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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Quantifying penetrance in a dominant disease gene using large
population control cohorts</title><author><name sortKey="Minikel, Eric Vallabh" sort="Minikel, Eric Vallabh" uniqKey="Minikel E" first="Eric Vallabh" last="Minikel">Eric Vallabh Minikel</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Prion Alliance, Cambridge, MA 02139, United States</nlm:aff></affiliation></author><author><name sortKey="Vallabh, Sonia M" sort="Vallabh, Sonia M" uniqKey="Vallabh S" first="Sonia M." last="Vallabh">Sonia M. Vallabh</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Prion Alliance, Cambridge, MA 02139, United States</nlm:aff></affiliation></author><author><name sortKey="Lek, Monkol" sort="Lek, Monkol" uniqKey="Lek M" first="Monkol" last="Lek">Monkol Lek</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Estrada, Karol" sort="Estrada, Karol" uniqKey="Estrada K" first="Karol" last="Estrada">Karol Estrada</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Samocha, Kaitlin E" sort="Samocha, Kaitlin E" uniqKey="Samocha K" first="Kaitlin E." last="Samocha">Kaitlin E. Samocha</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation></author><author><name sortKey="Sathirapongsasuti, J Fah" sort="Sathirapongsasuti, J Fah" uniqKey="Sathirapongsasuti J" first="J. Fah" last="Sathirapongsasuti">J. Fah Sathirapongsasuti</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Mclean, Cory Y" sort="Mclean, Cory Y" uniqKey="Mclean C" first="Cory Y." last="Mclean">Cory Y. Mclean</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Tung, Joyce Y" sort="Tung, Joyce Y" uniqKey="Tung J" first="Joyce Y." last="Tung">Joyce Y. Tung</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Yu, Linda P C" sort="Yu, Linda P C" uniqKey="Yu L" first="Linda P. C." last="Yu">Linda P. C. Yu</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Gambetti, Pierluigi" sort="Gambetti, Pierluigi" uniqKey="Gambetti P" first="Pierluigi" last="Gambetti">Pierluigi Gambetti</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Blevins, Janis" sort="Blevins, Janis" uniqKey="Blevins J" first="Janis" last="Blevins">Janis Blevins</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shulin" sort="Zhang, Shulin" uniqKey="Zhang S" first="Shulin" last="Zhang">Shulin Zhang</name><affiliation><nlm:aff id="A7">University Hospitals Case Medical Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Cohen, Yvonne" sort="Cohen, Yvonne" uniqKey="Cohen Y" first="Yvonne" last="Cohen">Yvonne Cohen</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Yamada, Masahito" sort="Yamada, Masahito" uniqKey="Yamada M" first="Masahito" last="Yamada">Masahito Yamada</name><affiliation><nlm:aff id="A8">Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan</nlm:aff></affiliation></author><author><name sortKey="Hamaguchi, Tsuyoshi" sort="Hamaguchi, Tsuyoshi" uniqKey="Hamaguchi T" first="Tsuyoshi" last="Hamaguchi">Tsuyoshi Hamaguchi</name><affiliation><nlm:aff id="A8">Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan</nlm:aff></affiliation></author><author><name sortKey="Sanjo, Nobuo" sort="Sanjo, Nobuo" uniqKey="Sanjo N" first="Nobuo" last="Sanjo">Nobuo Sanjo</name><affiliation><nlm:aff id="A9">Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name><affiliation><nlm:aff id="A10">National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Nakamura, Yosikazu" sort="Nakamura, Yosikazu" uniqKey="Nakamura Y" first="Yosikazu" last="Nakamura">Yosikazu Nakamura</name><affiliation><nlm:aff id="A11">Department of Public Health, Jichi Medical University, Shimotsuke, Japan</nlm:aff></affiliation></author><author><name sortKey="Kitamoto, Tetsuyuki" sort="Kitamoto, Tetsuyuki" uniqKey="Kitamoto T" first="Tetsuyuki" last="Kitamoto">Tetsuyuki Kitamoto</name><affiliation><nlm:aff id="A12">Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan</nlm:aff></affiliation></author><author><name sortKey="Collins, Steven J" sort="Collins, Steven J" uniqKey="Collins S" first="Steven J." last="Collins">Steven J. Collins</name><affiliation><nlm:aff id="A13">Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Boyd, Alison" sort="Boyd, Alison" uniqKey="Boyd A" first="Alison" last="Boyd">Alison Boyd</name><affiliation><nlm:aff id="A13">Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Will, Robert G" sort="Will, Robert G" uniqKey="Will R" first="Robert G." last="Will">Robert G. Will</name><affiliation><nlm:aff id="A14">National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Western General