Rare variant contribution to human disease in 281,104 UK Biobank exomes.
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Authors
Wang, Quanli
Carss, Keren
Nag, Abhishek
Tachmazidou, Ioanna
Vitsios, Dimitrios
Mackay, Alex
Muthas, Daniel
Hühn, Michael
Monkley, Susan
AstraZeneca Genomics Initiative
Wasilewski, Sebastian
Smith, Katherine R
March, Ruth
Publication Date
2021-09Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Volume
597
Issue
7877
Pages
527-532
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Wang, Q., Dhindsa, R. S., Carss, K., Harper, A. R., Nag, A., Tachmazidou, I., Vitsios, D., et al. (2021). Rare variant contribution to human disease in 281,104 UK Biobank exomes.. Nature, 597 (7877), 527-532. https://doi.org/10.1038/s41586-021-03855-y
Abstract
Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits1,2. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ ).
Keywords
AstraZeneca Genomics Initiative
Identifiers
External DOI: https://doi.org/10.1038/s41586-021-03855-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329919
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