Dataset Information

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

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 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 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.

SUBMITTER: Whiffin N

PROVIDER: S-EPMC7303015 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Whiffin Nicola N Armean Irina M IM Kleinman Aaron A Marshall Jamie L JL Minikel Eric V EV Goodrich Julia K JK Quaife Nicholas M NM Cole Joanne B JB Wang Qingbo Q Karczewski Konrad J KJ Cummings Beryl B BB Francioli Laurent L Laricchia Kristen K Guan Anna A Alipanahi Babak B Morrison Peter P Baptista Marco A S MAS Merchant Kalpana M KM Ware James S JS Havulinna Aki S AS Iliadou Bozenna B Lee Jung-Jin JJ Nadkarni Girish N GN Whiteman Cole C Daly Mark M Esko Tõnu T Hultman Christina C Loos Ruth J F RJF Milani Lili L Palotie Aarno A Pato Carlos C Pato Michele M Saleheen Danish D Sullivan Patrick F PF Alföldi Jessica J Cannon Paul P MacArthur Daniel G DG

Nature medicine 20200527 6

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 s ...[more]

PMID: 32461697

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Project description:Importance:Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. Objective:To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. Design, Setting, and Participants:To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23?000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Main Outcomes and Measures:Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Results:Among 11?095 cases with PD and 12?615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio,?1.48; SE,?0.571; 95% CI, 0.45-4.44; P?=?.49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE,?0.431; 95% CI, 0.63-3.50; P?=?.36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Conclusions and Relevance:Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

Dataset Information

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

Publications

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

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