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Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

View ORCID ProfileYosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Susanna Lemmelä, Joni A. Turunen, Robert Graham, Aki S. Havulinna, Markus Perola, Aarno Palotie, FinnGen, View ORCID ProfileMark J. Daly, View ORCID ProfileManuel A. Rivas
doi: https://doi.org/10.1101/677443
Yosuke Tanigawa
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA
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Michael Wainberg
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA
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Juha Karjalainen
2Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Tuomo Kiiskinen
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
5Finnish Institute for Health and Welfare, Helsinki, Finland
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Susanna Lemmelä
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
5Finnish Institute for Health and Welfare, Helsinki, Finland
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Joni A. Turunen
6Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
7Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
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Robert Graham
8Maze Therapeutics, San Francisco, CA, USA
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Aki S. Havulinna
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
5Finnish Institute for Health and Welfare, Helsinki, Finland
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Markus Perola
5Finnish Institute for Health and Welfare, Helsinki, Finland
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Aarno Palotie
2Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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Mark J. Daly
2Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA
3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
4Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
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  • For correspondence: mrivas@stanford.edu mjdaly@broadinstitute.org
Manuel A. Rivas
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, USA
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  • For correspondence: mrivas@stanford.edu mjdaly@broadinstitute.org
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Abstract

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data in UK Biobank and FinnGen to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through protein-altering variant association analysis we find a missense variant in UK Biobank (rs28991009 (MAF=0.8%) genotyped in 81,527 individuals with measured IOP and an independent set of 4,269 glaucoma patients and 251,355 controls) that significantly lowers IOP (β = −0.73 mmHg for heterozygotes, −2.96 mmHg for homozygotes, P = 1 × 10−13) and is associated with 34% reduced risk of glaucoma (P = 0.005). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.1%), which was genotyped in 5,177 glaucoma patients and 130,461 controls and is associated with 30% lower glaucoma risk (P = 1 × 10−9). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.002), suggesting the protective mechanism likely resides in the loss of an interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma

Footnotes

  • https://biobankengine.stanford.edu

  • https://github.com/rivas-lab/ANGPTL7

Copyright 
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 July 04, 2019.
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Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma
Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Susanna Lemmelä, Joni A. Turunen, Robert Graham, Aki S. Havulinna, Markus Perola, Aarno Palotie, FinnGen, Mark J. Daly, Manuel A. Rivas
bioRxiv 677443; doi: https://doi.org/10.1101/677443
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Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma
Yosuke Tanigawa, Michael Wainberg, Juha Karjalainen, Tuomo Kiiskinen, Susanna Lemmelä, Joni A. Turunen, Robert Graham, Aki S. Havulinna, Markus Perola, Aarno Palotie, FinnGen, Mark J. Daly, Manuel A. Rivas
bioRxiv 677443; doi: https://doi.org/10.1101/677443

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