Analysis of protein-coding genetic variation in 60,706 humans

Monkol Lek, Konrad J. Karczewski, Eric V. Minikel, Kaitlin E. Samocha, Eric Banks, Timothy Fennell, Anne H. O'Donnell-Luria, James S. Ware, Andrew J. Hill, Beryl B. Cummings, Taru Tukiainen, Daniel P. Birnbaum, Jack A. Kosmicki, Laramie E. Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, Joanne Berghout, David N. CooperNicole Deflaux, Mark DePristo, Ron Do, Jason Flannick, Menachem Fromer, Laura Gauthier, Jackie Goldstein, Namrata Gupta, Daniel Howrigan, Adam Kiezun, Mitja I. Kurki, Ami Levy Moonshine, Pradeep Natarajan, Lorena Orozco, Gina M. Peloso, Ryan Poplin, Manuel A. Rivas, Valentin Ruano-Rubio, Samuel A. Rose, Douglas M. Ruderfer, Khalid Shakir, Peter D. Stenson, Christine Stevens, Brett P. Thomas, Grace Tiao, Maria T. Tusie-Luna, Ben Weisburd, Hong Hee Won, Dongmei Yu, David M. Altshuler, Diego Ardissino, Michael Boehnke, John Danesh, Stacey Donnelly, Roberto Elosua, Jose C. Florez, Stacey B. Gabriel, Gad Getz, Stephen J. Glatt, Christina M. Hultman, Sekar Kathiresan, Markku Laakso, Steven McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, Benjamin M. Neale, Aarno Palotie, Shaun M. Purcell, Danish Saleheen, Jeremiah M. Scharf, Pamela Sklar, Patrick F. Sullivan, Jaakko Tuomilehto, Ming T. Tsuang, Hugh C. Watkins, James G. Wilson, Mark J. Daly, Daniel G. MacArthur, H. E. Abboud, G. Abecasis, C. A. Aguilar-Salinas, O. Arellano-Campos, G. Atzmon, I. Aukrust, C. L. Barr, G. I. Bell, S. Bergen, L. Bjørkhaug, J. Blangero, D. W. Bowden, C. L. Budman, N. P. Burtt, F. Centeno-Cruz, J. C. Chambers, K. Chambert, R. Clarke, R. Collins, G. Coppola, E. J. Córdova, M. L. Cortes, N. J. Cox, R. Duggirala, M. Farrall, J. C. Fernandez-Lopez, P. Fontanillas, T. M. Frayling, N. B. Freimer, C. Fuchsberger, H. García-Ortiz, A. Goel, M. J. Gómez-Vázquez, M. E. González-Villalpando, C. González-Villalpando, M. A. Grados, L. Groop, C. A. Haiman, C. L. Hanis, A. T. Hattersley, B. E. Henderson, J. C. Hopewell, A. Huerta-Chagoya, S. Islas-Andrade, S. B. Jacobs, S. Jalilzadeh, C. P. Jenkinson, J. Moran, S. Jiménez-Morale, A. Kähler, R. A. King, G. Kirov, J. S. Kooner, T. Kyriakou, J. Y. Lee, D. M. Lehman, G. Lyon, W. MacMahon, P. K. Magnusson, A. Mahajan, J. Marrugat, A. Martínez-Hernández, C. A. Mathews, G. McVean, J. B. Meigs, T. Meitinger, E. Mendoza-Caamal, J. M. Mercader, K. L. Mohlke, H. Moreno-Macías, A. P. Morris, L. A. Najmi, P. R. Njølstad, M. C. O'Donovan, M. L. Ordóñez-Sánchez, M. J. Owen, T. Park, D. L. Pauls, D. Posthuma, C. Revilla-Monsalve, L. Riba, S. Ripke, R. Rodríguez-Guillén, M. Rodríguez-Torres, P. Sandor, M. Seielstad, R. Sladek, X. Soberón, T. D. Spector, S. E. Tai, T. M. Teslovich, G. Walford, L. R. Wilkens, A. L. Williams

Research output: Contribution to journalArticlepeer-review

Abstract

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.

Original languageEnglish (US)
Pages (from-to)285-291
Number of pages7
JournalNature
Volume536
Issue number7616
DOIs
StatePublished - Aug 17 2016

ASJC Scopus subject areas

  • General

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