Polygenic Risk Score Prediction for Endometriosis

Abstract

Endometriosis is a major health care challenge because many young women with endometriosis go undetected for an extended period, which may lead to pain sensitization. Clinical tools to better identify candidates for laparoscopy-guided diagnosis are urgently needed. Since endometriosis has a strong genetic component, there is a growing interest in using genetics as part of the clinical risk assessment. The aim of this work was to investigate the discriminative ability of a polygenic risk score (PRS) for endometriosis using three different cohorts: surgically confirmed cases from the Western Danish endometriosis referral Center (249 cases, 348 controls), cases identified from the Danish Twin Registry (DTR) based on ICD-10 codes from the National Patient Registry (140 cases, 316 controls), and replication analysis in the UK Biobank (2,967 cases, 256,222 controls). Patients with adenomyosis from the DTR (25 cases) and from the UK Biobank (1,883 cases) were included for comparison. The PRS was derived from 14 genetic variants identified in a published genome-wide association study with more than 17,000 cases. The PRS was associated with endometriosis in surgically confirmed cases [odds ratio (OR) = 1.59, p = 2.57× 10^-7] and in cases from the DTR biobank (OR = 1.50, p = 0.0001). Combining the two Danish cohorts, each standard deviation increase in PRS was associated with endometriosis (OR = 1.57, p = 2.5× 10^-11), as well as the major subtypes of endometriosis; ovarian (OR = 1.72, p = 6.7× 10^-5), infiltrating (OR = 1.66, p = 2.7× 10^-9), and peritoneal (OR = 1.51, p = 2.6 × 10^-3). These findings were replicated in the UK Biobank with a much larger sample size (OR = 1.28, p < 2.2× 10^-16). The PRS was not associated with adenomyosis, suggesting that adenomyosis is not driven by the same genetic risk variants as endometriosis. Our results suggest that a PRS captures an increased risk of all types of endometriosis rather than an increased risk for endometriosis in specific locations. Although the discriminative accuracy is not yet sufficient as a stand-alone clinical utility, our data demonstrate that genetics risk variants in form of a simple PRS may add significant new discriminatory value. We suggest that an endometriosis PRS in combination with classical clinical risk factors and symptoms could be an important step in developing an urgently needed endometriosis risk stratification tool.

Keywords: ICD-10; endometriosis; genetic association; polygenic risk score; subtypes.

Figure 1

Conceptualization of the study. A total of 14 risk loci for endometriosis were identified from Sapkota et al. (9). Individuals from two Danish cohorts (a clinical cohort with surgically confirmed cases and a biobank cohort from the Danish Twin Registry (DTR) with cases and controls selected based on ICD-10 diagnosis codes) were genotyped for the 14 endometriosis risk variants. Unrelated, white British females from the UK Biobank served as an independent validation cohort. A 14 variant polygenic risk score (PRS) for endometriosis was computed for the Danish cohorts and the UK Biobank. Finally, the PRS was associated with different disease subtypes.

Figure 2

Density curves of standardized polygenic risk scores (PRS) stratified by case-control status for (A) clinical cohort (348 controls and 249 cases) and (B) DTR biobank cohort (316 controls and 140 cases). Vertical dashed lines indicate the within cohort sample mean, and P-values are from two-tailed Student's t-test.

Figure 3

Analysis of standardized polygenic risk scores (PRS) in the combined Danish cohort. (A) Stratified by case-control status. Vertical dashed lines indicate the within cohort sample mean, and P-value is from a two-tailed Student's t-test. (B) PRS divided into deciles and the proportion of cases and controls are counted within each decile (numbers written on each bar). (C) For each decile, the odds ratio was estimated from logistic regression (error bars indicate standard error of the estimate; reference decile was set to decile 5). The dashed horizontal line indicates an odds ratio of 1, which is the reference level (decile 5).

Figure 4

Forest plot of odds ratios (ORs) and their standard errors (error bars) computed for all endometriosis cases (N80.1–N80.9), the disease subtypes and adenomyosis within the combined Danish cohort and in the UK Biobank. Closed circles indicate a significant contribution of the standardized polygenic risk score (PRS) on case–control status (P < 0.05). See (Supplementary Table 4) for full statistical report.