| Title: | Ultra-rare functional variants reveal early-onset breast cancer risk genes and pathways in the UK Biobank and All of Us Research Program |
| Journal: | American Journal of Human Genetics |
| Published: | 30 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41916322/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2026.03.005 |
Publication 18155
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Abstract
Breast cancer (BRCA) affects one in eight women, and while past studies have identified susceptibility genes and variants, those driving early-onset disease remain opaque. We introduce EA-Pathways, a control-free association method that aggregates ultra-rare germline coding variants weighted by Evolutionary Action to detect functional impact distribution biases in genes and pathways. In UK Biobank women with BRCA, EA-Pathways prioritized candidate risk genes across pathways enriched in known familial genes. Ultra-rare, high-impact variants in these genes were BRCA specific, and variants from eight pathways were associated with 2-year-earlier disease, including homology-directed DNA repair, TP53, and pexophagy pathways. The early-onset effect replicated in All of Us with diagnoses up to 6, 9, and 3 years earlier in European, admixed American, and African genetic ancestries, highlighting risk alleles with differing frequencies between ancestry groups. These findings demonstrate EA-Pathways as a sensitive pathway association method capable of identifying cancer-predisposing genes and ancestry-informed BRCA screening opportunities.</p>
8 Authors
- Jennifer Asmussen
- Kevin Wilhelm
- Kwanghyuk Lee
- Chen Wang
- Panagiotis Katsonis
- Yi Li
- Lawrence A Donehower
- Olivier Lichtarge
1 Application
| Application ID | Title |
|---|---|
| 55532 | Integrating the impact of exome variations |
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