
Copyright © 2016, American Association for the Advancement of Science.
PY - 2016/1/20
Y1 - 2016/1/20
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aad5169
DO - 10.1126/scitranslmed.aad5169
M3 - Article
C2 - 26791950
AN - SCOPUS:84955582450
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 322
M1 - 322ra9
ER -