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The association between RHOJ and endometriosis is supported by convergent genetic evidence from multi‐patient studies. A large GWAS in a Polish cohort (171 patients (PMID:28881265)) identified a novel SNP in a region proximal to RHOJ that showed genome‐wide significance. In addition, a separate whole‐exome sequencing (WES) study of 80 deeply phenotyped endometriosis patients (PMID:37626618) further corroborated the involvement of RHOJ, among other candidate genes, in disease susceptibility. Although no inherited familial pattern could be established given the complex genetic nature of endometriosis, the observed associations across distinct cohorts increase the confidence in this link. The cumulative evidence thus far places the strength of the gene‑disease association in the Strong range using ClinGen criteria. This multi‐cohort analysis offers significant support for utilizing RHOJ in diagnostic decision‑making, commercial testing contexts, and future publication.
Genetic evidence for RHOJ in endometriosis is derived primarily from case–control analyses. The GWAS study reported significant association with endometriosis in a population sample, achieving a p‑value consistent with genome‑wide significance and notable odds ratios. Furthermore, the WES study detected rare and damaging variants in RHOJ among recurrent genes in affected individuals. While specific HGVS‐coded variants meeting the required format were not provided, the reproducibility of association signals across independent studies strengthens the genetic evidence. With multiple cohorts and variant classes implicated, the genetic evidence is assigned a Strong ClinGen tier. This demonstrates that rare damaging variants, even if not individually detailed by HGVS, contribute to the overall risk profile for endometriosis.
Functional studies further support the biological plausibility of RHOJ’s involvement in endometriosis. Experimental assessment in cellular models, as reported in a study characterizing a new member of the Rho family, has demonstrated that altered GTPase activity can modify cellular processes such as morphology, migration, and actin cytoskeleton dynamics (PMID:10967094). Although this study focused on TCL, the functional properties of Rho family members are generally conserved, and by extension, dysregulation of RHOJ is posited to impact pathways relevant to endometriosis pathophysiology. The demonstration of altered nucleotide cycling and downstream pathway modulation offers experimental support that is concordant with the genetic findings. Based on these observations, the functional evidence is rated as Moderate. This suggests that while experimental models support a potential role for RHOJ, additional corroborative studies are warranted.
There is limited conflicting evidence regarding the involvement of RHOJ in endometriosis. No studies were identified that directly refute this association or propose an alternative phenotype. However, the absence of detailed HGVS‐coded variants in the reported studies warrants caution in over‐interpretation. Future evaluations involving larger cohorts and familial segregation analyses might refine or re‐classify the gene‑disease relationship. Until then, the integrated evidence remains supportive of a strong association while acknowledging areas that require further experimental deepening.
In summary, both genetic and functional studies converge to implicate RHOJ as a contributor to endometriosis susceptibility. The GWAS and WES analyses provide robust statistical associations, and functional assays underscore the potential mechanistic relevance of RHOJ in cellular processes that are altered in endometriosis. Despite the inherent complexity of endometriosis genetics and the absence of a clear Mendelian inheritance mode, the overall evidence supports a strong gene‑disease association that is useful for diagnostic, commercial, and research purposes.
Key Take‑home: The integrated genetic and experimental data support the clinical utility of RHOJ as a biomarker for endometriosis risk, underscoring its potential role in personalized patient management.
Gene–Disease AssociationStrongA significant association was demonstrated in a GWAS cohort of 171 patients (PMID:28881265) along with additional support in a WES study of 80 patients (PMID:37626618). Genetic EvidenceStrongMultiple studies consistently identified RHOJ as a susceptibility gene for endometriosis through both common and rare variant analyses, reaching the ClinGen scoring threshold. Functional EvidenceModerateFunctional analyses in cellular models indicate altered GTPase activity relevant to endometriosis physiology (PMID:10967094), supporting a mechanistic role for RHOJ. |