Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339.
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.
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St Lucia, Brisbane, Australia.|The Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
Joseph E
JE
Powell
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Jenny N
JN
Fung
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St Lucia, Brisbane, Australia.
Konstantin
K
Shakhbazov
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Yadav
Y
Sapkota
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Nicole
N
Cloonan
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St Lucia, Brisbane, Australia.|MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, UK
Gibran
G
Hemani
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Kristine M
KM
Hillman
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Susanne
S
Kaufmann
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Hien T
HT
Luong
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Lisa
L
Bowdler
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Jodie N
JN
Painter
Gynaecology Research Centre, University of Melbourne, Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville VIC, Australia.
Sarah J
SJ
Holdsworth-Carson
Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, St Lucia, Brisbane, Australia.
Peter M
PM
Visscher
Garvan Medical Research Institute, Sydney, Australia|St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2052, Australia and
Marcel E
ME
Dinger
Gynaecology Research Centre, University of Melbourne, Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville VIC, Australia.
Martin
M
Healey
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
Dale R
DR
Nyholt
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Juliet D
JD
French
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Stacey L
SL
Edwards
Gynaecology Research Centre, University of Melbourne, Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville VIC, Australia.
Peter A W
PA
Rogers
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Grant W
GW
Montgomery
D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D004715:Endometriosis / Q000097:blood / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D044465:White People / Q000235:genetics; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
D062085:RNA, Long Noncoding; D060528:Wnt4 Protein; C000621675:long non-coding RNA LINC00341, human; D020764:cdc42 GTP-Binding Protein