An Integrative Genome-Wide Analysis Reveals Shared and Subtype-Specific Genetic Links Between Endometriosis and...

This study aimed to systematically assess the genetic comorbidity of endometriosis (EM) and its subtypes with menstrual-cycle-related traits, and to identify shared genetic mechanisms and key regulatory pathways underlying their association.

Using FinnGen-derived genome-wide association study (GWAS) data for overall EM and its lesion location-defined subtypes, including endometriosis of ovary (EO), deep endometriosis (DE), endometriosis of pelvic peritoneum (EPP), endometriosis of rectovaginal septum and vagina (ERSV), and endometriosis of intestine (EI), together with GWAS summary statistics for menstrual-cycle-related traits from European female populations, we conducted a comprehensive multi-subtype cross-trait analysis. Genetic correlations were assessed using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL). Shared signals were prioritized using Pleiotropic Analysis under Composite Null Hypothesis (PLACO), Functional Mapping and Annotation of GWAS (FUMA), Multi-marker Analysis of GenoMic Annotation (MAGMA), and Hypothesis Prioritization in Multi-Trait Colocalization (HyPrColoc), followed by functional enrichment and protein-protein interaction (PPI) network analyses.

Distinct genetic association patterns were observed in EM and across its different subtypes. Age at menarche (AAM) was negatively genetically correlated with EM and EPP, frequency of irregular menstruation (FIM) was positively correlated with EM, EO, and EPP, whereas length of menstrual cycle (LMC) was negatively correlated with EM, DE, and ERSV. Cross-trait analyses identified 96 pleiotropic loci and 136 unique genes, highlighting 11p14.1 as a key shared hotspot and 8p21.2 as a recurrent pleiotropic region. Prioritized genes and pathways implicated ovarian development, sex differentiation, chromatin remodeling, cAMP/PKA signaling, and estrogen-androgen regulation, with testosterone-related colocalization supporting androgen involvement.

A comprehensive multi-subtype analysis using FinnGen data revealed a complex and heterogeneous shared genetic architecture between EM and menstrual-cycle-related traits. These findings support genetic evidence for precision risk stratification and subtype-informed management of EM, but require validation in larger and more diverse populations.