The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses
Open accessAbstract
Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n ≈ 500,000) to impute exome-wide variants with accuracy R2 > 0.5 down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P < 5 × 10−8) involving 675 distinct rare protein-altering variants (MAF < 0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct ‘likely-causal’ variants. Our results demonstrate the utility of within-cohort imputation in population-scale genome-wide association studies, provide a catalog of likely-causal, large-effect coding variant associations and foreshadow the insights that will be revealed as genetic biobank studies continue to grow. Imputation of rare coding variants in the UK Biobank enables association and fine-mapping analyses of rare (minor allele frequency (MAF) = 0.00005) genotypes, identifying 600 new variant–trait associations, including long allelic series in individual genes.
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The UK Biobank resource with deep phenotyping and genomic data
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Self-citationCADD: predicting the deleteriousness of variants throughout the human genome
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Protein-coding repeat polymorphisms strongly shape diverse human phenotypes
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Self-citationWang, L., Nykänen, N.-P., Western, D., Gorijala, P., Timsina, J., Li, F., Wang, Z., Ali, M., Yang, C., Liu, M., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00687-4 · Cited by 58
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Metadata
- Authors
- Barton, A. R., Sherman, M. A., Mukamel, R. E., & Loh, P.-R.
- Venue
- Nature Genetics
- Published
- 2021-07-05
- Volume
- 53
- Issue
- 8
- Pages
- 1260-1269
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W3181537867
- Cited by
- 330
- References
- 16
- FWCI
- 24.80
- Type
- journal article
- Language
- en
- Open access
- green
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