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Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank

Christopher DeBoever, AJ Venkatakrishnan, Joseph M Paggi, Franziska M. Heydenreich, Suli-Anne Laurin, Matthieu Masureel, View ORCID ProfileYosuke Tanigawa, Guhan Venkataraman, Michel Bouvier, Ron O. Dror, Manuel A. Rivas
doi: https://doi.org/10.1101/2019.12.13.876250
Christopher DeBoever
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, 94305, USA
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  • For correspondence: cdeboeve@stanford.edu ajvenkat@stanford.edu rondror@stanford.edu mrivas@stanford.edu
AJ Venkatakrishnan
2Department of Computer Science, Stanford University, Stanford, CA, 94305, USA
3Department of Molecular and Cellular Physiology, School of Medicine, Stanford, CA 94305, USA
4Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
5Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: cdeboeve@stanford.edu ajvenkat@stanford.edu rondror@stanford.edu mrivas@stanford.edu
Joseph M Paggi
2Department of Computer Science, Stanford University, Stanford, CA, 94305, USA
3Department of Molecular and Cellular Physiology, School of Medicine, Stanford, CA 94305, USA
4Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
5Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA
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Franziska M. Heydenreich
3Department of Molecular and Cellular Physiology, School of Medicine, Stanford, CA 94305, USA
6Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, H3T 1J4, Canada
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Suli-Anne Laurin
6Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, H3T 1J4, Canada
7Faculty of Medicine, Molecular biology program, Université de Montréal, Montréal, QC, H3T 1J4, Canada
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Matthieu Masureel
3Department of Molecular and Cellular Physiology, School of Medicine, Stanford, CA 94305, USA
8Department of Structural Biology, Genentech, South San Francisco, CA 94080, USA
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Yosuke Tanigawa
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, 94305, USA
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  • ORCID record for Yosuke Tanigawa
Guhan Venkataraman
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, 94305, USA
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Michel Bouvier
6Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, H3T 1J4, Canada
9Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada
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Ron O. Dror
2Department of Computer Science, Stanford University, Stanford, CA, 94305, USA
3Department of Molecular and Cellular Physiology, School of Medicine, Stanford, CA 94305, USA
4Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA
5Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: cdeboeve@stanford.edu ajvenkat@stanford.edu rondror@stanford.edu mrivas@stanford.edu
Manuel A. Rivas
1Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, CA, 94305, USA
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  • For correspondence: cdeboeve@stanford.edu ajvenkat@stanford.edu rondror@stanford.edu mrivas@stanford.edu
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Abstract

G protein-coupled receptors (GPCRs) drive an array of critical physiological functions and are an important class of drug targets, though a map of which GPCR genetic variants are associated with phenotypic variation is lacking. We performed a phenome-wide association analysis for 269 common protein-altering variants in 156 GPCRs and 275 phenotypes, including disease outcomes and diverse quantitative measurements, using 337,205 UK Biobank participants and identified 138 associations. We discovered novel associations between GPCR variants and migraine risk, hypothyroidism, and dietary consumption. We also demonstrated experimentally that variants in the β2 adrenergic receptor (ADRB2) associated with immune cell counts and pulmonary function and variants in the gastric inhibitory polypeptide receptor (GIPR) associated with food intake and body size affect downstream signaling pathways. Overall, this study provides a map of genetic associations for GPCR coding variants across a wide variety of phenotypes, which can inform future drug discovery efforts targeting GPCRs.

Competing Interest Statement

M.B. is the president of the scientific advisory board of Domain Therapeutics. The BRET-based biosensors used in this study are licensed to Domain Therapeutics for commercial use, but all biosensors are available for free from the laboratory of M.B. for academic research without commercial goals upon request under a regular material transfer agreement. M.A.R. is on the SAB of 54Gene and Computational Advisory Board for Goldfinch Bio and has advised BioMarin, Third Rock Ventures, MazeTx and Related Sciences. The remaining authors declare no competing interests.

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-NC-ND 4.0 International license.
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Posted May 28, 2020.
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Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank
Christopher DeBoever, AJ Venkatakrishnan, Joseph M Paggi, Franziska M. Heydenreich, Suli-Anne Laurin, Matthieu Masureel, Yosuke Tanigawa, Guhan Venkataraman, Michel Bouvier, Ron O. Dror, Manuel A. Rivas
bioRxiv 2019.12.13.876250; doi: https://doi.org/10.1101/2019.12.13.876250
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Medical relevance of common protein-altering variants in GPCR genes across 337,205 individuals in the UK Biobank
Christopher DeBoever, AJ Venkatakrishnan, Joseph M Paggi, Franziska M. Heydenreich, Suli-Anne Laurin, Matthieu Masureel, Yosuke Tanigawa, Guhan Venkataraman, Michel Bouvier, Ron O. Dror, Manuel A. Rivas
bioRxiv 2019.12.13.876250; doi: https://doi.org/10.1101/2019.12.13.876250

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