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 Kitamoto; Steven 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

doi:10.1126/scitranslmed.aad5169

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 Kitamoto

Steven 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

Research output: Contribution to journal › Article › peer-review

309 Scopus citations

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.

Original language	English
Article number	322ra9
Journal	Science Translational Medicine
Volume	8
Issue number	322
DOIs	https://doi.org/10.1126/scitranslmed.aad5169
State	Published - Jan 20 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016, American Association for the Advancement of Science.

Funding

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.

Funders	Funder number
Broad Institute NextGen funds
Commonwealth Department of Health
ExAC
Netherlands Consortium for Healthy Aging	050-060-810
Prion Alliance
Robert Koch Institute
Scottish Executive Rural and Environment Research
National Science Foundation Arctic Social Science Program	2015214731, UR8/CCU515004
National Institutes of Health (NIH)
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM104371
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK072193, U54DK105566
University of Utah Gastroenterology Division in the Department of Internal Medicine
UK Department of Health and Social Care
European Commission
Australian National Health and Medical Research Council	APP1005816
ZonMw Memorabel	91111025
Erasmus Universiteit Rotterdam
Ministerie van Volksgezondheid, Welzijn en Sport
Erasmus Medisch Centrum	CP2010-41
Bundesministerium für Gesundheit	1369-341
Ministerie van Onderwijs, Cultuur en Wetenschap
Ministry of Health, Labour and Welfare
Institut de veille sanitaire
Directorate-General XII, Science, Research, and Development

ASJC Scopus subject areas

General Medicine

Access to Document

10.1126/scitranslmed.aad5169

Cite this

Minikel, E. V., Vallabh, S. M., Lek, M., Estrada, K., Samocha, K. E., Sathirapongsasuti, J. F., McLean, C. Y., Tung, J. Y., Yu, L. P. C., Gambetti, P., Blevins, J., Zhang, S., Cohen, Y., Chen, W., Yamada, M., Hamaguchi, T., Sanjo, N., Mizusawa, H., Nakamura, Y., ... MacArthur, D. G. (2016). Quantifying prion disease penetrance using large population control cohorts. Science Translational Medicine, 8(322), Article 322ra9. https://doi.org/10.1126/scitranslmed.aad5169

@article{08365264eea7491f8d991297d8788df5,

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2016, American Association for the Advancement of Science.",

year = "2016",

month = jan,

day = "20",

doi = "10.1126/scitranslmed.aad5169",

language = "English",

volume = "8",

number = "322",

}

Minikel, EV, Vallabh, SM, Lek, M, Estrada, K, Samocha, KE, Sathirapongsasuti, JF, McLean, CY, Tung, JY, Yu, LPC, Gambetti, P, Blevins, J, Zhang, S, Cohen, Y, Chen, W, Yamada, M, Hamaguchi, T, Sanjo, N, Mizusawa, H, Nakamura, Y, Kitamoto, T, Collins, SJ, Boyd, A, Will, RG, Knight, R, Ponto, C, Zerr, I, Kraus, TFJ, Eigenbrod, S, Giese, A, Calero, M, De Pedro-Cuesta, J, Haïk, S, Laplanche, JL, Bouaziz-Amar, E, Brandel, JP, Capellari, S, Parchi, P, Poleggi, A, Ladogana, A, O'Donnell-Luria, AH, Karczewski, KJ, Marshall, JL, Boehnke, M, Laakso, M, Mohlke, KL, Kähler, A, Chambert, K, McCarroll, S, Sullivan, PF, Hultman, CM, Purcell, SM, Sklar, P, Van Der Lee, SJ, Rozemuller, A, Jansen, C, Hofman, A, Kraaij, R, Van Rooij, JGJ, Ikram, MA, Uitterlinden, AG, Van Duijn, CM, Daly, MJ & MacArthur, DG 2016, 'Quantifying prion disease penetrance using large population control cohorts', Science Translational Medicine, vol. 8, no. 322, 322ra9. https://doi.org/10.1126/scitranslmed.aad5169

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.

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.

UR - https://www.scopus.com/pages/publications/84955582450

UR - https://www.scopus.com/pages/publications/84955582450#tab=citedBy

U2 - 10.1126/scitranslmed.aad5169

DO - 10.1126/scitranslmed.aad5169

M3 - Article

C2 - 26791950

AN - SCOPUS:84955582450

SN - 1946-6234

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 322

M1 - 322ra9

ER -

Quantifying prion disease penetrance using large population control cohorts

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this