Journal Article

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

Cole, Joanne B., Baptista, Marco A. S., Whiteman, Cole, Cummings, Beryl B., Merchant, Kalpana M., Lee, Jung-Jin, Whiffin, Nicola, Sullivan, Patrick F., Cannon, Paul, Havulinna, Aki S., Morrison, Peter, Wang, Qingbo, Armean, Irina M., Goodrich, Julia K., Iliadou, Bozenna, Loos, Ruth J. F., Hultman, Christina, Kleinman, Aaron, Alföldi, Jessica, Alipanahi, Babak, Quaife, Nicholas M., Nadkarni, Girish N., Pato, Carlos, Ware, James S., Saleheen, Danish, Karczewski, Konrad J., Milani, Lili, Palotie, Aarno, Pato, Michele, Francioli, Laurent, Minikel, Eric V., Esko, Tõnu, Guan, Anna, Marshall, Jamie L., Daly, Mark, Laricchia, Kristen, MacArthur, Daniel G.

2020

Overview

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. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212 / 692/699/375 / Adult / Aged / Aged, 80 and over / Basic Medicine / Biocompatibility / Biological Specimen Banks / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell Line / Datasets / Deactivation / Drug discovery / Embryonic Stem Cells - metabolism / Female / Gain of Function Mutation - genetics / Genetic aspects / Genetic diversity / Genetic variance / Genetic variation / Genetics / Genomes / Genomic analysis / Health aspects / Heterozygote / Humans / Inactivation / Infectious Diseases / Kinases / Letter / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - antagonists & inhibitors / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics / Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism / Life Sciences / Longevity - genetics / Loss of Function Mutation - genetics / LRRK2 protein / Lymphocytes - metabolism / Male / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Metabolic Diseases / Middle Aged / Molecular Medicine / Myocytes, Cardiac - metabolism / Neurosciences / Parkinson Disease - drug therapy / Parkinson Disease - genetics / Parkinson's disease / Phenotype / Phenotypes / Phenotyping / Phosphotransferases / Proteins / Risk factors / Toxicity