Evaluating drug targets through human loss-of-function genetic variation - Sorbonne Université Access content directly
Journal Articles Nature Year : 2020

Evaluating drug targets through human loss-of-function genetic variation

Eric Vallabh Minikel , Konrad Karczewski , Hilary Martin , Beryl Cummings , Nicola Whiffin , Daniel Rhodes , Jessica Alföldi , Richard Trembath , David van Heel , Mark Daly , Jessica Alföldi , Irina Armean , Eric Banks , Louis Bergelson , Kristian Cibulskis , Ryan Collins , Kristen Connolly , Miguel Covarrubias , Beryl Cummings , Mark Daly , Stacey Donnelly , Yossi Farjoun , Steven Ferriera , Laurent Francioli , Stacey Gabriel , Laura Gauthier , Jeff Gentry , Namrata Gupta , Thibault Jeandet , Diane Kaplan , Konrad Karczewski , Kristen Laricchia , Christopher Llanwarne , Eric Minikel , Ruchi Munshi , Benjamin Neale , Sam Novod , Anne O’donnell-Luria , Nikelle Petrillo , Timothy Poterba , David Roazen , Valentin Ruano-Rubio , Andrea Saltzman , Kaitlin Samocha , Molly Schleicher , Cotton Seed , Matthew Solomonson , Jose Soto , Grace Tiao , Kathleen Tibbetts , Charlotte Tolonen , Christopher Vittal , Gordon Wade , Arcturus Wang , Qingbo Wang , James Ware , Nicholas Watts , Ben Weisburd , Nicola Whiffin , Carlos Aguilar Salinas , Tariq Ahmad , Christine Albert , Diego Ardissino , Gil Atzmon , John Barnard , Laurent Beaugerie , Emelia Benjamin , Michael Boehnke , Lori Bonnycastle , Erwin Bottinger , Donald Bowden , Matthew Bown , John Chambers , Juliana Chan , Daniel Chasman , Judy Cho , Mina Chung , Bruce Cohen , Adolfo Correa , Dana Dabelea , Mark Daly , Dawood Darbar , Ravindranath Duggirala , Josée Dupuis , Patrick Ellinor , Roberto Elosua , Jeanette Erdmann , Tõnu Esko , Martti Färkkilä , Jose Florez , Andre Franke , Gad Getz , Benjamin Glaser , Stephen Glatt , David Goldstein , Clicerio Gonzalez , Leif Groop , Christopher Haiman , Craig Hanis , Matthew Harms , Mikko Hiltunen , Matti Holi , Christina Hultman , Mikko Kallela , Jaakko Kaprio , Sekar Kathiresan , Bong-Jo Kim , Young Jin Kim , George Kirov , Jaspal Kooner , Seppo Koskinen , Harlan Krumholz , Subra Kugathasan , Soo Heon Kwak , Markku Laakso , Terho Lehtimäki , Ruth Loos , Steven Lubitz , Ronald Ma , Daniel Macarthur , Jaume Marrugat , Kari Mattila , Steven Mccarroll , Mark Mccarthy , Dermot Mcgovern , Ruth Mcpherson , James Meigs , Olle Melander , Andres Metspalu , Benjamin Neale , Peter Nilsson , Michael O’donovan , Dost Ongur , Lorena Orozco , Michael Owen , Colin Palmer , Aarno Palotie , Kyong Soo Park , Carlos Pato , Ann Pulver , Nazneen Rahman , Anne Remes , John Rioux , Samuli Ripatti , Dan Roden , Danish Saleheen , Veikko Salomaa , Nilesh Samani , Jeremiah Scharf , Heribert Schunkert , Moore Shoemaker , Pamela Sklar , Hilkka Soininen , Harry Sokol (1) , Tim Spector , Patrick Sullivan , Jaana Suvisaari , E. Shyong Tai , Yik Ying Teo , Tuomi Tiinamaija , Ming Tsuang , Teresa Dan Turner , Teresa Tusie-Luna , Erkki Vartiainen , Marquis Vawter , James. Ware , Hugh Watkins , Rinse Weersma , Maija Wessman , James Wilson , Ramnik Xavier , Stuart Schreiber , Daniel Macarthur
Eric Vallabh Minikel
  • Function : Author
Konrad Karczewski
Hilary Martin
  • Function : Author
Beryl Cummings
  • Function : Author
Nicola Whiffin
