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Cited by 346Endometriosis Research and TreatmentGenetic Associations and EpidemiologyPlant and fungal interactions

Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

Open access
Sapkota, Yadav, Steinthorsdottir, Valgerdur, Morris, Andrew P., Fassbender, Amelie, Rahmioglu, Nilufer, De Vivo, Immaculata, Buring, Julie E., Zhang, Futao +36 more·2017·Nature Communications
DOI 10.1038/ncomms15539PMC PMC5458088
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Abstract

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk ( P <5 × 10 −8 ), implicating genes involved in sex steroid hormone pathways ( FN1 , CCDC170 , ESR1 , SYNE1 and FSHB ). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts.

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Written from the paper’s full text.

TL;DR

This meta-analysis of 11 genome-wide association case-control datasets (17,045 endometriosis cases and 191,596 controls) replicated 9 of 11 previously reported European risk loci and identified five novel endometriosis loci implicating sex steroid hormone pathway genes. Conditional analysis yielded 19 independent SNPs at 14 loci, which together explained up to 5.19% of phenotypic variance in Grade B endometriosis.

Key findings

  • The study replicated 9 of 11 previously reported European SNP risk loci; it did not confirm associations at 2q23.3 and 9p22.
  • Five novel loci reached genome-wide significance: CCDC170 on 6q25.1 (rs1971256: OR=1.09, 95% CI 1.06–1.13; P=3.74×10−8), SYNE1 on 6q25.1 (rs71575922: OR=1.11, 95% CI 1.07–1.15; P=2.02×10−8), near FSHB on 11p14.1 (rs74485684: OR=1.11, 95% CI 1.07–1.15; P=2.00×10−8), FN1 on 2q35 (rs1250241: OR=1.23, 95% CI 1.15–1.30; P Grade B=2.99×10−9), and 7p12.3 (rs74491657: OR=1.46, 95% CI 1.28–1.59; P Grade B=2.24×10−8).
  • Conditional analysis identified five secondary signals: rs77294520 near GREB1 on 2p25.1; rs2206949 in ESR1 and rs17803970 in SYNE1 on 6q25.1; and rs10757272 in CDKN2B-AS1 and rs1448792 on 9p21.3, giving 19 independent SNPs at 14 loci.
  • The 9 previously reported SNPs explained 0.97% of liability-scale variance; the 10 new SNPs explained a further 0.78% in all cases (total 1.75%), while the 19 SNPs together explained 5.19% in Grade B endometriosis, of which 2.46% was from the 10 new SNPs.

Methods

  • Meta-analysis of 11 GWA case-control datasets of European and Japanese ancestry, totalling 17,045 endometriosis cases and 191,596 controls (Results section reports 191,858 controls); ~93% of effective sample size was European and ~7% Japanese.
  • Primary fixed-effect inverse-variance meta-analysis in METAL included 6,979,035 SNPs passing QC in at least 50% of studies; genome-wide significance was P<5×10−8. A secondary “Grade B” analysis excluded minimal/mild rAFS I/II cases from QIMRHCS, deCODE, LEUVEN, and OX cohorts.
  • Follow-up analyses included GCTA approximate conditional analysis, VEGAS2 gene-based testing, Bayesian fine-mapping, GTEx eQTL lookups, SMR, DEPICT pathway analysis, and liability-threshold variance-explained estimation.

Limitations

  • Stated: target genes in most regions remain unidentified and further functional studies are needed; DEPICT provided little support for genes, pathways, tissues, or cell types at FDR≤0.05; SMR showed significant heterogeneity for VEZT, suggesting possible colocalization that needs further investigation.
  • Stated/evident: the sample is predominantly European (~93% of effective sample size), and only 6 of 19 SNPs showed significant association in Japanese-only analysis, although effect directions were concordant.
  • Evident from text: some studies used self-reported endometriosis or mixed surgical/self-report diagnosis, and the authors note disease misclassification may contribute to smaller effect sizes; six loci showed between-study heterogeneity in the all-case fixed-effect meta-analysis.

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Crossref · 10.1038/ncomms15539

Cites

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Statistics

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Claims the paper makes

0 of 68 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The 19 independent SNPs are robustly associated with endometriosis.

    “resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis.”
    Quote in the paperSubstantial claim
  • Findingcitation

    The current meta-analysis represents an approximate five-fold increase in effective sample size compared with the previously largest multi-ethnic GWA meta-analysis of 4,604 endometriosis cases and 9,393 controls.

    “the current meta-analysis represents an approximate five-fold increase in the effective sample size13 in comparison to the previously largest multi-ethnic GWA meta-analysis of 4,604 endometriosis cases and 9,393 controls from Australia, United Kingdom and Japan8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). source

      Not checked in the free run.

    • cites [8] Nyholt, D. R. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 44, 1355–1359 (2012). source

      Not checked in the free run.

  • Findingown data

    Conditional analysis identified five secondary association signals, including two at the ESR1 locus.

    “Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis”
    Quote in the paperSubstantial claim
  • Findingown data

    The meta-analysis identified five novel loci significantly associated with endometriosis risk at P<5 × 10−8.

    “In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10−8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB).”
    • Also stated in: § Risk loci associated with endometriosis · plain
      “the meta-analysis identified five new genomic regions harbouring risk loci for endometriosis (Fig. 1 and Table 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    The 19 independent SNPs together explain up to 5.19% of variance in endometriosis.

