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PLoS Genet. 2017 Mar 31;13(3):e1006690. doi: 10.1371/journal.pgen.1006690. eCollection 2017 Mar.

Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk.

Author information

1
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States of America.
2
Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, CA, United States of America.
3
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States of America.
4
Department of Medicine, University of California San Francisco, San Francisco, CA, United States of America.
5
Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States of America.
6
Department of Urology, University of California San Francisco, San Francisco, CA, United States of America.
7
Institute for Human Genetics, University of California San Francisco, San Francisco, CA, United States of America.

Abstract

Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute's "Up for a Challenge" (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to examine associations between imputed gene expression and breast cancer risk. In particular, we used reference datasets describing the breast tissue and whole blood transcriptomes to impute expression levels in breast cancer cases and controls. In trans-ethnic meta-analyses of U4C and UK Biobank data, we found significant associations between breast cancer risk and the expression of RCCD1 (joint p-value: 3.6x10-06) and DHODH (p-value: 7.1x10-06) in breast tissue, as well as a suggestive association for ANKLE1 (p-value: 9.3x10-05). Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes. Among the genetic variants that contributed to the predicted expression of the five genes, we found 23 nominally (p-value < 0.05) associated with breast cancer risk, among which 15 are not in high linkage disequilibrium with risk variants previously identified by GWAS. In summary, we used a transcriptome-based approach to investigate the genetic underpinnings of breast carcinogenesis. This approach provided an avenue for deciphering the functional relevance of genes and genetic variants involved in breast cancer.

PMID:
28362817
PMCID:
PMC5391966
DOI:
10.1371/journal.pgen.1006690
[Indexed for MEDLINE]
Free PMC Article

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