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Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease

View ORCID ProfileNicola Whiffin, Irina M. Armean, Aaron Kleinman, Jamie L. Marshall, View ORCID ProfileEric V. Minikel, View ORCID ProfileKonrad J. Karczewski, View ORCID ProfileBeryl B. Cummings, View ORCID ProfileLaurent Francioli, Kristen Laricchia, Qingbo Wang, Anna Guan, View ORCID ProfileBabak Alipanahi, Peter Morrison, Marco A.S. Baptista, Kalpana M. Merchant, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, View ORCID ProfileJames S. Ware, Aki S. Havulinna, Bozenna Iliadou, Jung-Jin Lee, Girish N. Nadkarni, Cole Whiteman, the 23andMe Research Team, Mark Daly, View ORCID ProfileTõnu Esko, View ORCID ProfileChristina Hultman, View ORCID ProfileRuth J.F. Loos, View ORCID ProfileLili Milani, Aarno Palotie, Carlos Pato, Michele Pato, View ORCID ProfileDanish Saleheen, Patrick F. Sullivan, Jessica Alföldi, Paul Cannon, Daniel G. MacArthur
doi: https://doi.org/10.1101/561472
Nicola Whiffin
1National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
2Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Irina M. Armean
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Aaron Kleinman
523andMe, Inc.
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Jamie L. Marshall
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Eric V. Minikel
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Konrad J. Karczewski
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Beryl B. Cummings
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
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Laurent Francioli
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Kristen Laricchia
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Qingbo Wang
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
7Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
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Anna Guan
523andMe, Inc.
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Babak Alipanahi
523andMe, Inc.
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Peter Morrison
523andMe, Inc.
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Marco A.S. Baptista
8Michael J. Fox Foundation
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Kalpana M. Merchant
8Michael J. Fox Foundation
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James S. Ware
1National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
2Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Aki S. Havulinna
9Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
10National Institute for Health and Welfare, 00271, Helsinki, Finland
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Bozenna Iliadou
11Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Jung-Jin Lee
12Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Girish N. Nadkarni
13The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
14Department of Medicine, Icahn School of Medicine at Mount Sinai
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Cole Whiteman
15Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, New York
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Mark Daly
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
16Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Tõnu Esko
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
17Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Christina Hultman
11Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
14Department of Medicine, Icahn School of Medicine at Mount Sinai
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Ruth J.F. Loos
13The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
18The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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Lili Milani
17Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Aarno Palotie
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
16Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Carlos Pato
15Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, New York
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Michele Pato
15Department of Psychiatry and the Behavioral Sciences, State University of New York, Downstate Medical Center, New York, New York
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Danish Saleheen
12Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
19Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
20Center for Non-Communicable Diseases, Karachi, Pakistan
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Patrick F. Sullivan
11Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
21Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
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Jessica Alföldi
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Paul Cannon
523andMe, Inc.
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Daniel G. MacArthur
3Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Abstract

Human genetic variants causing loss-of-function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns5–8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9 and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 27, 2019.
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Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease
Nicola Whiffin, Irina M. Armean, Aaron Kleinman, Jamie L. Marshall, Eric V. Minikel, Konrad J. Karczewski, Beryl B. Cummings, Laurent Francioli, Kristen Laricchia, Qingbo Wang, Anna Guan, Babak Alipanahi, Peter Morrison, Marco A.S. Baptista, Kalpana M. Merchant, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, James S. Ware, Aki S. Havulinna, Bozenna Iliadou, Jung-Jin Lee, Girish N. Nadkarni, Cole Whiteman, the 23andMe Research Team, Mark Daly, Tõnu Esko, Christina Hultman, Ruth J.F. Loos, Lili Milani, Aarno Palotie, Carlos Pato, Michele Pato, Danish Saleheen, Patrick F. Sullivan, Jessica Alföldi, Paul Cannon, Daniel G. MacArthur
bioRxiv 561472; doi: https://doi.org/10.1101/561472
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Human loss-of-function variants suggest that partial LRRK2 inhibition is a safe therapeutic strategy for Parkinson’s disease
Nicola Whiffin, Irina M. Armean, Aaron Kleinman, Jamie L. Marshall, Eric V. Minikel, Konrad J. Karczewski, Beryl B. Cummings, Laurent Francioli, Kristen Laricchia, Qingbo Wang, Anna Guan, Babak Alipanahi, Peter Morrison, Marco A.S. Baptista, Kalpana M. Merchant, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, James S. Ware, Aki S. Havulinna, Bozenna Iliadou, Jung-Jin Lee, Girish N. Nadkarni, Cole Whiteman, the 23andMe Research Team, Mark Daly, Tõnu Esko, Christina Hultman, Ruth J.F. Loos, Lili Milani, Aarno Palotie, Carlos Pato, Michele Pato, Danish Saleheen, Patrick F. Sullivan, Jessica Alföldi, Paul Cannon, Daniel G. MacArthur
bioRxiv 561472; doi: https://doi.org/10.1101/561472

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