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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Mueller, S.H. ; Augustinsson, A. LU ; Olsson, H. LU orcid and Kuchenbaecker, Karoline B. (2023) In Genome Medicine 15(1).
Abstract
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... (More)
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. © 2023, The Author(s). (Less)
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keywords
Breast cancer susceptibility, Diverse ancestry, Gene regulation, Genome-wide association study, Rare variants, African, ancestry group, Article, Asian, boredom susceptibility, breast cancer, cancer prognosis, CBLB gene, cohort analysis, controlled study, ESR1 gene, European, FGFR2 gene, FMNL3 gene, gene base aggregation, gene expression level, gene structure, genetic association, genetic association study, genetic code, genetic variability, Hispanic, human, human cell, human tissue, LSP1 gene, major clinical study, MAP3K1 gene, meta analysis (topic), South and Central America, SRGAP2C gene, statistical significance, tumor-related gene, Black person, breast tumor, female, genetic predisposition, genetic screening, genetics, genome-wide association study, meta analysis, procedures, single nucleotide polymorphism, FMNL3 protein, human, methenamine, Black People, Breast Neoplasms, Female, Formins, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide
in
Genome Medicine
volume
15
issue
1
article number
7
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85146966233
  • pmid:36703164
ISSN
1756-994X
DOI
10.1186/s13073-022-01152-5
language
English
LU publication?
yes
id
03b290d6-d650-490a-9e52-2fcb867a25b3
date added to LUP
2023-02-16 08:51:42
date last changed
2023-02-17 03:00:11
@article{03b290d6-d650-490a-9e52-2fcb867a25b3,
  abstract     = {{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 &lt; 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. © 2023, The Author(s).}},
  author       = {{Mueller, S.H. and Augustinsson, A. and Olsson, H. and Kuchenbaecker, Karoline B.}},
  issn         = {{1756-994X}},
  keywords     = {{Breast cancer susceptibility; Diverse ancestry; Gene regulation; Genome-wide association study; Rare variants; African; ancestry group; Article; Asian; boredom susceptibility; breast cancer; cancer prognosis; CBLB gene; cohort analysis; controlled study; ESR1 gene; European; FGFR2 gene; FMNL3 gene; gene base aggregation; gene expression level; gene structure; genetic association; genetic association study; genetic code; genetic variability; Hispanic; human; human cell; human tissue; LSP1 gene; major clinical study; MAP3K1 gene; meta analysis (topic); South and Central America; SRGAP2C gene; statistical significance; tumor-related gene; Black person; breast tumor; female; genetic predisposition; genetic screening; genetics; genome-wide association study; meta analysis; procedures; single nucleotide polymorphism; FMNL3 protein, human; methenamine; Black People; Breast Neoplasms; Female; Formins; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Humans; Polymorphism, Single Nucleotide}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Medicine}},
  title        = {{Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry}},
  url          = {{http://dx.doi.org/10.1186/s13073-022-01152-5}},
  doi          = {{10.1186/s13073-022-01152-5}},
  volume       = {{15}},
  year         = {{2023}},
}