Are rare variants in <em>WNT4</em> associated with endometriosis risk? — ASN Events

Are rare variants in WNT4 associated with endometriosis risk? (#291)

Hien T.T. Luong 1 , Jodie N. Painter 1 , Brett Chapman 1 , Susan A. Treloar 1 2 , Krina T. Zondervan 3 , Dale R. Nyholt 1 , Grant W. Montgomery 1
  1. Queensland Institute of Medical Research, Brisbane, QLD, Australia
  2. University of Queensland, Brisbane, Australia
  3. Wellcome Trust Centre for Human Genetics, Oxford, U.K.

Endometriosis is a common, chronic gynaecological disease characterised by pelvic pain and sub-fertility. It is a complex genetic disease affecting 7-10% of women of reproductive age and up to 50% of women with infertility. Evidence from genome-wide association studies (GWAS) in women with endometriosis identified association near wingless-type MMTV integration site family, member 4 (WNT4), a strong candidate gene for development and function of the endometrium. The initial association was identified with SNP rs7521902 ~20 kb upstream of the promoter of WNT4. We genotyped additional common variants in a subset of cases and controls and confirmed a stronger association signal for a SNP located within intron 1 of WNT4. Rare variants in genes identified from GWAS studies contribute to risk in some common diseases and provide one way to identify the genes contributing to disease risk. We sequenced all exons and exon/intron boundaries of WNT4 in 100 affected individuals from families with multiple cases of endometriosis. We identified two novel variants including a coding variant in exon 2 and an insertion/deletion in the 3’UTR. These variants were also found in other affected members of their families. In addition, we screened data from international sequencing projects and identified other rare coding variants in WNT4. Variants found from re-sequencing and known coding variants are being genotyped in 958 familial cases and 959 controls. Results show many coding variants were not polymorphic in our samples and the novel variant in exon 2 is restricted to the family included in the initial screen. Further studies will be required to determine whether WNT4 plays a role in increased risk of endometriosis.