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

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Genome Aggregation Database Prod T , Genome Aggregation Database Consor , 23andMe Res Team , Whiffin , N , Armean , I M , Kleinman , A , Havulinna , A S , Daly , M , Palotie , A , MacArthur , D G & Ripatti , S 2020 , ' The effect of LRRK2 loss-of-function variants in humans ' , Nature Medicine , vol. 26 , no. 6 , pp. 869-+ .

Title: The effect of LRRK2 loss-of-function variants in humans
Author: Genome Aggregation Database Prod T; Genome Aggregation Database Consor; 23andMe Res Team; Whiffin, Nicola; Armean, Irina M.; Kleinman, Aaron; Havulinna, Aki S.; Daly, Mark; Palotie, Aarno; MacArthur, Daniel G.; Ripatti, Samuli
Contributor organization: Medicum
Institute for Molecular Medicine Finland
Complex Disease Genetics
University of Helsinki
Centre of Excellence in Complex Disease Genetics
Research Programs Unit
Aarno Palotie / Principal Investigator
Genomics of Neurological and Neuropsychiatric Disorders
Helsinki Institute of Life Science HiLIFE
Department of Public Health
Samuli Olli Ripatti / Principal Investigator
University Management
Biostatistics Helsinki
HUS Helsinki and Uusimaa Hospital District
Date: 2020-06
Language: eng
Number of pages: 18
Belongs to series: Nature Medicine
ISSN: 1078-8956
Abstract: Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. 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.
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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