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Open Targets Genetics: An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci

Edward Mountjoy, Ellen M. Schmidt, Miguel Carmona, Gareth Peat, Alfredo Miranda, Luca Fumis, James Hayhurst, Annalisa Buniello, Jeremy Schwartzentruber, Mohd Anisul Karim, Daniel Wright, Andrew Hercules, Eliseo Papa, Eric Fauman, Jeffrey C. Barrett, John A. Todd, David Ochoa, Ian Dunham, Maya Ghoussaini
doi: https://doi.org/10.1101/2020.09.16.299271
Edward Mountjoy
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Ellen M. Schmidt
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Miguel Carmona
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Gareth Peat
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Alfredo Miranda
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Luca Fumis
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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James Hayhurst
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Annalisa Buniello
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Jeremy Schwartzentruber
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Mohd Anisul Karim
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Daniel Wright
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Andrew Hercules
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Eliseo Papa
4Systems Biology, Biogen, Cambridge, MA, 02142, United States
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Eric Fauman
5Integrative Biology, Internal Medicine Research Unit, Pfizer Worldwide Research, Development and Medical, Cambridge, MA 02139, United States
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Jeffrey C. Barrett
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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John A. Todd
6Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
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David Ochoa
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Ian Dunham
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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Maya Ghoussaini
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
2Open Targets, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK
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  • For correspondence: mg29@sanger.ac.uk
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Abstract

Genome-wide association studies (GWAS) have identified many variants robustly associated with complex traits but identifying the gene(s) mediating such associations is a major challenge. Here we present an open resource that provides systematic fine-mapping and protein-coding gene prioritization across 133,441 published human GWAS loci. We integrate diverse data sources, including genetics (from GWAS Catalog and UK Biobank) as well as transcriptomic, proteomic and epigenomic data across many tissues and cell types. We also provide systematic disease-disease and disease-molecular trait colocalization results across 92 cell types and tissues and identify 729 loci fine-mapped to a single coding causal variant and colocalized with a single gene. We trained a machine learning model using the fine mapped genetics and functional genomics data using 445 gold standard curated GWAS loci to distinguish causal genes from background genes at the same loci, outperforming a naive distance based model. Genes prioritized by our model are enriched for known approved drug targets (OR = 8.1, 95% CI: [5.7, 11.5]). These results will be regularly updated and are publicly available through a web portal, Open Targets Genetics (OTG, http://genetics.opentargets.org), enabling users to easily prioritize genes at disease-associated loci and assess their potential as drug targets.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • We have pointed out that this paper is focused on human GWAS rather than GWAS in general.

  • http://genetics.opentargets.org

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-ND 4.0 International license.
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Posted September 21, 2020.
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Open Targets Genetics: An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci
Edward Mountjoy, Ellen M. Schmidt, Miguel Carmona, Gareth Peat, Alfredo Miranda, Luca Fumis, James Hayhurst, Annalisa Buniello, Jeremy Schwartzentruber, Mohd Anisul Karim, Daniel Wright, Andrew Hercules, Eliseo Papa, Eric Fauman, Jeffrey C. Barrett, John A. Todd, David Ochoa, Ian Dunham, Maya Ghoussaini
bioRxiv 2020.09.16.299271; doi: https://doi.org/10.1101/2020.09.16.299271
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Open Targets Genetics: An open approach to systematically prioritize causal variants and genes at all published human GWAS trait-associated loci
Edward Mountjoy, Ellen M. Schmidt, Miguel Carmona, Gareth Peat, Alfredo Miranda, Luca Fumis, James Hayhurst, Annalisa Buniello, Jeremy Schwartzentruber, Mohd Anisul Karim, Daniel Wright, Andrew Hercules, Eliseo Papa, Eric Fauman, Jeffrey C. Barrett, John A. Todd, David Ochoa, Ian Dunham, Maya Ghoussaini
bioRxiv 2020.09.16.299271; doi: https://doi.org/10.1101/2020.09.16.299271

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