An international team of researchers led by Wei Zheng Ph.D., of Vanderbilt University and Georgia Chenevix-Trench Ph.D., of QIMR Berghofer Medical Research Institute in Australia have identified 48 gene with ties to breast cancer—34 previously known to be associated with breast cancer and 14 previously unidentified risk genes.
The researchers conducted a transcription-wide association study (TWAS) using genetically predicted gene expression information from nearly 229,000 women of European ancestry—122,977 women with cancer, and 105,974 controls. Using these profiles, the team created genetic models to predict gene expression in breast tissue using data form the Genotype-Tissue Expression Project (GTEx) and then evaluated performance of the model against data contained in The Cancer Genome Atlas (TCGA).
While the high level of heritability of breast cancer is known, and it is one of the most forms of cancer in women, progress has been slow in identifying known risk genes. The authors of this TWAS study, which appeared online in Nature Genetics, noted that genome-wide association studies (GWAS) dating back to 2007 have identified approximately 170 genetic loci with common, low-penetrance risk variants for breast cancer yet the identified variants only explain about 20% of familial risk.
“Recent studies have already shown that GWAS-identified associations at more than 15 loci are likely due to the effect of risk variants at these loci on regulating the expression of either nearby or more distal genes. However, for the large majority of the GWAS-identified breast cancer risk loci, the genes responsible for the associations remain unknown,” the study’s authors wrote.
While regulatory variants are suspected to account for a large portion of breast cancer heritability, these have not yet been discovered through GWAS studies. One reason for this, the authors note, is the small effect size these variants may have, which would make them difficult to identify in individual SNP-based GWAS. For this reason, the researchers turned to TWAS, which they noted was an effective approach to identifying novel risk genes.
The work builds on an earlier TWAS from last year which identified five new genes with significant breast cancer risk associations. That study included 15,440 women with breast cancer and 31,159 controls, however several associations were discounted after further analysis due to the relatively small sample size.