Genome-wide association studies for pelvic organ prolapse in the Japanese population

Abstract

Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29-1.68, P = 6.72 × 10^-9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04-1.08, P = 4.11 × 10^-8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10^-4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.

Fig. 1. Manhattan Plots of genome-wide association studies (GWAS) for pelvic organ prolapse (POP).

A GWAS meta-analysis for POP in Japanese populations Each plot indicates the individual association data of 9,862,117 SNPs in the GWAS meta-analysis combining four Japanese study sets (BBJ_Hondo, OBi_Hondo, BBJ_Ryukyu, OBi_Ryukyu; Total N = 77, 396). B Cross ancestry GWAS meta-analysis for POP in Japanese and European populations Each plot indicates the individual association data of 5,417,787 SNPs in the GWAS meta-analysis, combining five study sets (BBJ_Hondo, OBi_Hondo, BBJ_Ryukyu, OBi_Ryukyu, European*; Total n = 651,773). Black arrow indicates a novel susceptibility locus for POP. The y-axis shows −log₁₀ P values of association analysis of each SNP. The red line indicates the genome-wide significant threshold (P = 5 × 10⁻⁸). * Publicly available summary statistics of the GWAS data were used.

Fig. 2. Regional association plots of FGFR2 locus in the cross-ancestry genome-wide association study (GWAS) meta-analysis and expression quantitative trait loci (eQTL) analysis.

A Results of the association study for POP (upper panel) and eQTL for FGFR2 expression (lower panel) in the tibial artery. Each plot shows −log₁₀ P-values. The variants with the most significant associations (lead SNPs) within this locus, rs7072877 for the association study and rs12255289 for the eQTL, are shown as purple diamonds. The colours in the other plots indicate the extent of linkage disequilibrium (LD) (hg19/1KGP 2014 EUR), as shown in the inset to the lead variants. The estimated recombination rates from the 1KGP 2014 EUR reference are indicated by the blue lines. B Comparison of the effect sizes of variants used for the HEIDI test between GWAS and eQTL data for the tibial artery. Orange dashed line indicates the expected beta (x and y) based on eQTL lead SNP (red triangles). Vertical and horizontal bars represent standard errors of the effects of individual SNPs.