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

Autor: Whiffin N; National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK. n.whiffin@imperial.ac.uk.; Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK. n.whiffin@imperial.ac.uk.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. n.whiffin@imperial.ac.uk., Armean IM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Kleinman A; 23andMe, Inc., Sunnyvale, CA, USA., Marshall JL; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Minikel EV; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Goodrich JK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Quaife NM; National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.; Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK., Cole JB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA., Wang Q; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA., Karczewski KJ; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Cummings BB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA., Francioli L; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Laricchia K; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Guan A; 23andMe, Inc., Sunnyvale, CA, USA., Alipanahi B; 23andMe, Inc., Sunnyvale, CA, USA.; Google, Inc., Mountain View, CA, USA., Morrison P; 23andMe, Inc., Sunnyvale, CA, USA., Baptista MAS; Michael J. Fox Foundation, New York, NY, USA., Merchant KM; Michael J. Fox Foundation, New York, NY, USA., Ware JS; National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK.; Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Havulinna AS; National Institute for Health and Welfare, Helsinki, Finland.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland., Iliadou B; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Lee JJ; Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Nadkarni GN; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Whiteman C; Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA., Daly M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Esko T; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Hultman C; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Loos RJF; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Milani L; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Palotie A; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pato C; Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA., Pato M; Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, NY, USA., Saleheen D; Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.; Center for Non-Communicable Diseases, Karachi, Pakistan., Sullivan PF; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA., Alföldi J; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA., Cannon P; 23andMe, Inc., Sunnyvale, CA, USA., MacArthur DG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. d.macarthur@garvan.org.au.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. d.macarthur@garvan.org.au.; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia. d.macarthur@garvan.org.au.; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia. d.macarthur@garvan.org.au.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2020 Jun; Vol. 26 (6), pp. 869-877. Date of Electronic Publication: 2020 May 27.
DOI: 10.1038/s41591-020-0893-5
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: