The effect of LRRK2 loss-of-function variants in humans
Authors: Whiffin Nicola , Armean Irina M. , Kleinman Aaron , Marshall Jamie L. , Minikel Eric V. , Goodrich Julia K. , Quaife Nicholas M. , Cole Joanne B. , Wang Qingbo , Karczewski Konrad J. , Cummings Beryl B. , Francioli Laurent , Laricchia Kristen , Guan Anna , Alipanahi Babak , Morrison Peter , Baptista Marco A. S. , Merchant Kalpana M. ,   Genome Aggregation Database Production Team, Armean Irina M. , Banks Eric , Bergelson Louis , Cibulskis Kristian , Collins Ryan L. , Connolly Kristen M. , Covarrubias Miguel , Cummings Beryl , Daly Mark J. , Donnelly Stacey , Farjoun Yossi , Ferriera Steven , Gabriel Stacey , Gauthier Laura D. , Gentry Jeff , Gupta Namrata , Jeandet Thibault , Kaplan Diane , Laricchia Kristen M. , Llanwarne Christopher , 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 , Watts Nicholas A. , Weisburd Ben ,   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 , Darbar Dawood , Duggirala Ravindranath , Dupuis Josée , Ellinor Patrick T. , Elosua Roberto , Erdmann Jeanette , 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 , 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. , Riou 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 , Turner Dan , Tusie-Luna Teresa , Vartiainen Erkki , Vawter Marquis P. , Ware James S. , Watkins Hugh , Weersma Rinse K. , Wessman Maija , Wilson James G. , Xavier Ramnik J. , Ware James S. , Havulinna Aki S. , Iliadou Bozenna , Lee Jung-Jin , Nadkarni Girish N. , Whiteman Cole ,   23andMe Research Team, Agee Michelle , Auton Adam , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Fontanillas Pierre , Furlotte Nicholas A. , Hicks Barry , Hinds David A. , Huber Karen E. , Jewett Ethan M. , Jiang Yunxuan , Lin Keng-Han , Litterman Nadia K. , McIntyre Matthew H. , McManus Kimberly F. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Pitts Steven J. , Poznik G. David , Sathirapongsasuti J. Fah , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Vacic Vladimir , Wang Xin , Wilson Catherine H. , Daly Mark , Esko Tõnu , Hultman Christina , Loos Ruth J. F. , Milani Lili , Palotie Aarno , Pato Carlos , Pato Michele , Saleheen Danish , Sullivan Patrick F. , Alföldi Jessica , Cannon Paul , MacArthur Daniel G. 
Published: May 2020

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 genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5–8, 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 work10, 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.