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Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants

Quanli Wang, View ORCID ProfileRyan S. Dhindsa, View ORCID ProfileKeren Carss, View ORCID ProfileAndrew Harper, Abhishek Nag, View ORCID ProfileIoanna Tachmazidou, View ORCID ProfileDimitrios Vitsios, View ORCID ProfileSri VV Deevi, Alex Mackay, View ORCID ProfileDaniel Muthas, Michael Hühn, View ORCID ProfileSusan Monkley, View ORCID ProfileHenric Olsson, Sebastian Wasilewski, Katherine R. Smith, View ORCID ProfileRuth March, View ORCID ProfileAdam Platt, Carolina Haefliger, View ORCID ProfileSlavé Petrovski, AstraZeneca Genomics Initiative
doi: https://doi.org/10.1101/2020.12.13.422582
Quanli Wang
1Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, USA
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Ryan S. Dhindsa
1Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, USA
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Keren Carss
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Andrew Harper
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Abhishek Nag
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Ioanna Tachmazidou
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Dimitrios Vitsios
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Sri VV Deevi
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Alex Mackay
3Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Daniel Muthas
3Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Michael Hühn
3Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Susan Monkley
3Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Henric Olsson
3Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Sebastian Wasilewski
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Katherine R. Smith
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Ruth March
4Precision Medicine & Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK
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Adam Platt
5Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Carolina Haefliger
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Slavé Petrovski
2Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
6Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
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  • For correspondence: slav.petrovski@astrazeneca.com
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Summary

The UK Biobank (UKB) represents an unprecedented population-based study of 502,543 participants with detailed phenotypic data and linkage to medical records. While the release of genotyping array data for this cohort has bolstered genomic discovery for common variants, the contribution of rare variants to this broad phenotype collection remains relatively unknown. Here, we use exome sequencing data from 177,882 UKB participants to evaluate the association between rare protein-coding variants with 10,533 binary and 1,419 quantitative phenotypes. We performed both a variant-level phenome-wide association study (PheWAS) and a gene-level collapsing analysis-based PheWAS tailored to detecting the aggregate contribution of rare variants. The latter revealed 911 statistically significant gene-phenotype relationships, with a median odds ratio of 15.7 for binary traits. Among the binary trait associations identified using collapsing analysis, 83% were undetectable using single variant association tests, emphasizing the power of collapsing analysis to detect signal in the setting of high allelic heterogeneity. As a whole, these genotype-phenotype associations were significantly enriched for loss-of-function mediated traits and currently approved drug targets. Using these results, we summarise the contribution of rare variants to common diseases in the context of the UKB phenome and provide an example of how novel gene-phenotype associations can aid in therapeutic target prioritisation.

Competing Interest Statement

The authors have declared no competing interest.

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 December 13, 2020.
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Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants
Quanli Wang, Ryan S. Dhindsa, Keren Carss, Andrew Harper, Abhishek Nag, Ioanna Tachmazidou, Dimitrios Vitsios, Sri VV Deevi, Alex Mackay, Daniel Muthas, Michael Hühn, Susan Monkley, Henric Olsson, Sebastian Wasilewski, Katherine R. Smith, Ruth March, Adam Platt, Carolina Haefliger, Slavé Petrovski, AstraZeneca Genomics Initiative
bioRxiv 2020.12.13.422582; doi: https://doi.org/10.1101/2020.12.13.422582
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Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants
Quanli Wang, Ryan S. Dhindsa, Keren Carss, Andrew Harper, Abhishek Nag, Ioanna Tachmazidou, Dimitrios Vitsios, Sri VV Deevi, Alex Mackay, Daniel Muthas, Michael Hühn, Susan Monkley, Henric Olsson, Sebastian Wasilewski, Katherine R. Smith, Ruth March, Adam Platt, Carolina Haefliger, Slavé Petrovski, AstraZeneca Genomics Initiative
bioRxiv 2020.12.13.422582; doi: https://doi.org/10.1101/2020.12.13.422582

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