Hospital, Edinburgh, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Knight, Richard" sort="Knight, Richard" uniqKey="Knight R" first="Richard" last="Knight">Richard Knight</name><affiliation><nlm:aff id="A14">National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Western General Hospital, Edinburgh, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Ponto, Claudia" sort="Ponto, Claudia" uniqKey="Ponto C" first="Claudia" last="Ponto">Claudia Ponto</name><affiliation><nlm:aff id="A15">National Reference Center for TSE, Georg-August University, Goettingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Zerr, Inga" sort="Zerr, Inga" uniqKey="Zerr I" first="Inga" last="Zerr">Inga Zerr</name><affiliation><nlm:aff id="A15">National Reference Center for TSE, Georg-August University, Goettingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Kraus, Theo F J" sort="Kraus, Theo F J" uniqKey="Kraus T" first="Theo F. J." last="Kraus">Theo F. J. Kraus</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Eigenbrod, Sabina" sort="Eigenbrod, Sabina" uniqKey="Eigenbrod S" first="Sabina" last="Eigenbrod">Sabina Eigenbrod</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Giese, Armin" sort="Giese, Armin" uniqKey="Giese A" first="Armin" last="Giese">Armin Giese</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Calero, Miguel" sort="Calero, Miguel" uniqKey="Calero M" first="Miguel" last="Calero">Miguel Calero</name><affiliation><nlm:aff id="A17">Instituto de Salud Carlos III and CIBERNED, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="De Pedro Cuesta, Jesus" sort="De Pedro Cuesta, Jesus" uniqKey="De Pedro Cuesta J" first="Jesús" last="De Pedro-Cuesta">Jesús De Pedro-Cuesta</name><affiliation><nlm:aff id="A17">Instituto de Salud Carlos III and CIBERNED, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Haik, Stephane" sort="Haik, Stephane" uniqKey="Haik S" first="Stéphane" last="Haïk">Stéphane Haïk</name><affiliation><nlm:aff id="A18">Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A19">AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Laplanche, Jean Louis" sort="Laplanche, Jean Louis" uniqKey="Laplanche J" first="Jean-Louis" last="Laplanche">Jean-Louis Laplanche</name><affiliation><nlm:aff id="A20">AP-HP, Service de Biochimie et Biologie moléculaire, Hôpital Lariboisière, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bouaziz Amar, Elodie" sort="Bouaziz Amar, Elodie" uniqKey="Bouaziz Amar E" first="Elodie" last="Bouaziz-Amar">Elodie Bouaziz-Amar</name><affiliation><nlm:aff id="A20">AP-HP, Service de Biochimie et Biologie moléculaire, Hôpital Lariboisière, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Brandel, Jean Philippe" sort="Brandel, Jean Philippe" uniqKey="Brandel J" first="Jean-Philippe" last="Brandel">Jean-Philippe Brandel</name><affiliation><nlm:aff id="A18">Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A19">AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Capellari, Sabina" sort="Capellari, Sabina" uniqKey="Capellari S" first="Sabina" last="Capellari">Sabina Capellari</name><affiliation><nlm:aff id="A21">IRCCS Institute of Neurological Sciences, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Parchi, Piero" sort="Parchi, Piero" uniqKey="Parchi P" first="Piero" last="Parchi">Piero Parchi</name><affiliation><nlm:aff id="A21">IRCCS Institute of Neurological Sciences, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Poleggi, Anna" sort="Poleggi, Anna" uniqKey="Poleggi A" first="Anna" last="Poleggi">Anna Poleggi</name><affiliation><nlm:aff id="A23">Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Ladogana, Anna" sort="Ladogana, Anna" uniqKey="Ladogana A" first="Anna" last="Ladogana">Anna Ladogana</name><affiliation><nlm:aff id="A23">Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="O Donnell Luria, Anne H" sort="O Donnell Luria, Anne H" uniqKey="O Donnell Luria A" first="Anne H." last="O'Donnell-Luria">Anne H. O'Donnell-Luria</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A24">Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, United States</nlm:aff></affiliation></author><author><name sortKey="Karczewski, Konrad J" sort="Karczewski, Konrad J" uniqKey="Karczewski K" first="Konrad J." last="Karczewski">Konrad J. Karczewski</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Marshall, Jamie L" sort="Marshall, Jamie L" uniqKey="Marshall J" first="Jamie L." last="Marshall">Jamie L. Marshall</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Boehnke, Michael" sort="Boehnke, Michael" uniqKey="Boehnke M" first="Michael" last="Boehnke">Michael Boehnke</name><affiliation><nlm:aff id="A25">University of Michigan