Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339

Powell, Joseph E., Fung, Jenny N., Shakhbazov, Konstantin, Sapkota, Yadav, Cloonan, Nicole, Hemani, Gibran, Hillman, Kristine M., Kaufmann, Susanne, Luong, Hien T., Bowdler, Lisa, Painter, Jodie N., Holdsworth-Carson, Sarah J., Visscher, Peter M., Dinger, Marcel E., Healey, Martin, Nyholt, Dale R., French, Juliet D., Edwards, Stacey L., Rogers, Peter A. W. and Montgomery, Grant W. (2016) Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Human Molecular Genetics, 25 22: 5046-5058. doi:10.1093/hmg/ddw320

Author Powell, Joseph E.
Fung, Jenny N.
Shakhbazov, Konstantin
Sapkota, Yadav
Cloonan, Nicole
Hemani, Gibran
Hillman, Kristine M.
Kaufmann, Susanne
Luong, Hien T.
Bowdler, Lisa
Painter, Jodie N.
Holdsworth-Carson, Sarah J.
Visscher, Peter M.
Dinger, Marcel E.
Healey, Martin
Nyholt, Dale R.
French, Juliet D.
Edwards, Stacey L.
Rogers, Peter A. W.
Montgomery, Grant W.
Title Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339
Formatted title
Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
Publication date 2016-11-15
Sub-type Article (original research)
DOI 10.1093/hmg/ddw320
Open Access Status Not yet assessed
Volume 25
Issue 22
Start page 5046
End page 5058
Total pages 13
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted abstract
Genome-wide association studies (GWAS) have identified markers within the WNT4 region on chromosome 1p36.12 showing consistent and strong association with increasing endometriosis risk. Fine mapping using sequence and imputed genotype data has revealed strong candidates for the causal SNPs within these critical regions; however, the molecular pathogenesis of these SNPs is currently unknown. We used gene expression data collected from whole blood from 862 individuals and endometrial tissue from 136 individuals from independent populations of European descent to examine the mechanism underlying endometriosis susceptibility. Association mapping results from 7,090 individuals (2,594 cases and 4,496 controls) supported rs3820282 as the SNP with the strongest association for endometriosis risk (P = 1.84 × 10−5, OR = 1.244 (1.126-1.375)). SNP rs3820282 is a significant eQTL in whole blood decreasing expression of LINC00339 (also known as HSPC157) and increasing expression of CDC42 (P = 2.0 ×10−54 and 4.5x10−4 respectively). The largest effects were for two LINC00339 probes (P = 2.0 ×10−54; 1.0 × 10−34). The eQTL for LINC00339 was also observed in endometrial tissue (P = 2.4 ×10−8) with the same direction of effect for both whole blood and endometrial tissue. There was no evidence for eQTL effects for WNT4. Chromatin conformation capture provides evidence for risk SNPs interacting with the promoters of both LINC00339 and CDC4 and luciferase reporter assays suggest the risk SNP rs12038474 is located in a transcriptional silencer for CDC42 and the risk allele increases expression of CDC42. However, no effect of rs3820282 was observed in the LINC00339 expression in Ishikawa cells. Taken together, our results suggest that SNPs increasing endometriosis risk in this region act through CDC42, but further functional studies are required to rule out inverse regulation of both LINC00339 and CDC42.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 4 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 16 Feb 2017, 15:31:53 EST by Kirstie Asmussen on behalf of School of Music