| Title: | Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses |
| Journal: | Nature Genetics |
| Published: | 5 Jul 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34226706/ |
| DOI: | https://doi.org/10.1038/s41588-021-00892-1 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349845 |
| Citations: | 131 (99 in last 2 years) as of 8 Aug 2024 |
Publication 6009
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Abstract
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.</p>
4 Authors
- Alison R. Barton
- Maxwell A. Sherman
- Ronen E. Mukamel
- Po-Ru Loh
Enabling scientific discoveries that improve human health