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

Whiffin, Nicola ; Groop, Leif LU ; Melander, Olle LU orcid ; Nilsson, Peter M. LU and MacArthur, Daniel G (2020) In Nature Medicine p.869-877
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... (More)

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.

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author
; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Medicine
pages
869 - 877
publisher
Nature Publishing Group
external identifiers
  • pmid:32461697
  • scopus:85085479654
ISSN
1078-8956
DOI
10.1038/s41591-020-0893-5
language
English
LU publication?
yes
id
7cc3be42-2a25-45b9-9d96-9b974fda97fd
date added to LUP
2020-06-23 11:57:35
date last changed
2024-11-01 06:40:00
@article{7cc3be42-2a25-45b9-9d96-9b974fda97fd,
  abstract     = {{<p>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<sup>1,2</sup>. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease<sup>3,4</sup>, 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<sup>5–8</sup>, 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)<sup>9</sup>, 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<sup>10</sup>, 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.</p>}},
  author       = {{Whiffin, Nicola and Groop, Leif and Melander, Olle and Nilsson, Peter M. and MacArthur, Daniel G}},
  issn         = {{1078-8956}},
  language     = {{eng}},
  pages        = {{869--877}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Medicine}},
  title        = {{The effect of LRRK2 loss-of-function variants in humans}},
  url          = {{http://dx.doi.org/10.1038/s41591-020-0893-5}},
  doi          = {{10.1038/s41591-020-0893-5}},
  year         = {{2020}},
}