School of Public Health, Ann Arbor, MI 48109, United States</nlm:aff></affiliation></author><author><name sortKey="Laakso, Markku" sort="Laakso, Markku" uniqKey="Laakso M" first="Markku" last="Laakso">Markku Laakso</name><affiliation><nlm:aff id="A26">Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland</nlm:aff></affiliation></author><author><name sortKey="Mohlke, Karen L" sort="Mohlke, Karen L" uniqKey="Mohlke K" first="Karen L." last="Mohlke">Karen L. Mohlke</name><affiliation><nlm:aff id="A27">Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States</nlm:aff></affiliation></author><author><name sortKey="K Hler, Anna" sort="K Hler, Anna" uniqKey="K Hler A" first="Anna" last="K Hler">Anna K Hler</name><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Chambert, Kimberly" sort="Chambert, Kimberly" uniqKey="Chambert K" first="Kimberly" last="Chambert">Kimberly Chambert</name><affiliation><nlm:aff id="A29">Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Mccarroll, Steven" sort="Mccarroll, Steven" uniqKey="Mccarroll S" first="Steven" last="Mccarroll">Steven Mccarroll</name><affiliation><nlm:aff id="A29">Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Sullivan, Patrick F" sort="Sullivan, Patrick F" uniqKey="Sullivan P" first="Patrick F." last="Sullivan">Patrick F. Sullivan</name><affiliation><nlm:aff id="A27">Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Hultman, Christina M" sort="Hultman, Christina M" uniqKey="Hultman C" first="Christina M." last="Hultman">Christina M. Hultman</name><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Purcell, Shaun M" sort="Purcell, Shaun M" uniqKey="Purcell S" first="Shaun M." last="Purcell">Shaun M. Purcell</name><affiliation><nlm:aff id="A30">Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States</nlm:aff></affiliation></author><author><name sortKey="Sklar, Pamela" sort="Sklar, Pamela" uniqKey="Sklar P" first="Pamela" last="Sklar">Pamela Sklar</name><affiliation><nlm:aff id="A30">Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States</nlm:aff></affiliation></author><author><name sortKey="Van Der Lee, Sven J" sort="Van Der Lee, Sven J" uniqKey="Van Der Lee S" first="Sven J." last="Van Der Lee">Sven J. Van Der Lee</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rozemuller, Annemieke" sort="Rozemuller, Annemieke" uniqKey="Rozemuller A" first="Annemieke" last="Rozemuller">Annemieke Rozemuller</name><affiliation><nlm:aff id="A32">Prion Surveillance Center, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Jansen, Casper" sort="Jansen, Casper" uniqKey="Jansen C" first="Casper" last="Jansen">Casper Jansen</name><affiliation><nlm:aff id="A32">Prion Surveillance Center, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Kraaij, Robert" sort="Kraaij, Robert" uniqKey="Kraaij R" first="Robert" last="Kraaij">Robert Kraaij</name><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Rooij, Jeroen G J" sort="Van Rooij, Jeroen G J" uniqKey="Van Rooij J" first="Jeroen G. J." last="Van Rooij">Jeroen G. J. Van Rooij</name><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Macarthur, Daniel G" sort="Macarthur, Daniel G" uniqKey="Macarthur D" first="Daniel G." last="Macarthur">Daniel G. Macarthur</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26791950</idno><idno type="pmc">4774245</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774245</idno><idno type="RBID">PMC:4774245</idno><idno type="doi">10.1126/scitranslmed.aad5169</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">001E65</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001E65</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Quantifying penetrance in a dominant disease gene using large
population control cohorts</title><author><name sortKey="Minikel, Eric Vallabh" sort="Minikel, Eric Vallabh" uniqKey="Minikel E" first="Eric Vallabh" last="Minikel">Eric Vallabh Minikel</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Prion Alliance, Cambridge, MA 02139, United States</nlm:aff></affiliation></author><author><name sortKey="Vallabh, Sonia M" sort="Vallabh, Sonia M" uniqKey="Vallabh S" first="Sonia M." last="Vallabh">Sonia M. Vallabh</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Prion Alliance, Cambridge, MA 02139, United States</nlm:aff></affiliation></author><author><name sortKey="Lek, Monkol" sort="Lek, Monkol" uniqKey="Lek M" first="Monkol" last="Lek">Monkol Lek</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Estrada, Karol" sort="Estrada, Karol" uniqKey="Estrada K" first="Karol" last="Estrada">Karol Estrada</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Samocha, Kaitlin