A transcriptome-wide association study of uterine fibroids to identify potential genetic markers and toxic chemicals

Abstract

Uterine fibroid is one of the most prevalent benign tumors in women, with high socioeconomic costs. Although genome-wide association studies (GWAS) have identified several loci associated with uterine fibroid risks, they could not successfully interpret the biological effects of genomic variants at the gene expression levels. To prioritize uterine fibroid susceptibility genes that are biologically interpretable, we conducted a transcriptome-wide association study (TWAS) by integrating GWAS data of uterine fibroid and expression quantitative loci data. We identified nine significant TWAS genes including two novel genes, RP11-282O18.3 and KBTBD7, which may be causal genes for uterine fibroid. We conducted functional enrichment network analyses using the TWAS results to investigate the biological pathways in which the overall TWAS genes were involved. The results demonstrated the immune system process to be a key pathway in uterine fibroid pathogenesis. Finally, we carried out chemical–gene interaction analyses using the TWAS results and the comparative toxicogenomics database to determine the potential risk chemicals for uterine fibroid. We identified five toxic chemicals that were significantly associated with uterine fibroid TWAS genes, suggesting that they may be implicated in the pathogenesis of uterine fibroid. In this study, we performed an integrative analysis covering the broad application of bioinformatics approaches. Our study may provide a deeper understanding of uterine fibroid etiologies and informative notifications about potential risk chemicals for uterine fibroid.

A Transcriptome-Wide Analysis of Psoriasis: Identifying the Potential Causal Genes and Drug Candidates

“…TWAS is used to investigate the genetic effects of pathogenesis in various diseases. It has the advantage of estimating the genotype-mediated gene expression changes at the population level as it calculates expected gene expression values using large-scale GWAS summary statistics data [58][59][60][61]. In the GWAS summary statistics data we used, healthy subjects (n = 324,074) were approximately 60 times larger than psoriasis patients (n = 5459), which could cause biased results.…”

Uterine Transcriptome: Understanding Physiology and Disease Processes

“…A recent transcriptome-wide association study (TWAS) conducted by Kim et al [ 71 ] including roughly 20,000 patients with fibroids and 223,000 control subjects identified nine fibroid susceptibility genes, including two novel genes, RP11-282O18.3 (a long non-coding RNA that is involved in immune and hormonal regulation via estradiol) and KBTBD7 (encoding a transcriptional activator that participates in Ras/ECM signaling to mediate tumorogenesis). These investigators also discovered changes in expression patterns of several microRNAs (miRNAs), the relevance of which we now discuss in greater detail.…”

Challenges and Opportunities for Data Science in Women's Health

“…The goal of GTEx was to create a map of genetic determinants of gene expression [expression quantitative trait loci (eQTLs)]. The most recent version of this resource contains eQTL information from 54 human tissues of 948 mostly postmortem donors (85,86). These data can be leveraged in concert with GWAS to conduct transcriptome-wide association studies (TWAS) in which associations between genetically predicted gene expression levels and outcomes can be statistically inferred (87)(88)(89)(90).…”