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

Genome Aggregation Database Consortium, 23andMe Research Team, Genome Aggregation Database Production Team

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalNature Medicine
Volume26
Issue number6
DOIs
StatePublished - 1 Jun 2020

Bibliographical note

Funding Information:
We thank the research participants and employees of 23andMe, Inc. and the research participants in gnomAD and the UK Biobank, for making this work possible. N. Whiffin is supported by a Rosetrees and Stoneygate Imperial College Research Fellowship. E.V. Minikel is supported by National Institutes of Health F31 AI22592. K.J.K. was supported by NIGMS F32 GM115208. This work was supported by the Michael J. Fox Foundation for Parkinson’s Research grant 12868, NIDDK U54DK105566, NIGMS R01GM104371, Wellcome Trust (107469/Z/15/Z); Medical Research Council (UK); NIHR Royal Brompton Biomedical Research Unit; NIHR Imperial Biomedical Research Centre. T.E is supported by Estonian Research Council grant PUT1660. L.M. is supported by Estonian Research Council grant PRG184. This research has been conducted using the UK Biobank Resource (https://doi.org/10.1101/572347) under Application Number 42890.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)

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