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

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.

Type Journal
ISBN 1546-170X (Electronic) 1078-8956 (Linking)
Authors Whiffin, N.; Armean, I. M.; Kleinman, A.; Marshall, J. L.; Minikel, E. V.; Goodrich, J. K.; Quaife, N. M.; Cole, J. B.; Wang, Q.; Karczewski, K. J.; Cummings, B. B.; Francioli, L.; Laricchia, K.; Guan, A.; Alipanahi, B.; Morrison, P.; Baptista, M. A. S.; Merchant, K. M.; Genome Aggregation Database Production, Team; Genome Aggregation Database, Consortium; Ware, J. S.; Havulinna, A. S.; Iliadou, B.; Lee, J. J.; Nadkarni, G. N.; Whiteman, C.; andMe Research, Team; Daly, M.; Esko, T.; Hultman, C.; Loos, R. J. F.; Milani, L.; Palotie, A.; Pato, C.; Pato, M.; Saleheen, D.; Sullivan, P. F.; Alfoldi, J.; Cannon, P.; MacArthur, D. G.
Responsible Garvan Author Daniel MacArthur
Publisher Name NATURE MEDICINE
Published Date 2020-06-01
Published Volume 26
Published Issue 6
Published Pages 869-877
Status Published in-print
DOI 10.1038/s41591-020-0893-5
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32461697