The effect of LRRK2 loss-of-function variants in humans.
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2020-05-27
Date Acceptance
2020-04-20
Citation
Nature Medicine, 2020, 26, pp.869-877
ISSN
1078-8956
Publisher
Nature Research
Start Page
869
End Page
877
Journal / Book Title
Nature Medicine
Volume
26
Replaces
10044/1/79583
Copyright Statement
© The Author(s) 2020. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The images or other
third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
Sponsor
Imper
Rosetrees Trust
Wellcome Trust
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32461697
PII: 10.1038/s41591-020-0893-5
Grant Number
Imperial College London
M735
107469/Z/15/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
DISEASE-ASSOCIATED MUTATIONS
PARKINSONS-DISEASE
EPIDEMIOLOGY
COHORT
GENE
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
DISEASE-ASSOCIATED MUTATIONS
PARKINSONS-DISEASE
EPIDEMIOLOGY
COHORT
GENE
Adult
Aged
Aged, 80 and over
Biological Specimen Banks
Cell Line
Embryonic Stem Cells
Female
Gain of Function Mutation
Heterozygote
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Longevity
Loss of Function Mutation
Lymphocytes
Male
Middle Aged
Myocytes, Cardiac
Parkinson Disease
Phenotype
Genome Aggregation Database Production Team
Genome Aggregation Database Consortium
23andMe Research Team
Lymphocytes
Cell Line
Myocytes, Cardiac
Humans
Parkinson Disease
Longevity
Heterozygote
Phenotype
Adult
Aged
Aged, 80 and over
Middle Aged
Biological Specimen Banks
Female
Male
Embryonic Stem Cells
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Loss of Function Mutation
Gain of Function Mutation
Genome Aggregation Database Production Team
Genome Aggregation Database Consortium
the 23andMe Research Team
Immunology
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-05-27