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Genome-wide association studies (GWAS) have revealed sixteen risk loci for endoemtrial cancer but the identification of candidate susceptibility genes remains challenging. Here, we perform transcriptome-wide association study (TWAS) analyses using the largest endometrial cancer GWAS and gene expression from six relevant tissues, prioritizing eight candidate endometrial cancer susceptibility genes, one of which ( EEFSEC ) is located at a potentially novel endometrial cancer risk locus. We also show evidence of biologically relevant tissue-specific expression associations for  CYP19A1  (adipose),  HEY2  (ovary) and  SKAP1  (whole blood). A phenome-wide association study demonstrates associations of candidate susceptibility genes with anthropometric, cardiovascular, diabetes, bone health and sex hormone traits that are related to endometrial cancer risk factors. Lastly, analysis of TWAS data highlights candidate compounds for endometrial cancer repurposing. In summary, this study reveals endometrial cancer susceptibility genes, including those with evidence of tissue specificity, providing insights into endometrial cancer aetiology and avenues for therapeutic development.

communications biology

Multi-tissue transcriptome-wide association study identifies eight candidate genes and tissue-specific gene expression underlying endometrial cancer susceptibility