Deciphering the shared genetic architecture between female reproductive disorders and psychiatric disorders.

BACKGROUND

The clinical association between female reproductive disorders, such as endometriosis, polycystic ovary syndrome(PCOS), uterine leiomyoma, and female infertility and psychiatric disorders, such as major depressive disorder(MDD), schizophrenia, and anxiety disorders has been widely reported. However, the genetic mechanisms underlying their comorbidity remain unclear. This study aimed to elucidate the genetic links between these disease categories through comprehensive genomic analyses.

METHODS

We analyzed genome-wide association study data from the Psychiatric Genomics Consortium and FinnGen database. Genetic correlations were estimated using linkage disequilibrium score regression and high-definition likelihood methods. Cross-trait meta-analyses through Multi-Trait Analysis of Genome-Wide Association Studies and Cross-Phenotype Association Analysis identified pleiotropic loci, followed by Fine-mapping with the ANNOVAR tool. Gene-based analyses integrated summary-data-based Mendelian randomization, multi-marker analysis of genomic annotation, and genome-wide complex trait analysis-fast gene-based association test approaches. Bidirectional Mendelian randomization assessed causal relationships using several complementary methods.

RESULTS

We identified significant genetic correlations between endometriosis and Attention-Deficit/Hyperactivity Disorder, Bipolar disorder(BD), and MDD, as well as between infertility/PCOS and MDD. Cross-trait analyses pinpointed five shared loci, with fine-mapping supporting their role as credible causal variants. Gene annotation implicated specific candidate genes, including ARL14EP for the endometriosis-BD link, which was further validated across SMR, MAGMA, and GCTAfastBAT analyses. Mendelian randomization demonstrated a causal effect of MDD on the risk of both endometriosis and infertility.