Female genital tract (FGT) polyps form on the lining of the uterus, cervix, vagina, or vulva. Among these, endometrial (uterine) polyps are the most common, affecting between 8% - 50% of women, depending on the population. While generally considered benign, the potential for malignancy of FGT polyps ranges from 2.5% in women under 35, to 37% in those over 65. Little is known about the genetic drivers of FGT polyp formation and what genetic pathways are involved in mutagenesis of polyps to cancer.
We meta-analysed GWAS from the UK Biobank, FinnGen, Estonian Biobank, and the Michigan Genomics Initiative (44,227 cases, 473,321 controls) to identify 26 genome-wide significant loci associated with FGT Polyp risk. Through TWAS, MAGMA and intersecting candidate causal variants with chromatin looping anchors from healthy endometrial tissue, we prioritised a total of 173 genes with potential significant effects on FGT polyp risk. Six genes (ACTRT3, BET1L, EEFSEC, MYNN, PLCE1 and ZBTB38) were highlighted across all methods. Functional follow-up revealed gene-enrichment for three main pathways, estrogen receptiveness, DNA repair and obesity. Assessing genetic correlation with LDSC revealed strong genetic overlap between FGT polyps and multiple gynecological disorders including endometrial and ovarian cancers, uterine fibroids and endometriosis. Combining these traits in a multi-trait analysis of GWAS (MTAG) identified a further 26 loci, bringing the total to 52. Of these 52 loci, 21 loci from the original meta-analysis 18 of the additional MTAG loci had a consistent effect estimate in an independent cohort.
In conclusion, our results reveal 44 genetic loci (26 meta-analysis + 18 replicated MTAG) robustly associated with FGT polyps risk, and highlights the importance of both estrogen- and non-estrogen-related (i.e., DNA repair and obesity) pathways in FGT polyp risk. Our future work aims to expand our GWAS results to identify loci specific to polyp mutagenesis.