Protein-Modifying Variants in the Genome and Their Role in Endometriosis

Protein-Modifying Variants in the Genome and Their Role in Endometriosis

This study seeks to identify protein-modifying variants and their roles in endometriosis by comparing a discovery group of international participants to a replication cohort.

Key Points


  • This study is the first sizeable exome-array analysis, including cases and controls from individuals with European ancestry. The authors hope to identify genomic protein modifying variants and their roles in endometriosis.


  • Endometriosis is an allusive disease as researchers have yet to figure out its molecular and genetic components. It is vital to understand the mechanisms that cause this condition to help in the synthesis of new and more efficient treatments.

What’s done here?

  • This study consisted of 6 individuals international cohorts: QIMR-Australia, LEUVEN-Belgium, NHS2-USA, BioVU-USA, WGHS-USA, and iPSYCH-Denmark.
  • Exome-arrays
    • Three genotyping arrays used in this study: the Illumina HumanExome, HumanCoreExome, and PsychArray Beadchips.
    • This study concentrated on the autosomal and X-linked exome variants.
  • Genotyping and Quality Control
    • Cases and Controls were genotyped using different arrays and at various institutions; however, all cluster files created similarly, and the data was then processed using a rare variant caller.
    • There were strict quality control measures in place for this experiment.
  • Single-variant association analysis
    • This test was conducted using RareMetalWorker, a program used to analyze quantitative traits.
  • Single-variant meta-analysis
    • The RareMetalWorker data was converted into a binary scale and then underwent meta-analysis using METAL. Bonferroni correction was later used to determine if a single variant is an exome-wide significant.
    • A secondary analysis was conducted for individuals with moderate to severe endometriosis since the exclusion of persons with minimal endometriosis has the potential to enrich the effects of true genetic risk.
    • Cochran’s test was used to determine the heterogeneity of allelic associations.
    • The conditional analysis was also performed independent association signals that reach significant loci.
  • Gene-level meta-analysis
    • RareMetal used once again, but this time there was no MAC filter, which allowed researchers to look at all polymorphic variants.
    • The analyses were concentrated on three primary variant sets.
  • The replication cohort consisted of Icelandic women with endometriosis and a control group of women with European origin.
    • All of these individuals’ genes underwent total association analyses and some individuals had genes that were chosen for replication.
    • Meta-analysis was also conducted on this data set.

Key results:

  • The discovery group consisted of 7164 cases and 21005 controls, whereas the replication group consisted of 1840 cases and 129016 controls.
  • Meta-analyses of single-variant, specifically rs1801232-CUBN, and gene-level, namely CIITA and PARP4, revealed endometriosis association of coding variants for the discovery group.
  • Above foci did not survive in the replication cohort.
  • Combined analysis showed a locus of interest of rs13394619 in GREB1 at 2p25.1, which is found in women with European ancestry.
  • Despite the researchers best efforts, the study did not find any protein-modifying variants that have a profound effect on endometriosis.
  • The researchers suggest that future studies should utilize more cases and controls and sequence high-risk families.

Limitations of the study:

  • The researchers themselves state that exome-arrays are not as comprehensive as whole genome/exome sequencing would be for the identification of variants; however, the latter option is quite costly.
  • The authors also state that the results of their studies are limited by the fact that they did not have enough participants with moderate to severe endometriosis.

Lay Summary

The results of many endometriosis studies are limited in the fact that they only recruit patients from one geographical area; however, this particular study specifically narrowed their participant search to individuals from one continent, namely Europe. Sapkota et al. chose this subset of the world population because studies had previously identified a large number of endometriosis-related single nucleotide polymorphisms (SNPs), 11 to be exact, exist in individuals of European descent. In this study, the authors used the first sizeable exome-array analysis to identify some protein modifying variants and hope to understand the function of the previously identified coding variants on endometriosis disease progression. This study and its results can be found in a paper titled “Analysis of potential protein modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry” that has been published

The study used exome-array genotyping on two sets of cases and controls, the former was referred to as the discovery sample and the latter was the replication set. The researchers also utilized genotyping and quality control, single-variant association analysis, single-variant meta-analysis, gene-level meta-analysis, and replication and total association analyses in order to produce the results delineated below.

The results showed that there were coding variants in the single-variant and gene-level analyses for the discovery sample, but these results could not be reproduced in the replication set. The combined analysis showed rs13394619 in GREB1 at 2p25.1, found in women with European ancestry, as a locus of interest. It is also important to note that the results did not show any protein modifying variants that play a large role in endometriosis.

The authors continue to suggest that further genotyping and sequencing should be done in order to understand the disease at a genetic level.

Research Source:

coding variant SNP genotyping sequencing exome-array genotyping Europe


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