ESHRE2012: Common genetic variants underlie endometriosis and obesity-related traits

Istanbul, 3 July 2012

Nilufer Rahmioglu, representing The International EndoGene Consortium (IEC), today presented the first ever data supporting commonality in genetic variants underlying endometriosis and obesity-related traits. She also pinpointed several novel genetic loci with plausible biological candidacy.

Drs Krina Zondervan, Nilufer Rahmioglu, and Christian Becker from Oxford University, who are part of the IEC team and the ENDOX Study

Susceptibility to endometriosis has been associated with genetic factors.  These genetic variants, accounting for this heritable component of endometriosis, have started to emerge from large-scale genome-wide association studies (GWAS).

The IEC previously performed the largest endometriosis GWAS to date, which identified one novel genetic variant associated with endometriosis in women of European ancestry and confirmed another from the GWAS of women of  Japanese ancestry [1,2].

What was special in the IEC study was that the top genetic variant associated moderate-to-severe endometriosis marked one of the top loci associated with waist-hip ratio (WHR*) adjusted for body mass index (BMI*) in a GWAS by the GIANT Consortium involving 77,167 individuals [3].

Lower BMI and WHR have previously been associated with an increased risk of endometriosis in epidemiological and biological studies. As both endometriosis and obesity-related traits are heritable, the IEC team therefore investigated the potential commonality (pleiotropy) in genetic variants underlying their aetiology and identified common pathogenic pathways, using data from three large-scale genome-wide association studies (GWAS).

Genetic variants found on several chromosomes

The team performed a systematic investigation of common genetic variants contributing to the pathogenesis of endometriosis as well as regulation of overall body fat and fat distribution (ie. where the fat is situated) [4].  This was done in three parts:

  1. A genetic enrichment analysis, which compared the tails of the association p-value distributions of three large scale GWAS aiming to identify specific common genetic variants.This showed a significant enrichment in genetic variance underlying endometriosis and variation of fat distribution (WHR) but not with overall body fat (BMI).  The team also identified several key pleiotropic genetic regions including on chromosome 7 (in between genes), chromosome 1 (in the WNT4 gene), and chromosome 3 (in the PPARG gene).
  2. A polygenic prediction analysis to evaluate the extent of the genetic commonality between endometriosis and regulation of overall body fat and fat distribution, which showed there are unlikely to be a totally shared genetic component between endometriosis and fat distribution (ie. not all obese women have endometriosis, nor are all women with endometriosis obese).
  3. A bioinformatic pathway analysis on genes with evidence for pleiotropy, where potential common biological pathways were identified, including the WNT signalling pathway which has a critical role in female reproductive tract development and sex hormone homeostatis regulation.

Dr Nilufer Rahmioglu

These highly novel findings present an exciting potential opportunity for further cross-trait comparisons, with  fat distribution research into specific genetic loci potentially contributing to the field of endometriosis – and vice versa!

said Dr Rahmioglu, who emphasised the importance of identifying genetic variants to help us understand the underlying causal pathways of endometriosis, create opportunities for developing a non-surgical method of diagnosis, as well as aiding and identifying new treatments.

  1. Painter JL, et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 2011;43(1):51-4
  2. Uno S, et al. A genome-wide association study identifies genetic variants in the DKHN2BAS locus associated with endometriosis in Japanese. Nat Genet 2010;42(8):707-10
  3. Heid IM, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphisms in the genetic basis of fat distribution. Nat Genet 2010;42(11):949-60
  4. Rahmioglu N, Harris HR, Macgregor S, The International EndoGene Consortium (IEC), The GIANT Consortium, Morris A, Montgomery GW, Missmer SA, Lindgren CM, Zondervan KT. Common genetic variants underlie endometriosis and obesity-related traits. 28th Annual Meeting of the European Society of Human Reproduction and Embryology O-131.

*Body Mass Index (BMI) is a measure of overall body fat (adiposity), and Waist-Hip Ratio (WHR) is a measure of fat distribution (central adiposity).  These are obesity related measurements.


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