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Journal Articles Nature Medicine Year : 2020

The effect of LRRK2 loss-of-function variants in humans

Nicola Whiffin , Irina Armean , Aaron Kleinman , Jamie Marshall , Eric Minikel , Julia Goodrich , Nicholas Quaife , Joanne Cole , Qingbo Wang , Konrad Karczewski , Beryl Cummings , Laurent Francioli , Kristen Laricchia , Anna Guan , Babak Alipanahi , Peter Morrison , Marco Baptista , Kalpana Merchant , Irina Armean , Eric Banks , Louis Bergelson , Kristian Cibulskis , Ryan Collins , Kristen Connolly , Miguel Covarrubias , Beryl Cummings , Mark Daly , Stacey Donnelly , Yossi Farjoun , Steven Ferriera , Stacey Gabriel , Laura Gauthier , Jeff Gentry , Namrata Gupta , Thibault Jeandet , Diane Kaplan , Kristen Laricchia , Christopher Llanwarne , 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 , Nicholas Watts , Ben Weisburd , 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 , Dawood Darbar , Ravindranath Duggirala , Josée Dupuis , Patrick Ellinor , Roberto Elosua , Jeanette Erdmann , 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 , 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 Riou , 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 , Dan Turner , Teresa Tusie-Luna , Erkki Vartiainen , Marquis Vawter , James Ware , Hugh Watkins , Rinse Weersma , Maija Wessman , James Wilson , Ramnik Xavier , James Ware , Aki Havulinna , Bozenna Iliadou , Jung-Jin Lee , Girish Nadkarni , Cole Whiteman , Michelle Agee , Adam Auton , Robert Bell , Katarzyna Bryc , Sarah Elson , Pierre Fontanillas , Nicholas Furlotte , Barry Hicks , David Hinds , Karen Huber , Ethan Jewett , Yunxuan Jiang , Keng-Han Lin , Nadia Litterman , Matthew Mcintyre , Kimberly Mcmanus , Joanna Mountain , Elizabeth Noblin , Carrie Northover , Steven Pitts , G. David Poznik , J. Fah Sathirapongsasuti , Janie Shelton , Suyash Shringarpure , Chao Tian , Joyce Tung , Vladimir Vacic , Xin Wang , Catherine Wilson , Mark Daly , Tõnu Esko , Christina Hultman , Ruth Loos , Lili Milani , Aarno Palotie , Carlos Pato , Michele Pato , Danish Saleheen , Patrick Sullivan , Jessica Alföldi , Paul Cannon , Daniel Macarthur
Nicola Whiffin
Irina Armean
Aaron Kleinman
  • Function : Author
Jamie Marshall
Eric Minikel
  • Function : Author
Julia Goodrich
  • Function : Author
Nicholas Quaife
Joanne Cole
Qingbo Wang
Konrad Karczewski
Beryl Cummings
Laurent Francioli
Kristen Laricchia
  • Function : Author
Anna Guan
  • Function : Author
Babak Alipanahi
Peter Morrison
  • Function : Author
Marco Baptista
  • Function : Author
Kalpana Merchant
  • 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
Stacey Gabriel
  • Function : Author
Laura Gauthier
  • Function : Author
Jeff Gentry
  • Function : Author
Namrata Gupta
  • Function : Author
Thibault Jeandet
  • Function : Author
Diane Kaplan
  • Function : Author
Kristen Laricchia
  • Function : Author
Christopher Llanwarne
  • 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
Nicholas Watts
  • Function : Author
Ben Weisburd
  • 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
Dawood Darbar
  • Function : Author
Ravindranath Duggirala
  • Function : Author
Josée Dupuis
  • Function : Author
Patrick Ellinor
  • Function : Author
Roberto Elosua
  • Function : Author
Jeanette Erdmann
  • 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
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 Riou
  • 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
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
James Ware
Aki Havulinna
Bozenna Iliadou
  • Function : Author
Jung-Jin Lee
  • Function : Author
Girish Nadkarni
  • Function : Author
Cole Whiteman
  • Function : Author
Michelle Agee
  • Function : Author
Adam Auton
  • Function : Author
Robert Bell
  • Function : Author
Katarzyna Bryc
  • Function : Author
Sarah Elson
  • Function : Author
Pierre Fontanillas
  • Function : Author
Nicholas Furlotte
  • Function : Author
Barry Hicks
  • Function : Author
David Hinds
  • Function : Author
Karen Huber
  • Function : Author
Ethan Jewett
  • Function : Author
Yunxuan Jiang
  • Function : Author
Keng-Han Lin
  • Function : Author
Nadia Litterman
  • Function : Author
Matthew Mcintyre
  • Function : Author
Kimberly Mcmanus
  • Function : Author
Joanna Mountain
  • Function : Author
Elizabeth Noblin
  • Function : Author
Carrie Northover
  • Function : Author
Steven Pitts
  • Function : Author
G. David Poznik
  • Function : Author
J. Fah Sathirapongsasuti
  • Function : Author
Janie Shelton
  • Function : Author
Suyash Shringarpure
  • Function : Author
Chao Tian
  • Function : Author
Joyce Tung
  • Function : Author
Vladimir Vacic
  • Function : Author
Xin Wang
  • Function : Author
Catherine Wilson
  • Function : Author
Mark Daly
  • Function : Author
Tõnu Esko
Christina Hultman
  • Function : Author
Ruth Loos
Lili Milani
Aarno Palotie
  • Function : Author
Carlos Pato
  • Function : Author
Michele Pato
  • Function : Author
Danish Saleheen
Patrick Sullivan
  • Function : Author
Jessica Alföldi
Paul Cannon
  • Function : Author
Daniel Macarthur

Abstract

Abstract Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes 1,2 . Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease 3,4 , suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns 5–8 , the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) 9 , 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2 . Experimental validation of three variants, combined with previous work 10 , confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.

Dates and versions

hal-04007431 , version 1 (28-02-2023)

Identifiers

Cite

Nicola Whiffin, Irina Armean, Aaron Kleinman, Jamie Marshall, Eric Minikel, et al.. The effect of LRRK2 loss-of-function variants in humans. Nature Medicine, 2020, 26 (6), pp.869-877. ⟨10.1038/s41591-020-0893-5⟩. ⟨hal-04007431⟩
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