TY - JOUR
T1 - The effect of LRRK2 loss-of-function variants in humans
AU - Genome Aggregation Database Production Team
AU - Genome Aggregation Database Consortium
AU - 23andMe Research Team
AU - Whiffin, Nicola
AU - Armean, Irina M.
AU - Kleinman, Aaron
AU - Marshall, Jamie L.
AU - Minikel, Eric V.
AU - Goodrich, Julia K.
AU - Quaife, Nicholas M.
AU - Cole, Joanne B.
AU - Wang, Qingbo
AU - Karczewski, Konrad J.
AU - Cummings, Beryl B.
AU - Francioli, Laurent
AU - Laricchia, Kristen
AU - Guan, Anna
AU - Alipanahi, Babak
AU - Morrison, Peter
AU - Baptista, Marco A.S.
AU - Merchant, Kalpana M.
AU - Alföldi, Jessica
AU - Armean, Irina M.
AU - Banks, Eric
AU - Bergelson, Louis
AU - Cibulskis, Kristian
AU - Collins, Ryan L.
AU - Connolly, Kristen M.
AU - Covarrubias, Miguel
AU - Cummings, Beryl
AU - Daly, Mark J.
AU - Donnelly, Stacey
AU - Farjoun, Yossi
AU - Ferriera, Steven
AU - Francioli, Laurent
AU - Gabriel, Stacey
AU - Gauthier, Laura D.
AU - Gentry, Jeff
AU - Gupta, Namrata
AU - Jeandet, Thibault
AU - Kaplan, Diane
AU - Karczewski, Konrad J.
AU - Laricchia, Kristen M.
AU - Llanwarne, Christopher
AU - Minikel, Eric V.
AU - Munshi, Ruchi
AU - Neale, Benjamin M.
AU - Novod, Sam
AU - O’Donnell-Luria, Anne H.
AU - Petrillo, Nikelle
AU - Poterba, Timothy
AU - Roazen, David
AU - Turner, Dan
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085479654&partnerID=8YFLogxK
U2 - 10.1038/s41591-020-0893-5
DO - 10.1038/s41591-020-0893-5
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C2 - 32461697
AN - SCOPUS:85085479654
SN - 1078-8956
VL - 26
SP - 869
EP - 877
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -