The effect of LRRK2 loss-of-function variants in humans
Authors: Nicola Whiffin, Irina M. Armean, Aaron Kleinman, Jamie L. Marshall, Eric V. Minikel, Julia K. Goodrich, Nicholas M. Quaife, Joanne B. Cole, Qingbo Wang, Konrad J. Karczewski, Beryl B. Cummings, Laurent Francioli, Kristen Laricchia, Anna Guan, Babak Alipanahi, Peter Morrison, Marco A. S. Baptista, Kalpana M. Merchant, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L. Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Stacey Gabriel, Laura D. Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Kristen M. Laricchia, Christopher Llanwarne, Ruchi Munshi, Benjamin M. Neale, Sam Novod, Anne H. O’Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, Matthew Solomonson, Jose Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Nicholas A. Watts, Ben Weisburd, Carlos A. Aguilar-Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, John C. Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J. F. Loos, Steven A. Lubitz, Ronald C. W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Peter M. Nilsson, Michael C. O’Donovan, Dost Ongur, Lorena Orozco, Michael J. Owen, Colin N. A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Riou, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Sokol, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Marquis P. Vawter, James S. Ware, Hugh Watkins, Rinse K. Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, James S. Ware, Aki S. Havulinna, Bozenna Iliadou, Jung-Jin Lee, Girish N. Nadkarni, Cole Whiteman, Michelle Agee, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, Barry Hicks, David A. Hinds, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Keng-Han Lin, Nadia K. Litterman, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A. M. Northover, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Xin Wang, Catherine H. Wilson, Mark Daly, Tõnu Esko, Christina Hultman, Ruth J. F. Loos, Lili Milani, Aarno Palotie, Carlos Pato, Michele Pato, Danish Saleheen, Patrick F. Sullivan, Jessica Alföldi, Paul Cannon, Daniel G. MacArthur
Journal: Nature Medicine (2020)

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.