  • Function : Author
Daniel Rhodes
  • Function : Author
Jessica Alföldi
Richard Trembath
  • Function : Author
David van Heel
Mark Daly
Jessica Alföldi
  • Function : Author
Irina Armean
  • Function : Author
Eric Banks
  • Function : Author
Louis Bergelson
  • Function : Author
Kristian Cibulskis
  • Function : Author
Ryan Collins
  • Function : Author
Kristen Connolly
  • Function : Author
Miguel Covarrubias
  • Function : Author
Beryl Cummings
  • Function : Author
Mark Daly
  • Function : Author
Stacey Donnelly
  • Function : Author
Yossi Farjoun
  • Function : Author
Steven Ferriera
  • Function : Author
Laurent Francioli
  • Function : Author
Stacey Gabriel
  • Function : Author
Laura Gauthier
  • Function : Author
Jeff Gentry
  • Function : Author
Namrata Gupta
  • Function : Author
Thibault Jeandet
  • Function : Author
Diane Kaplan
  • Function : Author
Konrad Karczewski
  • Function : Author
Kristen Laricchia
  • Function : Author
Christopher Llanwarne
  • Function : Author
Eric Minikel
  • Function : Author
Ruchi Munshi
  • Function : Author
Benjamin Neale
  • Function : Author
Sam Novod
  • Function : Author
Anne O’donnell-Luria
  • Function : Author
Nikelle Petrillo
  • Function : Author
Timothy Poterba
  • Function : Author
David Roazen
  • Function : Author
Valentin Ruano-Rubio
  • Function : Author
Andrea Saltzman
  • Function : Author
Kaitlin Samocha
  • Function : Author
Molly Schleicher
  • Function : Author
Cotton Seed
  • Function : Author
Matthew Solomonson
  • Function : Author
Jose Soto
  • Function : Author
Grace Tiao
  • Function : Author
Kathleen Tibbetts
  • Function : Author
Charlotte Tolonen
  • Function : Author
Christopher Vittal
  • Function : Author
Gordon Wade
  • Function : Author
Arcturus Wang
  • Function : Author
Qingbo Wang
  • Function : Author
James Ware
  • Function : Author
Nicholas Watts
  • Function : Author
Ben Weisburd
  • Function : Author
Nicola Whiffin
  • Function : Author
Carlos Aguilar Salinas
  • Function : Author
Tariq Ahmad
  • Function : Author
Christine Albert
  • Function : Author
Diego Ardissino
  • Function : Author
Gil Atzmon
  • Function : Author
John Barnard
  • Function : Author
Laurent Beaugerie
  • Function : Author
Emelia Benjamin
  • Function : Author
Michael Boehnke
  • Function : Author
Lori Bonnycastle
  • Function : Author
Erwin Bottinger
  • Function : Author
Donald Bowden
  • Function : Author
Matthew Bown
  • Function : Author
John Chambers
  • Function : Author
Juliana Chan
  • Function : Author
Daniel Chasman
  • Function : Author
Judy Cho
  • Function : Author
Mina Chung
  • Function : Author
Bruce Cohen
  • Function : Author
Adolfo Correa
  • Function : Author
Dana Dabelea
  • Function : Author
Mark Daly
  • Function : Author
Dawood Darbar
  • Function : Author
Ravindranath Duggirala
  • Function : Author
Josée Dupuis
  • Function : Author
Patrick Ellinor
  • Function : Author
Roberto Elosua
  • Function : Author
Jeanette Erdmann
  • Function : Author
Tõnu Esko
  • Function : Author
Martti Färkkilä
  • Function : Author
Jose Florez
  • Function : Author
Andre Franke
  • Function : Author
Gad Getz
  • Function : Author
Benjamin Glaser
  • Function : Author
Stephen Glatt
  • Function : Author
David Goldstein
  • Function : Author