E" sort="Samocha, Kaitlin E" uniqKey="Samocha K" first="Kaitlin E." last="Samocha">Kaitlin E. Samocha</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</nlm:aff></affiliation></author><author><name sortKey="Sathirapongsasuti, J Fah" sort="Sathirapongsasuti, J Fah" uniqKey="Sathirapongsasuti J" first="J. Fah" last="Sathirapongsasuti">J. Fah Sathirapongsasuti</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Mclean, Cory Y" sort="Mclean, Cory Y" uniqKey="Mclean C" first="Cory Y." last="Mclean">Cory Y. Mclean</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Tung, Joyce Y" sort="Tung, Joyce Y" uniqKey="Tung J" first="Joyce Y." last="Tung">Joyce Y. Tung</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Yu, Linda P C" sort="Yu, Linda P C" uniqKey="Yu L" first="Linda P. C." last="Yu">Linda P. C. Yu</name><affiliation><nlm:aff id="A5">Research, 23andMe Inc., Mountain View, CA 94041, United States</nlm:aff></affiliation></author><author><name sortKey="Gambetti, Pierluigi" sort="Gambetti, Pierluigi" uniqKey="Gambetti P" first="Pierluigi" last="Gambetti">Pierluigi Gambetti</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Blevins, Janis" sort="Blevins, Janis" uniqKey="Blevins J" first="Janis" last="Blevins">Janis Blevins</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Zhang, Shulin" sort="Zhang, Shulin" uniqKey="Zhang S" first="Shulin" last="Zhang">Shulin Zhang</name><affiliation><nlm:aff id="A7">University Hospitals Case Medical Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Cohen, Yvonne" sort="Cohen, Yvonne" uniqKey="Cohen Y" first="Yvonne" last="Cohen">Yvonne Cohen</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Chen, Wei" sort="Chen, Wei" uniqKey="Chen W" first="Wei" last="Chen">Wei Chen</name><affiliation><nlm:aff id="A6">National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</nlm:aff></affiliation></author><author><name sortKey="Yamada, Masahito" sort="Yamada, Masahito" uniqKey="Yamada M" first="Masahito" last="Yamada">Masahito Yamada</name><affiliation><nlm:aff id="A8">Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan</nlm:aff></affiliation></author><author><name sortKey="Hamaguchi, Tsuyoshi" sort="Hamaguchi, Tsuyoshi" uniqKey="Hamaguchi T" first="Tsuyoshi" last="Hamaguchi">Tsuyoshi Hamaguchi</name><affiliation><nlm:aff id="A8">Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan</nlm:aff></affiliation></author><author><name sortKey="Sanjo, Nobuo" sort="Sanjo, Nobuo" uniqKey="Sanjo N" first="Nobuo" last="Sanjo">Nobuo Sanjo</name><affiliation><nlm:aff id="A9">Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Mizusawa, Hidehiro" sort="Mizusawa, Hidehiro" uniqKey="Mizusawa H" first="Hidehiro" last="Mizusawa">Hidehiro Mizusawa</name><affiliation><nlm:aff id="A10">National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan</nlm:aff></affiliation></author><author><name sortKey="Nakamura, Yosikazu" sort="Nakamura, Yosikazu" uniqKey="Nakamura Y" first="Yosikazu" last="Nakamura">Yosikazu Nakamura</name><affiliation><nlm:aff id="A11">Department of Public Health, Jichi Medical University, Shimotsuke, Japan</nlm:aff></affiliation></author><author><name sortKey="Kitamoto, Tetsuyuki" sort="Kitamoto, Tetsuyuki" uniqKey="Kitamoto T" first="Tetsuyuki" last="Kitamoto">Tetsuyuki Kitamoto</name><affiliation><nlm:aff id="A12">Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan</nlm:aff></affiliation></author><author><name sortKey="Collins, Steven J" sort="Collins, Steven J" uniqKey="Collins S" first="Steven J." last="Collins">Steven J. Collins</name><affiliation><nlm:aff id="A13">Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Boyd, Alison" sort="Boyd, Alison" uniqKey="Boyd A" first="Alison" last="Boyd">Alison Boyd</name><affiliation><nlm:aff id="A13">Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia</nlm:aff></affiliation></author><author><name sortKey="Will, Robert G" sort="Will, Robert G" uniqKey="Will R" first="Robert G." last="Will">Robert G. Will</name><affiliation><nlm:aff id="A14">National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Western General Hospital, Edinburgh, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Knight, Richard" sort="Knight, Richard" uniqKey="Knight R" first="Richard" last="Knight">Richard Knight</name><affiliation><nlm:aff id="A14">National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Western General Hospital, Edinburgh, United Kingdom</nlm:aff></affiliation></author><author><name sortKey="Ponto, Claudia" sort="Ponto, Claudia" uniqKey="Ponto C" first="Claudia" last="Ponto">Claudia Ponto</name><affiliation><nlm:aff id="A15">National Reference Center