| Title: | Uncovering variable neoplasms between ATM protein-truncating and common missense variants using 394 694 UK Biobank exomes |
| Journal: | Genes Chromosomes and Cancer |
| Published: | 16 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35394676/ |
| DOI: | https://doi.org/10.1002/gcc.23042 |
| Citations: | 3 (3 in last 2 years) as of 8 Aug 2024 |
Publication 12410
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Abstract
As an essential regulator of DNA damage, ataxia-telangiectasia mutated (ATM) gene has been widely studied in oncology. However, the independent effects of ATM missense variants and protein-truncating variants (PTVs) on neoplasms have not been heavily studied. Whole-exome sequencing data and the clinical health records of 394,694 UK Biobank European participants were used in this analysis. We mined genetic associations from gene-level and variant-level phenome-wide association studies, and conducted a variant-level conditional association study to test whether the effects of ATM missense variants on neoplasms were independent of ATM PTV carrier status. The gene-level PTV collapsing analysis was consistent with established ATM PTV literature showing that the aggregated impact of 286 ATM PTVs significantly (p < 2 × 10-9 ) associated with 31 malignant neoplasm phenotypes. Of 773 distinct protein-coding variants in ATM, three individual missense variants significantly (p < 2 × 10-9 ) associated with nine phenotypes. Remarkably, although the nine phenotypes were tumor-related, none overlapped the established ATM PTV-linked malignancies. A subsequent conditional analysis identified that the missense signals were acting independently of the known clinically relevant ATM PTVs.</p>
12 Keywords
- Ataxia Telangiectasia Mutated Proteins
- Biological Specimen Banks
- Breast Neoplasms
- Cell Cycle Proteins
- DNA-Binding Proteins
- Exome
- Female
- Genetic Predisposition to Disease
- Humans
- Mutation, Missense
- Neoplasms
- United Kingdom
7 Authors
- Xiao Jiang
- Amanda O'Neill
- Katherine R. Smith
- Zhongwu Lai
- Keren Carss
- Quanli Wang
- Slavé Petrovski
1 Application
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
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