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Network expansion of genetic associations defines a pleiotropy map of human cell biology

View ORCID ProfileInigo Barrio-Hernandez, View ORCID ProfileJeremy Schwartzentruber, View ORCID ProfileAnjali Shrivastava, View ORCID ProfileNoemi del-Toro, Qian Zhang, Glyn Bradley, View ORCID ProfileHenning Hermjakob, View ORCID ProfileSandra Orchard, View ORCID ProfileIan Dunham, View ORCID ProfileCarl A. Anderson, View ORCID ProfilePablo Porras, View ORCID ProfilePedro Beltrao
doi: https://doi.org/10.1101/2021.07.19.452924
Inigo Barrio-Hernandez
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
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  • ORCID record for Inigo Barrio-Hernandez
Jeremy Schwartzentruber
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
3Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge,CB10 1SA, UK
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Anjali Shrivastava
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
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Noemi del-Toro
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
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Qian Zhang
3Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge,CB10 1SA, UK
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Glyn Bradley
4Computational Biology, Functional Genomics, GSK, Stevenage UK
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Henning Hermjakob
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
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  • ORCID record for Henning Hermjakob
Sandra Orchard
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
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  • ORCID record for Sandra Orchard
Ian Dunham
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
3Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge,CB10 1SA, UK
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Carl A. Anderson
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
3Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge,CB10 1SA, UK
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Pablo Porras
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
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Pedro Beltrao
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK
2Open Targets, Wellcome Genome Campus, Cambridge, CB10 1SA, UK
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  • For correspondence: pbeltrao@ebi.ac.uk
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Abstract

Proteins that interact within molecular networks tend to have similar functions and when perturbed influence the same organismal traits. Interaction networks can be used to expand the list of likely trait associated genes from genome-wide association studies (GWAS). Here, we used improvements in SNP-to-gene mapping to perform network based expansion of trait associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share a common genetic basis as well as the biological processes underlying this. We identified 73 pleiotropic gene modules linked to multiple traits that are enriched in genes involved in processes such as protein ubiquitination and RNA processing. We show examples of modules linked to human diseases enriched in genes with pathogenic variants found in patients or relevant mouse knock-out phenotypes and can be used to map targets of approved drugs for repurposing opportunities. Finally, we illustrate the use of the network expansion scores to study genes at inflammatory bowel disease (IBD) GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support.

Competing Interest Statement

CAA has received consultancy fees from Genomics plc and BridgeBio inc. GB is an employee of GSK.

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 19, 2021.
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Network expansion of genetic associations defines a pleiotropy map of human cell biology
Inigo Barrio-Hernandez, Jeremy Schwartzentruber, Anjali Shrivastava, Noemi del-Toro, Qian Zhang, Glyn Bradley, Henning Hermjakob, Sandra Orchard, Ian Dunham, Carl A. Anderson, Pablo Porras, Pedro Beltrao
bioRxiv 2021.07.19.452924; doi: https://doi.org/10.1101/2021.07.19.452924
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Network expansion of genetic associations defines a pleiotropy map of human cell biology
Inigo Barrio-Hernandez, Jeremy Schwartzentruber, Anjali Shrivastava, Noemi del-Toro, Qian Zhang, Glyn Bradley, Henning Hermjakob, Sandra Orchard, Ian Dunham, Carl A. Anderson, Pablo Porras, Pedro Beltrao
bioRxiv 2021.07.19.452924; doi: https://doi.org/10.1101/2021.07.19.452924

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