for TSE, Georg-August University, Goettingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Zerr, Inga" sort="Zerr, Inga" uniqKey="Zerr I" first="Inga" last="Zerr">Inga Zerr</name><affiliation><nlm:aff id="A15">National Reference Center for TSE, Georg-August University, Goettingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Kraus, Theo F J" sort="Kraus, Theo F J" uniqKey="Kraus T" first="Theo F. J." last="Kraus">Theo F. J. Kraus</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Eigenbrod, Sabina" sort="Eigenbrod, Sabina" uniqKey="Eigenbrod S" first="Sabina" last="Eigenbrod">Sabina Eigenbrod</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Giese, Armin" sort="Giese, Armin" uniqKey="Giese A" first="Armin" last="Giese">Armin Giese</name><affiliation><nlm:aff id="A16">Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Calero, Miguel" sort="Calero, Miguel" uniqKey="Calero M" first="Miguel" last="Calero">Miguel Calero</name><affiliation><nlm:aff id="A17">Instituto de Salud Carlos III and CIBERNED, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="De Pedro Cuesta, Jesus" sort="De Pedro Cuesta, Jesus" uniqKey="De Pedro Cuesta J" first="Jesús" last="De Pedro-Cuesta">Jesús De Pedro-Cuesta</name><affiliation><nlm:aff id="A17">Instituto de Salud Carlos III and CIBERNED, Madrid, Spain</nlm:aff></affiliation></author><author><name sortKey="Haik, Stephane" sort="Haik, Stephane" uniqKey="Haik S" first="Stéphane" last="Haïk">Stéphane Haïk</name><affiliation><nlm:aff id="A18">Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A19">AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Laplanche, Jean Louis" sort="Laplanche, Jean Louis" uniqKey="Laplanche J" first="Jean-Louis" last="Laplanche">Jean-Louis Laplanche</name><affiliation><nlm:aff id="A20">AP-HP, Service de Biochimie et Biologie moléculaire, Hôpital Lariboisière, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Bouaziz Amar, Elodie" sort="Bouaziz Amar, Elodie" uniqKey="Bouaziz Amar E" first="Elodie" last="Bouaziz-Amar">Elodie Bouaziz-Amar</name><affiliation><nlm:aff id="A20">AP-HP, Service de Biochimie et Biologie moléculaire, Hôpital Lariboisière, Paris, France</nlm:aff></affiliation></author><author><name sortKey="Brandel, Jean Philippe" sort="Brandel, Jean Philippe" uniqKey="Brandel J" first="Jean-Philippe" last="Brandel">Jean-Philippe Brandel</name><affiliation><nlm:aff id="A18">Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France</nlm:aff></affiliation><affiliation><nlm:aff id="A19">AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Capellari, Sabina" sort="Capellari, Sabina" uniqKey="Capellari S" first="Sabina" last="Capellari">Sabina Capellari</name><affiliation><nlm:aff id="A21">IRCCS Institute of Neurological Sciences, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Parchi, Piero" sort="Parchi, Piero" uniqKey="Parchi P" first="Piero" last="Parchi">Piero Parchi</name><affiliation><nlm:aff id="A21">IRCCS Institute of Neurological Sciences, Bologna, Italy</nlm:aff></affiliation><affiliation><nlm:aff id="A22">Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy</nlm:aff></affiliation></author><author><name sortKey="Poleggi, Anna" sort="Poleggi, Anna" uniqKey="Poleggi A" first="Anna" last="Poleggi">Anna Poleggi</name><affiliation><nlm:aff id="A23">Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="Ladogana, Anna" sort="Ladogana, Anna" uniqKey="Ladogana A" first="Anna" last="Ladogana">Anna Ladogana</name><affiliation><nlm:aff id="A23">Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy</nlm:aff></affiliation></author><author><name sortKey="O Donnell Luria, Anne H" sort="O Donnell Luria, Anne H" uniqKey="O Donnell Luria A" first="Anne H." last="O'Donnell-Luria">Anne H. O'Donnell-Luria</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A24">Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, United States</nlm:aff></affiliation></author><author><name sortKey="Karczewski, Konrad J" sort="Karczewski, Konrad J" uniqKey="Karczewski K" first="Konrad J." last="Karczewski">Konrad J. Karczewski</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Marshall, Jamie L" sort="Marshall, Jamie L" uniqKey="Marshall J" first="Jamie L." last="Marshall">Jamie L. Marshall</name><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation></author><author><name sortKey="Boehnke, Michael" sort="Boehnke, Michael" uniqKey="Boehnke M" first="Michael" last="Boehnke">Michael Boehnke</name><affiliation><nlm:aff id="A25">University of Michigan School of Public Health, Ann Arbor, MI 48109, United States</nlm:aff></affiliation></author><author><name