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

Abstract

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 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.

Keywords

Affiliated Institutions

• Columbia University Irving Medical Center US
• Harefield Hospital GB
• Harvard University US
• Assistance Publique – Hôpitaux de Paris FR
• Helsinki University Hospital FI
• Sorbonne Université FR
• Colorado School of Public Health US
• University of Pennsylvania US
• Hospital Del Mar ES
• Broad Institute US
• Wake Forest University US
• National Human Genome Research Institute US
• Massachusetts General Hospital US
• Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán MX
• University of Leicester GB
• University of Mississippi Medical Center US
• Christian-Albrechts-Universität zu Kiel DE
• Cleveland Clinic Lerner College of Medicine US
• Universitat de Vic - Universitat Central de Catalunya ES
• Imperial College London GB
• Albert Einstein College of Medicine US
• Instituto Nacional de Salud Pública MX
• Brigham and Women's Hospital US
• Framingham Heart Study US
• University of Illinois Chicago US
• University of Parma IT
• The University of Texas Health Science Center at Houston US
• Hadassah Medical Center IL
• Hôpital Saint-Antoine FR
• Michael J. Fox Foundation US
• Boston University US
• Lund University SE
• Glenfield Hospital GB
• University of Haifa IL
• National Institutes of Health US
• Cleveland Clinic US
• University of Eastern Finland FI
• 23andMe (United States) US
• Hospital del Mar Research Institute ES
• University of Michigan US
• NIHR Leicester Biomedical Research Centre GB
• Jackson Memorial Hospital US
• University of Lübeck DE
• Peninsula College of Medicine and Dentistry GB
• Chinese University of Hong Kong HK
• National Heart Lung and Blood Institute US
• Wellcome Sanger Institute GB
• MRC London Institute of Medical Sciences GB
• Statistical Research (United States) US
• German Centre for Cardiovascular Research DE
• Texas Biomedical Research Institute US
• SUNY Upstate Medical University US

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