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

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dc.contributor.author Genome Aggregation Database Prod T
dc.contributor.author Genome Aggregation Database Consor
dc.contributor.author 23andMe Res Team
dc.contributor.author Whiffin, Nicola
dc.contributor.author Armean, Irina M.
dc.contributor.author Kleinman, Aaron
dc.contributor.author Havulinna, Aki S.
dc.contributor.author Daly, Mark
dc.contributor.author Palotie, Aarno
dc.contributor.author MacArthur, Daniel G.
dc.contributor.author Ripatti, Samuli
dc.date.accessioned 2020-07-16T05:31:01Z
dc.date.available 2020-07-16T05:31:01Z
dc.date.issued 2020-06
dc.identifier.citation 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-+ . https://doi.org/10.1038/s41591-020-0893-5
dc.identifier.other PURE: 140714433
dc.identifier.other PURE UUID: 01ab5f3b-7a09-4c6a-a0bc-cae4245bbd96
dc.identifier.other WOS: 000541166000028
dc.identifier.other WOS: 000535873800002
dc.identifier.other ORCID: /0000-0002-2527-5874/work/97266661
dc.identifier.uri http://hdl.handle.net/10138/317759
dc.description.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. en
dc.format.extent 18
dc.language.iso eng
dc.relation.ispartof Nature Medicine
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject DISEASE-ASSOCIATED MUTATIONS
dc.subject PARKINSONS-DISEASE
dc.subject EPIDEMIOLOGY
dc.subject COHORT
dc.subject GENE
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title The effect of LRRK2 loss-of-function variants in humans en
dc.type Article
dc.contributor.organization Medicum
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Complex Disease Genetics
dc.contributor.organization University of Helsinki
dc.contributor.organization Centre of Excellence in Complex Disease Genetics
dc.contributor.organization Research Programs Unit
dc.contributor.organization Aarno Palotie / Principal Investigator
dc.contributor.organization Genomics of Neurological and Neuropsychiatric Disorders
dc.contributor.organization Helsinki Institute of Life Science HiLIFE
dc.contributor.organization Department of Public Health
dc.contributor.organization Samuli Olli Ripatti / Principal Investigator
dc.contributor.organization University Management
dc.contributor.organization Biostatistics Helsinki
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1038/s41591-020-0893-5
dc.relation.issn 1078-8956
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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