sortKey="Laakso, Markku" sort="Laakso, Markku" uniqKey="Laakso M" first="Markku" last="Laakso">Markku Laakso</name><affiliation><nlm:aff id="A26">Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland</nlm:aff></affiliation></author><author><name sortKey="Mohlke, Karen L" sort="Mohlke, Karen L" uniqKey="Mohlke K" first="Karen L." last="Mohlke">Karen L. Mohlke</name><affiliation><nlm:aff id="A27">Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States</nlm:aff></affiliation></author><author><name sortKey="K Hler, Anna" sort="K Hler, Anna" uniqKey="K Hler A" first="Anna" last="K Hler">Anna K Hler</name><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Chambert, Kimberly" sort="Chambert, Kimberly" uniqKey="Chambert K" first="Kimberly" last="Chambert">Kimberly Chambert</name><affiliation><nlm:aff id="A29">Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Mccarroll, Steven" sort="Mccarroll, Steven" uniqKey="Mccarroll S" first="Steven" last="Mccarroll">Steven Mccarroll</name><affiliation><nlm:aff id="A29">Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Sullivan, Patrick F" sort="Sullivan, Patrick F" uniqKey="Sullivan P" first="Patrick F." last="Sullivan">Patrick F. Sullivan</name><affiliation><nlm:aff id="A27">Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Hultman, Christina M" sort="Hultman, Christina M" uniqKey="Hultman C" first="Christina M." last="Hultman">Christina M. Hultman</name><affiliation><nlm:aff id="A28">Karolinska Institutet, Stockholm, Sweden</nlm:aff></affiliation></author><author><name sortKey="Purcell, Shaun M" sort="Purcell, Shaun M" uniqKey="Purcell S" first="Shaun M." last="Purcell">Shaun M. Purcell</name><affiliation><nlm:aff id="A30">Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States</nlm:aff></affiliation></author><author><name sortKey="Sklar, Pamela" sort="Sklar, Pamela" uniqKey="Sklar P" first="Pamela" last="Sklar">Pamela Sklar</name><affiliation><nlm:aff id="A30">Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States</nlm:aff></affiliation></author><author><name sortKey="Van Der Lee, Sven J" sort="Van Der Lee, Sven J" uniqKey="Van Der Lee S" first="Sven J." last="Van Der Lee">Sven J. Van Der Lee</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Rozemuller, Annemieke" sort="Rozemuller, Annemieke" uniqKey="Rozemuller A" first="Annemieke" last="Rozemuller">Annemieke Rozemuller</name><affiliation><nlm:aff id="A32">Prion Surveillance Center, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Jansen, Casper" sort="Jansen, Casper" uniqKey="Jansen C" first="Casper" last="Jansen">Casper Jansen</name><affiliation><nlm:aff id="A32">Prion Surveillance Center, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands</nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Kraaij, Robert" sort="Kraaij, Robert" uniqKey="Kraaij R" first="Robert" last="Kraaij">Robert Kraaij</name><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Rooij, Jeroen G J" sort="Van Rooij, Jeroen G J" uniqKey="Van Rooij J" first="Jeroen G. J." last="Van Rooij">Jeroen G. J. Van Rooij</name><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Ikram, M Arfan" sort="Ikram, M Arfan" uniqKey="Ikram M" first="M. Arfan" last="Ikram">M. Arfan Ikram</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation><affiliation><nlm:aff id="A33">Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Van Duijn, Cornelia M" sort="Van Duijn, Cornelia M" uniqKey="Van Duijn C" first="Cornelia M." last="Van Duijn">Cornelia M. Van Duijn</name><affiliation><nlm:aff id="A31">Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</nlm:aff></affiliation></author><author><name sortKey="Daly, Mark J" sort="Daly, Mark J" uniqKey="Daly M" first="Mark J." last="Daly">Mark J. Daly</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author><author><name sortKey="Macarthur, Daniel G" sort="Macarthur, Daniel G" uniqKey="Macarthur D" first="Daniel G." last="Macarthur">Daniel G. Macarthur</name><affiliation><nlm:aff id="A2">Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A1">Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</nlm:aff></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="ISSN">1946-6234</idno><idno type="eISSN">1946-6242</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">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. Here we assess the impact of variants in the prion protein
gene (<italic>PRNP</italic>) 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
<italic>PRNP</italic> previously reported to be pathogenic are at least
30× more common in the population than expected based on genetic prion
