Journal article
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- Abstract:
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Background
Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.
Methods
We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.
Results
In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10−6) and AC058822.1 (P = 1.47 × 10−4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.
Conclusions
Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.9MB, Terms of use)
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- Publisher copy:
- 10.1186/s13073-022-01152-5
- Publisher:
- BioMed Central
- Journal:
- Genome Medicine More from this journal
- Volume:
- 15
- Issue:
- 1
- Article number:
- 7
- Place of publication:
- England
- Publication date:
- 2023-01-26
- Acceptance date:
- 2022-12-16
- DOI:
- EISSN:
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1756-994X
- Pmid:
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36703164
- Language:
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English
- Keywords:
- Pubs id:
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1326242
- Local pid:
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pubs:1326242
- Deposit date:
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2024-02-23
Terms of use
- Copyright holder:
- Mueller et al
- Copyright date:
- 2023
- Rights statement:
- © 2023, The Author(s) This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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