Clicerio Gonzalez
  • Function : Author
Leif Groop
  • Function : Author
Christopher Haiman
  • Function : Author
Craig Hanis
  • Function : Author
Matthew Harms
  • Function : Author
Mikko Hiltunen
  • Function : Author
Matti Holi
  • Function : Author
Christina Hultman
  • Function : Author
Mikko Kallela
  • Function : Author
Jaakko Kaprio
  • Function : Author
Sekar Kathiresan
  • Function : Author
Bong-Jo Kim
  • Function : Author
Young Jin Kim
  • Function : Author
George Kirov
  • Function : Author
Jaspal Kooner
  • Function : Author
Seppo Koskinen
  • Function : Author
Harlan Krumholz
  • Function : Author
Subra Kugathasan
  • Function : Author
Soo Heon Kwak
  • Function : Author
Markku Laakso
  • Function : Author
Terho Lehtimäki
  • Function : Author
Ruth Loos
  • Function : Author
Steven Lubitz
  • Function : Author
Ronald Ma
  • Function : Author
Daniel Macarthur
  • Function : Author
Jaume Marrugat
  • Function : Author
Kari Mattila
  • Function : Author
Steven Mccarroll
  • Function : Author
Mark Mccarthy
  • Function : Author
Dermot Mcgovern
  • Function : Author
Ruth Mcpherson
  • Function : Author
James Meigs
  • Function : Author
Olle Melander
  • Function : Author
Andres Metspalu
  • Function : Author
Benjamin Neale
  • Function : Author
Peter Nilsson
  • Function : Author
Michael O’donovan
  • Function : Author
Dost Ongur
  • Function : Author
Lorena Orozco
  • Function : Author
Michael Owen
  • Function : Author
Colin Palmer
  • Function : Author
Aarno Palotie
  • Function : Author
Kyong Soo Park
  • Function : Author
Carlos Pato
  • Function : Author
Ann Pulver
  • Function : Author
Nazneen Rahman
  • Function : Author
Anne Remes
  • Function : Author
John Rioux
  • Function : Author
Samuli Ripatti
  • Function : Author
Dan Roden
  • Function : Author
Danish Saleheen
  • Function : Author
Veikko Salomaa
  • Function : Author
Nilesh Samani
  • Function : Author
Jeremiah Scharf
  • Function : Author
Heribert Schunkert
  • Function : Author
Moore Shoemaker
  • Function : Author
Pamela Sklar
  • Function : Author
Hilkka Soininen
  • Function : Author
Tim Spector
  • Function : Author
Patrick Sullivan
  • Function : Author
Jaana Suvisaari
  • Function : Author
E. Shyong Tai
  • Function : Author
Yik Ying Teo
  • Function : Author
Tuomi Tiinamaija
  • Function : Author
Ming Tsuang
  • Function : Author
Teresa Dan Turner
  • Function : Author
Teresa Tusie-Luna
  • Function : Author
Erkki Vartiainen
  • Function : Author
Marquis Vawter
  • Function : Author
James. Ware
  • Function : Author
Hugh Watkins
  • Function : Author
Rinse Weersma
  • Function : Author
Maija Wessman
  • Function : Author
James Wilson
  • Function : Author
Ramnik Xavier
  • Function : Author
Stuart Schreiber
  • Function : Author
Daniel Macarthur

Abstract

Abstract 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.

Dates and versions

hal-04007373 , version 1 (28-02-2023)

Identifiers

Cite

Eric Vallabh Minikel, Konrad Karczewski, Hilary Martin, Beryl Cummings, Nicola Whiffin, et al.. Evaluating drug targets through human loss-of-function genetic variation. Nature, 2020, 581 (7809), pp.459-464. ⟨10.1038/s41586-020-2267-z⟩. ⟨hal-04007373⟩
14 View
0 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More