Insights from Mendelian randomization and genetic correlation analyses into the relationship between endometriosis and its comorbidities

Abstract

BACKGROUND Endometriosis remains a poorly understood disease, despite its high prevalence and debilitating symptoms. The overlap in symptoms and the increased risk of multiple other traits in women with endometriosis is becoming increasingly apparent through epidemiological data. Genetic studies offer a method of investigating these comorbid relationships through the assessment of causal relationships with Mendelian randomization (MR), as well as identification of shared genetic variants and genes involved across traits. This has the capacity to identify risk factors for endometriosis as well as provide insight into the aetiology of disease. OBJECTIVE AND RATIONALE We aim to review the current literature assessing the relationship between endometriosis and other traits using genomic data, primarily through the methods of MR and genetic correlation. We critically examine the limitations of these studies in accordance with the assumptions of the utilized methods. SEARCH METHODS The PubMed database was used to search for peer-reviewed original research articles using the terms ‘Mendelian randomization endometriosis’ and ‘“genetic correlation” endometriosis’. Additionally, a Google Scholar search using the terms ‘“endometriosis” “mendelian randomization” “genetic correlation”’ was performed. All relevant publications (n = 21) published up until 7 October 2022 were included in this review. Upon compilation of all traits with published MR and/or genetic correlation with endometriosis, additional epidemiological and genetic information on their comorbidity with endometriosis was sourced by searching for the trait in conjunction with ‘endometriosis’ on Google Scholar. OUTCOMES The association between endometriosis and multiple pain, gynaecological, cancer, inflammatory, gastrointestinal, psychological, and anthropometric traits has been assessed using MR analysis and genetic correlation analysis. Genetic correlation analyses provide evidence that genetic factors contributing to endometriosis are shared with multiple traits: migraine, uterine fibroids, subtypes of ovarian cancer, melanoma, asthma, gastro-oesophageal reflux disease, gastritis/duodenitis, and depression, suggesting the involvement of multiple biological mechanisms in endometriosis. The assessment of causality with MR has revealed several potential causes (e.g. depression) and outcomes (e.g. ovarian cancer and uterine fibroids) of a genetic predisposition to endometriosis; however, interpretation of these results requires consideration of potential violations of the MR assumptions. WIDER IMPLICATIONS Genomic studies have demonstrated that there is a molecular basis for the co-occurrence of endometriosis with other traits. Dissection of this overlap has identified shared genes and pathways, which provide insight into the biology of endometriosis. Thoughtful MR studies are necessary to ascertain causality of the comorbidities of endometriosis. Given the significant diagnostic delay of endometriosis of 7–11 years, determining risk factors is necessary to aid diagnosis and reduce the disease burden. Identification of traits for which endometriosis is a risk factor is important for holistic treatment and counselling of the patient. The use of genomic data to disentangle the overlap of endometriosis with other traits has provided insights into the aetiology of endometriosis.

Blood pressure, cardiometabolic traits and cardiovascular events in women with uterine fibroids: a genetic correlation and Mendelian randomization study

“…We report for the first time a genetic correlation between UFs and migraine. Recently, a significant genetic correlations was reported between endometriosis and migraine 37 . These findings linking genetically migraine to several women’s reproductive diseases stresses further the need to dig into these shared molecular mechanisms, especially that migraine is a neurovascular disorder predominantly affecting women.…”

Epidemiologic and genetic associations of female reproductive disorders with depression or dysthymia: a Mendelian randomization study

“…Two-sample bi-directional MR analysis explores both directions of causality, providing a comprehensive comprehension of the association between exposure and outcome variables. MR studies have been conducted to explore the causal relationship between depression and PCOS 21 , endometriosis 22 , and ovarian cancer 23 . However, to date, there is a lack of systematic MR studies that have revealed the causal association between depression/dysthymia and other female reproductive disorders.…”

Identification of miR-30c-5p microRNA in Serum as a Candidate Biomarker to Diagnose Endometriosis

“…The comorbidities with the highest frequency in our study cohort are listed. The "Other" comorbidities section includes inflammatory traits (celiac disease, Crohn's disease and multiple sclerosis), gastrointestinal features (chronic gastritis) and mental disorders (anxiety, ADHD, bipolar and personality disorders) based on McGrath et al's (2023) review[49].…”