Genome-wide association identifies seven loci for pelvic organ prolapse in Iceland and the UK Biobank

Abstract

Pelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P < 5 × 10^-8); seven common (minor allele frequency >5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.

Fig. 1. Manhattan plot of association results between sequence variants from Iceland and UK Biobank and pelvic organ prolapse in the meta-analysis.

The significance of association for each variant (P-values on -log₁₀ scale) are plotted against the respective position on each chromosome. Red line indicates genome-wide significance level (5 × 10⁻⁸). Genes closest to the 7 loci of interest are annotated in the Figure. The plot was created using qqman: an R package for visualizing GWAS results using Q-Q and Manhattan plots. Variants with imputation information >0.9 are displayed.