@article {Karczewski531210, author = {Konrad J. Karczewski and Laurent C. Francioli and Grace Tiao and Beryl B. Cummings and Jessica Alf{\"o}ldi and Qingbo Wang and Ryan L. Collins and Kristen M. Laricchia and Andrea Ganna and Daniel P. Birnbaum and Laura D. Gauthier and Harrison Brand and Matthew Solomonson and Nicholas A. Watts and Daniel Rhodes and Moriel Singer-Berk and Eleanor G. Seaby and Jack A. Kosmicki and Raymond K. Walters and Katherine Tashman and Yossi Farjoun and Eric Banks and Timothy Poterba and Arcturus Wang and Cotton Seed and Nicola Whiffin and Jessica X. Chong and Kaitlin E. Samocha and Emma Pierce-Hoffman and Zachary Zappala and Anne H. O{\textquoteright}Donnell-Luria and Eric Vallabh Minikel and Ben Weisburd and Monkol Lek and James S. Ware and Christopher Vittal and Irina M. Armean and Louis Bergelson and Kristian Cibulskis and Kristen M. Connolly and Miguel Covarrubias and Stacey Donnelly and Steven Ferriera and Stacey Gabriel and Jeff Gentry and Namrata Gupta and Thibault Jeandet and Diane Kaplan and Christopher Llanwarne and Ruchi Munshi and Sam Novod and Nikelle Petrillo and David Roazen and Valentin Ruano-Rubio and Andrea Saltzman and Molly Schleicher and Jose Soto and Kathleen Tibbetts and Charlotte Tolonen and Gordon Wade and Michael E. Talkowski and The Genome Aggregation Database Consortium and Benjamin M. Neale and Mark J. Daly and Daniel G. MacArthur}, editor = {Salinas, Carlos A Aguilar and Ahmad, Tariq and Albert, Christine M. and Ardissino, Diego and Atzmon, Gil and Barnard, John and Beaugerie, Laurent and Benjamin, Emelia J. and Boehnke, Michael and Bonnycastle, Lori L. and Bottinger, Erwin P. and Bowden, Donald W and Bown, Matthew J and Chambers, John C and Chan, Juliana C. and Chasman, Daniel and Cho, Judy and Chung, Mina K. and Cohen, Bruce and Correa, Adolfo and Dabelea, Dana and Daly, Mark J. and Darbar, Dawood and Duggirala, Ravindranath and Dupuis, Jos{\'e}e and Ellinor, Patrick T. and Elosua, Roberto and Erdmann, Jeanette and Esko, T{\~o}nu and F{\"a}rkkil{\"a}, Martti and Florez, Jose and Franke, Andre and Getz, Gad and Glaser, Benjamin and Glatt, Stephen J. and Goldstein, David and Gonzalez, Clicerio and Groop, Leif and Haiman, Christopher and Hanis, Craig and Harms, Matthew and Hiltunen, Mikko and Holi, Matti M. and Hultman, Christina M. and Kallela, Mikko and Kaprio, Jaakko and Kathiresan, Sekar and Kim, Bong-Jo and Kim, Young Jin and Kirov, George and Kooner, Jaspal and Koskinen, Seppo and Krumholz, Harlan M. and Kugathasan, Subra and Kwak, Soo Heon and Laakso, Markku and Lehtim{\"a}ki, Terho and Loos, Ruth J.F. and Lubitz, Steven A. and Ma, Ronald C.W. and MacArthur, Daniel G. and Marrugat, Jaume and Mattila, Kari M. and McCarroll, Steven and McCarthy, Mark I and McGovern, Dermot and McPherson, Ruth and Meigs, James B. and Melander, Olle and Metspalu, Andres and Neale, Benjamin M and Nilsson, Peter M and O{\textquoteright}Donovan, Michael C and Ongur, Dost and Orozco, Lorena and Owen, Michael J and Palmer, Colin N. A. and Palotie, Aarno and Park, Kyong Soo and Pato, Carlos and Pulver, Ann E. and Rahman, Nazneen and Remes, Anne M. and Rioux, John D. and Ripatti, Samuli and Roden, Dan M. and Saleheen, Danish and Salomaa, Veikko and Samani, Nilesh J. and Scharf, Jeremiah and Schunkert, Heribert and Shoemaker, Moore B. and Sklar, Pamela and Soininen, Hilkka and Sokol, Harry and Spector, Tim and Sullivan, Patrick F. and Suvisaari, Jaana and Tai, E Shyong and Teo, Yik Ying and Tiinamaija, Tuomi and Tsuang, Ming and Turner, Dan and Tusie-Luna, Teresa and Vartiainen, Erkki and Ware, James S and Watkins, Hugh and Weersma, Rinse K and Wessman, Maija and Wilson, James G. and Xavier, Ramnik J.}, title = {Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes}, elocation-id = {531210}, year = {2019}, doi = {10.1101/531210}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism{\textquoteright}s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.}, URL = {https://www.biorxiv.org/content/early/2019/01/30/531210}, eprint = {https://www.biorxiv.org/content/early/2019/01/30/531210.full.pdf}, journal = {bioRxiv} }