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Cited by 161Endometriosis Research and TreatmentGenetic Associations and EpidemiologyPlant and fungal interactions

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Genome-Wide Association Study Link Novel Loci to Endometriosis

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Albertsen, Hans M., Chettier, Rakesh, Farrington, Pamela, Ward, Kenneth·2013·PLoS ONE
DOI 10.1371/journal.pone.0058257PMC PMC3589333
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Abstract

Endometriosis is a common gynecological condition with complex etiology defined by the presence of endometrial glands and stroma outside the womb. Endometriosis is a common cause of both cyclic and chronic pelvic pain, reduced fertility, and reduced quality-of-life. Diagnosis and treatment of endometriosis is, on average, delayed by 7-10 years from the onset of symptoms. Absence of a timely and non-invasive diagnostic tool is presently the greatest barrier to the identification and treatment of endometriosis. Twin and family studies have documented an increased relative risk in families. To identify genetic factors that contribute to endometriosis we conducted a two-stage genome-wide association study (GWAS) of a European cohort including 2,019 surgically confirmed endometriosis cases and 14,471 controls. Three of the SNPs we identify associated at P<5×10(-8) in our combined analysis belong to two loci: LINC00339-WNT4 on 1p36.12 (rs2235529; P = 8.65×10(-9), OR = 1.29, CI = 1.18-1.40) and RND3-RBM43 on 2q23.3 (rs1519761; P = 4.70×10(-8), OR = 1.20, Cl = 1.13-1.29, and rs6757804; P = 4.05×10(-8), OR = 1.20, Cl = 1.13-1.29). Using an adjusted Bonferoni significance threshold of 4.51×10(-7) we identify two additional loci in our meta-analysis that associate with endometriosis:, RNF144B-ID4 on 6p22.3 (rs6907340; P = 2.19×10(-7), OR = 1.20, Cl = 1.12-1.28), and HNRNPA3P1-LOC100130539 on 10q11.21 (rs10508881; P = 4.08×10(-7), OR = 1.19, Cl = 1.11-1.27). Consistent with previously suggested associations to WNT4 our study implicate a 150 kb region around WNT4 that also include LINC00339 and CDC42. A univariate analysis of documented infertility, age at menarche, and family history did not show allelic association with these SNP markers. Clinical data from patients in our study reveal an average delay in diagnosis of 8.4 years and confirm a strong correlation between endometriosis severity and infertility (n = 1182, P<0.001, OR = 2.18). This GWAS of endometriosis was conducted with high diagnostic certainty in cases, and with stringent handling of population substructure. Our findings broaden the understanding of the genetic factors that play a role in endometriosis.

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Figure 1 Regional association plot at the WNT4 region on chromosome 1. P-values of genotyped SNPs(•) and imputed SNPs (×) are plotted against their physical position on chromosome 1 as -log10(P-value) on the left (hg19/GRCh37). The plot identify a 150 kb LD-block (22.35 Mb-22.50 Mb) that show association with endometriosis and include WNT4, CDC42 and HSPC157 (gene symbol: LINC00339). Key SNPs are indicated in the Figure with their rsID. Two SNPs, rs16826658 (green arrow) and rs7521902 (green triangle), previously suggested to be associated with endometriosis (Uno et al. 2010; Painter et al. 2011), are located at the right-most boundary of the associated region. A third SNP, rs2473277, located at the left-most boundary of the LD-region was also tentatively associated by Uno et al. (2010). The genetic recombination rates estimated from 1000 Genome samples (EUR) are shown with a blue line according to the scale indicated to the right. The chromosomal position is indicated in Mb at the bottom of the figure.
Figure 1 Regional association plot at the WNT4 region on chromosome 1. P-values of genotyped SNPs(•) and imputed SNPs (×) are plotted against their physical position on chromosome 1 as -log10(P-value) on the left (hg19/GRCh37). The plot identify a 150 kb LD-block (22.35 Mb-22.50 Mb) that show association with endometriosis and include WNT4, CDC42 and HSPC157 (gene symbol: LINC00339). Key SNPs are indicated in the Figure with their rsID. Two SNPs, rs16826658 (green arrow) and rs7521902 (green triangle), previously suggested to be associated with endometriosis (Uno et al. 2010; Painter et al. 2011), are located at the right-most boundary of the associated region. A third SNP, rs2473277, located at the left-most boundary of the LD-region was also tentatively associated by Uno et al. (2010). The genetic recombination rates estimated from 1000 Genome samples (EUR) are shown with a blue line according to the scale indicated to the right. The chromosomal position is indicated in Mb at the bottom of the figure.CC BY · PubMed Central

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Metadata

Authors
Albertsen, H. M., Chettier, R., Farrington, P., & Ward, K.
Corresponding author
Ward, Kenneth
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-03-05
Volume
8
Issue
3
Pages
e58257
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0058257
PMC
PMC3589333
OpenAlex
W2051994829
Cited by
161
References
30
Citations by year
2026: 2 · 2025: 9 · 2024: 7 · 2023: 9 · 2022: 7 · 2021: 14 · 2020: 9 · 2019: 13 · 2018: 18 · 2017: 17 · 2016: 20 · 2015: 16 · 2014: 9 · 2013: 11
FWCI
22.54
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Plant and fungal interactions
Keywords
endometriosis, genetic susceptibility, genetic loci, single nucleotide polymorphisms, endometriosis diagnosis
MeSH terms
Adult, Algorithms, Alleles, Endometriosis, Female, Genotype, Humans, Software, Reproducibility of Results, Cohort Studies, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Principal Component Analysis, Genome-Wide Association Study, Young Adult

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