disease prevalence. While 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 <italic>PRNP</italic> have position-dependent effects, with true
loss-of-function alleles found in healthy older individuals, supporting the
safety of therapeutic suppression of prion protein expression.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101505086</journal-id><journal-id journal-id-type="pubmed-jr-id">36963</journal-id><journal-id journal-id-type="nlm-ta">Sci Transl Med</journal-id><journal-id journal-id-type="iso-abbrev">Sci Transl Med</journal-id><journal-title-group><journal-title>Science translational medicine</journal-title></journal-title-group><issn pub-type="ppub">1946-6234</issn><issn pub-type="epub">1946-6242</issn></journal-meta><article-meta><article-id pub-id-type="pmid">26791950</article-id><article-id pub-id-type="pmc">4774245</article-id><article-id pub-id-type="doi">10.1126/scitranslmed.aad5169</article-id><article-id pub-id-type="manuscript">NIHMS760972</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Quantifying penetrance in a dominant disease gene using large
population control cohorts</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Minikel</surname><given-names>Eric Vallabh</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A4">4</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Vallabh</surname><given-names>Sonia M.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Lek</surname><given-names>Monkol</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Estrada</surname><given-names>Karol</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Samocha</surname><given-names>Kaitlin E.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sathirapongsasuti</surname><given-names>J. 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contrib-type="author"><name><surname>McCarroll</surname><given-names>Steven</given-names></name><xref ref-type="aff" rid="A29">29</xref></contrib><contrib contrib-type="author"><name><surname>Sullivan</surname><given-names>Patrick F.</given-names></name><xref ref-type="aff" rid="A27">27</xref><xref ref-type="aff" rid="A28">28</xref></contrib><contrib contrib-type="author"><name><surname>Hultman</surname><given-names>Christina M.</given-names></name><xref ref-type="aff" rid="A28">28</xref></contrib><contrib contrib-type="author"><name><surname>Purcell</surname><given-names>Shaun M.</given-names></name><xref ref-type="aff" rid="A30">30</xref></contrib><contrib contrib-type="author"><name><surname>Sklar</surname><given-names>Pamela</given-names></name><xref ref-type="aff" rid="A30">30</xref></contrib><contrib contrib-type="author"><name><surname>van der Lee</surname><given-names>Sven J.</given-names></name><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Rozemuller</surname><given-names>Annemieke</given-names></name><xref ref-type="aff" rid="A32">32</xref></contrib><contrib contrib-type="author"><name><surname>Jansen</surname><given-names>Casper</given-names></name><xref ref-type="aff" rid="A32">32</xref></contrib><contrib contrib-type="author"><name><surname>Hofman</surname><given-names>Albert</given-names></name><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Kraaij</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="A33">33</xref></contrib><contrib contrib-type="author"><name><surname>van Rooij</surname><given-names>Jeroen G.J.</given-names></name><xref ref-type="aff" rid="A33">33</xref></contrib><contrib contrib-type="author"><name><surname>Ikram</surname><given-names>M. Arfan</given-names></name><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><name><surname>Uitterlinden</surname><given-names>André G.</given-names></name><xref ref-type="aff" rid="A31">31</xref><xref ref-type="aff" rid="A33">33</xref></contrib><contrib contrib-type="author"><name><surname>van Duijn</surname><given-names>Cornelia M.</given-names></name><xref ref-type="aff" rid="A31">31</xref></contrib><contrib contrib-type="author"><collab>Exome Aggregation Consortium (ExAC)</collab><xref ref-type="author-notes" rid="FN1">34</xref></contrib><contrib contrib-type="author"><name><surname>Daly</surname><given-names>Mark J.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>MacArthur</surname><given-names>Daniel G.