Endometriosis risk alleles at 1p36.12 act through inverse regulation ofCDC42andLINC00339

Joseph E Powell, Jenny N Fung, Konstantin Shakhbazov, Yadav Sapkota, Nicole Cloonan, Gibran Hemani, Kristine M Hillman, Susanne Kaufmann, Hien Luong, Hien T Luong, Lisa Bowdler, Jodie N Painter, Sarah J Holdsworth-Carson, Sarah J. Holdsworth‐Carson, Peter M Visscher, Marcel E Dinger, Martin Healey, Dale R Nyholt, Juliet D French, Stacey L Edwards, Peter A W Rogers, Grant W Montgomery
Human molecular genetics · 2016 · vol. 25(22) , pp. ddw320 · doi:10.1093/hmg/ddw320 · PMID:28171565 · W2523566009
article OA: bronze CC0 ⤵ 32 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Endometriosis risk SNP rs3820282 is an eQTL in blood and endometrium, decreasing LINC00339 and increasing CDC42 expression, with risk allele rs12038474 enhancing CDC42 transcription.

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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.

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Condition tags

endometriosis

MeSH descriptors

cdc42 GTP-Binding Protein Endometriosis RNA, Long Noncoding Case-Control Studies cdc42 GTP-Binding Protein cdc42 GTP-Binding Protein Chromosomes, Human, Pair 1 Endometriosis Endometriosis Female Gene Expression Gene Expression Regulation Gene Frequency Genetic Predisposition to Disease Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Polymorphism, Single Nucleotide Promoter Regions, Genetic

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