Endometriosis is a common estrogen-dependent gynecological disease defined as the presence of endometrial tissue outside of the uterus in lesions containing endometrial glands and stroma. The prevalence has been estimated at 5%–10% for women of reproductive age in the general population and between 35% and 50% for women with chronic pelvic pain and subfertility. The disease may be asymptomatic or associated with severe pelvic pain and subfertility.
The condition is influenced by multiple genetic and environmental factors. The contribution of genetic variation to endometriosis risk is well established from both clinic- and population-based samples.
In a recent review published in the journal Biology of Reproduction entitled “Identifying the Biological Basis of GWAS Hits for Endometriosis,” Grant Montgomery and colleagues from the QIMR Berghofer Medical Research Institute in Queensland Australia discuss the current state of the genome-wide association studies (GWAS) regarding the recent identification of eight genomic regions with strong evidence for association with the risk of endometriosis.
In the review, the authors examined GWAS studies on these multiple genetic variations and point out that associated DNA sequence variation in these regions must be linked to the altered regulation and/or function of specific genes and pathways modifying endometriosis risk to make further progress.
According to the authors, the genetic variation targets the mostly likely candidate in a few regions. However, GWAS results for other complex diseases have highlighted major gaps in the knowledge about gene regulation. Most GWAS signals are located outside of gene coding regions and are thought to increase disease risk by modifying gene regulation. There will be multiple independent signals in some regions and regulatory variation might target multiple local genes and/or downstream pathways. In this regard, it is difficult to provide strong evidence linking causal variants and gene targets to underpin the translational research needed to develop new treatments.
Identifying causal variants and interpreting the functional consequences of sequence variation in noncoding regions of the genome is challenging. The regulation of gene expression is complex with the expression of many genes influenced by SNP variation in promoters and enhancers and the indirect effects of SNP variation on epigenetic marks. Much of this variation is tissue specific. Fortunately, technical and conceptual advances are helping to develop more systematic approaches to address the functional mechanisms linked to common diseases such as endometriosis. Valuable insights into regulatory sequences in noncoding parts of the genome have come from international initiatives such as the ENCODE project.
Successful GWAS in endometriosis represents an important first step toward discovery of target genes and pathways responsible for increased risk of endometriosis. To capitalize on these results, follow-up studies require a range of skills combining genetics, genomics, cell biology, functional biology, and clinical research to eventually translate these results into clinical outcomes. Combining gene expression and methylation with genome-wide SNP data can help to identify genetic regulation of gene expression and the role of GWAS hits. Studies will need to be designed with sufficient power and combine genetic and functional biology to determine how these GWAS hits affect endometriosis risk.
The authors conclude the review pointing out the need for using standardized instruments and protocols for collection of phenotypic data and biological specimens which may help international collaborations to develop large datasets with sufficient power to first determine the key target genes.