Evaluating drug targets through human loss-of-function genetic variation
Authors: Minikel Eric Vallabh , Karczewski Konrad J. , Martin Hilary C. , Cummings Beryl B. , Whiffin Nicola , Rhodes Daniel , Alföldi Jessica , Trembath Richard C. , van Heel David A. , Daly Mark J. ,   Genome Aggregation Database Production Team, Alföldi Jessica , Armean Irina M. , Banks Eric , Bergelson Louis , Cibulskis Kristian , Collins Ryan L. , Connolly Kristen M. , Covarrubias Miguel , Cummings Beryl B. , Daly Mark J. , Donnelly Stacey , Farjoun Yossi , Ferriera Steven , Francioli Laurent , Gabriel Stacey , Gauthier Laura D. , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Karczewski Konrad J. , Laricchia Kristen M. , Llanwarne Christopher , Minikel Eric V. , Munshi Ruchi , Neale Benjamin M. , Novod Sam , O’Donnell-Luria Anne H. , Petrillo Nikelle , Poterba Timothy , Roazen David , Ruano-Rubio Valentin , Saltzman Andrea , Samocha Kaitlin E. , Schleicher Molly , Seed Cotton , Solomonson Matthew , Soto Jose , Tiao Grace , Tibbetts Kathleen , Tolonen Charlotte , Vittal Christopher , Wade Gordon , Wang Arcturus , Wang Qingbo , Ware James S. , Watts Nicholas A. , Weisburd Ben , Whiffin Nicola ,   Genome Aggregation Database Consortium, Aguilar Salinas Carlos A. , Ahmad Tariq , Albert Christine M. , Ardissino Diego , Atzmon Gil , Barnard John , Beaugerie Laurent , Benjamin Emelia J. , Boehnke Michael , Bonnycastle Lori L. , Bottinger Erwin P. , Bowden Donald W. , Bown Matthew J. , Chambers John C. , Chan Juliana C. , Chasman Daniel , Cho Judy , Chung Mina K. , Cohen Bruce , Correa Adolfo , Dabelea Dana , Daly Mark J. , Darbar Dawood , Duggirala Ravindranath , Dupuis Josée , Ellinor Patrick T. , Elosua Roberto , Erdmann Jeanette , Esko Tõnu , Färkkilä Martti , Florez Jose , Franke Andre , Getz Gad , Glaser Benjamin , Glatt Stephen J. , Goldstein David , Gonzalez Clicerio , Groop Leif , Haiman Christopher , Hanis Craig , Harms Matthew , Hiltunen Mikko , Holi Matti M. , Hultman Christina M. , Kallela Mikko , Kaprio Jaakko , Kathiresan Sekar , Kim Bong-Jo , Kim Young Jin , Kirov George , Kooner Jaspal , Koskinen Seppo , Krumholz Harlan M. , Kugathasan Subra , Kwak Soo Heon , Laakso Markku , Lehtimäki Terho , Loos Ruth J. F. , Lubitz Steven A. , Ma Ronald C. W. , MacArthur Daniel G. , Marrugat Jaume , Mattila Kari M. , McCarroll Steven , McCarthy Mark I. , McGovern Dermot , McPherson Ruth , Meigs James B. , Melander Olle , Metspalu Andres , Neale Benjamin M. , Nilsson Peter M. , O’Donovan Michael C. , Ongur Dost , Orozco Lorena , Owen Michael J. , Palmer Colin N. A. , Palotie Aarno , Park Kyong Soo , Pato Carlos , Pulver Ann E. , Rahman Nazneen , Remes Anne M. , Rioux John D. , Ripatti Samuli , Roden Dan M. , Saleheen Danish , Salomaa Veikko , Samani Nilesh J. , Scharf Jeremiah , Schunkert Heribert , Shoemaker Moore B. , Sklar Pamela , Soininen Hilkka , Sokol Harry , Spector Tim , Sullivan Patrick F. , Suvisaari Jaana , Tai E. Shyong , Teo Yik Ying , Tiinamaija Tuomi , Tsuang Ming , Dan Turner Teresa , Tusie-Luna Teresa , Vartiainen Erkki , Vawter Marquis P. , Ware James. S. , Watkins Hugh , Weersma Rinse K. , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Schreiber Stuart L. , MacArthur Daniel G. 
Published: May 2020

Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous ‘knockout’ humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.