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States</aff><aff id="A2"><label>2</label>Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States</aff><aff id="A3"><label>3</label>Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, United States</aff><aff id="A4"><label>4</label>Prion Alliance, Cambridge, MA 02139, United States</aff><aff id="A5"><label>5</label>Research, 23andMe Inc., Mountain View, CA 94041, United States</aff><aff id="A6"><label>6</label>National Prion Disease Pathology Surveillance Center, Cleveland, OH 44106, United States</aff><aff id="A7"><label>7</label>University Hospitals Case Medical Center, Cleveland, OH 44106, United States</aff><aff id="A8"><label>8</label>Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan</aff><aff id="A9"><label>9</label>Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan</aff><aff id="A10"><label>10</label>National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan</aff><aff id="A11"><label>11</label>Department of Public Health, Jichi Medical University, Shimotsuke, Japan</aff><aff id="A12"><label>12</label>Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan</aff><aff id="A13"><label>13</label>Australian National Creutzfeldt-Jakob Disease Registry, The University of Melbourne, Parkville, Australia</aff><aff id="A14"><label>14</label>National Creutzfeldt-Jakob Disease Research and Surveillance Unit, Western General Hospital, Edinburgh, United Kingdom</aff><aff id="A15"><label>15</label>National Reference Center for TSE, Georg-August University, Goettingen, Germany</aff><aff id="A16"><label>16</label>Center for Neuropathology and Prion Research (ZNP) at the Ludwig-Maximilians-University, Munich, Germany</aff><aff id="A17"><label>17</label>Instituto de Salud Carlos III and CIBERNED, Madrid, Spain</aff><aff id="A18"><label>18</label>Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ. Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France</aff><aff id="A19"><label>19</label>AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France</aff><aff id="A20"><label>20</label>AP-HP, Service de Biochimie et Biologie moléculaire, Hôpital Lariboisière, Paris, France</aff><aff id="A21"><label>21</label>IRCCS Institute of Neurological Sciences, Bologna, Italy</aff><aff id="A22"><label>22</label>Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy</aff><aff id="A23"><label>23</label>Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy</aff><aff id="A24"><label>24</label>Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, United States</aff><aff id="A25"><label>25</label>University of Michigan School of Public Health, Ann Arbor, MI 48109, United States</aff><aff id="A26"><label>26</label>Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland</aff><aff id="A27"><label>27</label>Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, United States</aff><aff id="A28"><label>28</label>Karolinska Institutet, Stockholm, Sweden</aff><aff id="A29"><label>29</label>Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, United States</aff><aff id="A30"><label>30</label>Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States</aff><aff id="A31"><label>31</label>Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands</aff><aff id="A32"><label>32</label>Prion Surveillance Center, Department of Pathology, University Medical Center, Utrecht 3584 CX, Netherlands</aff><aff id="A33"><label>33</label>Department of Internal Medicine, Erasmus MC, Rotterdam 3000 CA, The Netherlands</aff><author-notes><corresp id="cor1"><label>*</label>Correspondence may be addressed to:
<email>eminikel@broadinstitute.org</email> or
<email>macarthur@atgu.mgh.harvard.edu</email></corresp><fn id="FN1"><label>34</label><p id="P1">A list of consortium members may be found at <ext-link ext-link-type="uri" xlink:href="http://exac.broadinstitute.org/about">http://exac.broadinstitute.org/about</ext-link></p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>20</day><month>2</month><year>2016</year></pub-date><pub-date pub-type="ppub"><day>20</day><month>1</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>20</day><month>7</month><year>2016</year></pub-date><volume>8</volume><issue>322</issue><fpage>322ra9</fpage><lpage>322ra9</lpage><pmc-comment>elocation-id from pubmed: 10.1126/scitranslmed.aad5169</pmc-comment>
<abstract><p id="P2">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. Here we assess the impact of variants in the prion protein
gene (<italic>PRNP</italic>) 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
<italic>PRNP</italic> previously reported to be pathogenic are at least
30× more common in the population than expected based on genetic prion
disease prevalence. While 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 <italic>PRNP</italic> have position-dependent effects, with true
loss-of-function alleles found in healthy older individuals, supporting the
safety of therapeutic suppression of prion protein expression.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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