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.

Advancing our understanding of genetic risk factors and potential personalized strategies in pelvic organ prolapse: largest GWAS to date reveals 19 novel associated loci

“…As shown in Table 1 and Figure 1, 26 loci, with 30 independently significant lead signals, were associated with POP after meta-analysis. From these, 19 loci were novel findings and seven were reported previously (12). All lead variants were present in at least two out of the three datasets analyzed and were common variants (EAF>0.05) except for one replicated (EAF=0.01, rs72624976, p=1.14 × 10 -9 ) and one novel association (rs72839768, EAF=0.02, p=4.66 × 10 -9 ).…”

“…The copyright holder for this preprint this version posted July 10, 2021. ; https://doi.org/10.1101/2021.07.08.21260068 doi: medRxiv preprint CHRDL2, ACADVL, PLA2G6) which reinforce the role of connective tissue molecular changes as a key process in the pathogenesis of POP (38,39). For example, EFEMP1 encodes a fibulin and has been involved in alterations of connective tissue function as seen in inguinal hernia, pelvic organ prolapse and mouse studies (12,(40)(41)(42) . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

“…POP is a multifactorial disorder and genetic factors have been estimated to explain 43% of the variation in POP risk in a twin study (11). A recent genome-wide association study (GWAS) of Icelandic and UK Biobank (UKBB) cohorts reported seven loci that associate with POP and point to a role of connective tissue metabolism and estrogen exposure in its etiology (12). Nevertheless, increasing the sample size is likely to boost the power for detection of more common risk variants, thus advancing our understanding of genetic risk factors underlying POP.…”

Genomics of Endometriosis: From Genome Wide Association Studies to Exome Sequencing

“…Recently, in the Iceland population, Olafsdottir and coworkers [ 77 ], revealed an association of rs3820282 (in an intron of WNT4, probably encompassing the response to estrogen signaling) with Pelvic Organe Prolapse, thus allying this gene with endometriosis, leiomyoma, gestational duration, and as mentioned above, up to the early stages of female sex determination [ 50 ].…”

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

“…Although they did not identify any variants meeting genome-wide significance, they did identify a number of variants that met p < 10 −6 . The largest POP meta-analysis of two GWA studies involved 3409 cases from Iceland and 131,444 controls and 11,601 cases and 209,288 controls from UK Biobank, all of which were of European ancestry [34]. POP cases were identified based on ICD 9/10 coding therefore representing women who had presented for care.…”