Transcriptome‐wide association study of breast cancer risk by estrogen‐receptor status

Abstract

Previous transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

rs10514231 Leads to Breast Cancer Predisposition by Altering ATP6AP1L Gene Expression

“…Through eQTL analysis with the GTEx database and further gene expression assay on CRISPR/Cas9 genome-edited cells, we identified ATP6AP1L to be the target gene for rs10514231. TWAS (transcriptome-wide association study) analysis identified that the ATP6AP1L gene was significantly associated with breast cancer risk [35]. It was also reported that the increased expression of ATP6AP1L was associated with decreased breast risk [36].…”

TIGAR-V2: Efficient TWAS Tool with Nonparametric Bayesian eQTL Weights of 49 Tissue Types from GTEx V8

“…Independently significant TWAS risk genes by TIGAR Out of these 88 significant TWAS genes for breast cancer by TIGAR, 20 genes are known GWAS risk genes of breast cancer 11,[41][42][43][44][45][46][47][48] , 64 are located within 1MB region of a previously identified GWAS loci of breast cancer 11,[41][42][43][44][45][46][47][48] (Table S2), and 35 genes are identified by previous TWAS 21,39,[49][50][51][52] . Similarly, out of these 37 significant TWAS genes for ovarian cancer by TIGAR, 34 genes are located on chromosome 17 including two known GWAS risk genes (NSF and PLEKHM1) 12,53,54 , 33 genes are located within 1MB of these two known GWAS risk genes (Table S3), and 13 genes (including NSF 55 ) are identified by previous TWAS 39,55,56 .…”

Multitrait transcriptome‐wide association study (TWAS) tests

“…The development of TWAS and important considerations in their application and interpretation have been reviewed in detail elsewhere (Wainberg et al, 2019; Zhu & Zhou, 2020). TWAS have successfully identified novel risk loci and candidate susceptibility genes for many complex human traits, including cancers, schizophrenia, type 2 diabetes, smoking behavior, body mass index, and four traits related to the well‐being spectrum (Baselmans et al, 2019), among others (Feng et al, 2020; Gusev et al, 2018; Mancuso et al, 2018; TWAS HUB; Wu et al, 2018).…”