    “which together explain up to 5.19% of variance in endometriosis.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    Of the 11 previously reported European SNP risk loci, nine reached genome-wide significance in the present study; associations at 2q23.3 and 9p22 were not confirmed.

    “Of the 11 previously reported European SNP risk loci, nine reached genome-wide significance (P<5 × 10−8) in the present study (Fig. 1 and Table 1); we did not confirm associations at 2q23.3 and 9p22.”
    • Also stated in: § Abstract · plain
      “In addition to replicating 9 of the 11 previously reported European risk loci, this GWA meta-analysis identified 5 novel loci significantly associated with endometriosis risk (P<5 × 10−8)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The risk allele of six SNPs was the same for both breast cancer and endometriosis, including four SNPs in strong LD (r2≥0.60) with the secondary association signal rs2206949 at 6q25.1 (ESR1).

    “The risk allele of six SNPs was the same for both breast cancer and endometriosis, including four SNPs (rs851981, rs851980, rs2206948 and rs150182883) that are in strong LD (r2≥0.60) with our secondary association signal rs2206949 at 6q25.1 (ESR1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 19 independent SNPs together explained 5.19% of phenotypic variance in Grade B endometriosis cases, of which 2.46% was explained by the 10 new SNPs.

    “More importantly, the 19 independent SNPs together explained 5.19% of the phenotypic variance in Grade B endometriosis cases, of which 2.46% was explained by the 10 new SNPs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Based on results from all studies, the smallest 99% credible interval was ∼16.52 kb observed for rs11674184 on 2p25.1 and the largest was ∼604.80 kb for the 6q25.1 (SYNE1).

    “Based on results from all studies, the smallest 99% credible interval was ∼16.52 kb observed for rs11674184 on 2p25.1 and the largest was ∼604.80 kb for the 6q25.1 (SYNE1).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: A single causal variant underlies each association signal in the fine-mapping analysis.

  • May combine two claims.

    Findingown data

    In Europeans, five loci (2p14, 2q35, 4q12, 6q25.1 (SYNE1) and 7p15.2) showed heterogeneity in allelic associations, and except for 6q25.1 (SYNE1), this trend persisted in surgically confirmed endometriosis cases.

    “In Europeans, five loci (2p14, 2q35, 4q12, 6q25.1 (SYNE1) and 7p15.2) showed heterogeneity in allelic associations, and except for 6q25.1 (SYNE1), this trend persisted in surgically confirmed endometriosis cases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All 19 SNPs showed significant associations with endometriosis in Europeans; only six SNPs showed significance in Japanese alone; direction of effects for all SNPs was concordant with the meta-analysis.

    “Whereas all 19 SNPs showed significant associations with endometriosis (P<2.6 × 10−3 after multiple testing) in Europeans, only six SNPs showed significance in Japanese alone, although importantly, direction of effects for all SNPs were concordant with those produced in the meta-analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 19 SNPs and high-LD proxies, associations were observed with multiple diseases or traits, including epithelial ovarian cancer, low-density lipoprotein cholesterol, coronary heart disease, luteinizing hormone and follicle-stimulating hormone levels, and age at onset for menopause.

    “Of these, we observed associations with multiple diseases or traits, including epithelial ovarian cancer21, low-density lipoprotein cholesterol22, coronary heart disease23, luteinizing hormone and follicle-stimulating hormone levels, and age at onset for menopause24.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Pearce, C. L. et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol. 13, 385–394 (2012). source

      Not checked in the free run.

    • cites [22] Global Lipids Genetics, C.. et al. Discovery and refinement of loci associated with lipid levels. Nat. Genet. 45, 1274–1283 (2013). source

      Not checked in the free run.

    • cites [23] Lu, X. et al. Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease. Nat. Genet. 44, 890–894 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Of the 18 genes, 12 are located at six GWA SNP risk loci including 1p36.12 (WNT4, LINC00339, LOC101928043 and CDC42), 2p25.1 (GREB1), 2q13 (IL1A and CKAP2L), 7p15.2 (RNU6-16P), 9p21.3 (CDKN2A) and 12q22 (MIR331, MIR3685 and VEZT).

    “Of these, 12 genes are located at six GWA SNP risk loci including 1p36.12 (WNT4, LINC00339, LOC101928043 and CDC42), 2p25.1 (GREB1), 2q13 (IL1A and CKAP2L), 7p15.2 (RNU6-16P), 9p21.3 (CDKN2A) and 12q22 (MIR331, MIR3685 and VEZT).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These data implicate 19 independent SNPs at 14 distinct genomic loci, including four on 6q25.1.

    “Taken together, these data implicate 19 independent SNPs at 14 distinct genomic loci, including four on 6q25.1—a locus containing a cluster of genes including ESR1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Associations at the 6q25.1 CCDC170 and SYNE1 loci remained genome-wide significant in the Grade B analysis, with larger effects for the risk allele compared with all endometriosis cases.

    “Associations at the 6q25.1 CCDC170 and SYNE1 loci remained genome-wide significant in the ‘Grade B' analysis, with larger effects (ORs) for the risk allele in comparison to those based on analysis of all endometriosis cases (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GCTA conditional analysis identified five secondary signals: rs77294520 near GREB1 on 2p25.1; rs2206949 in ESR1 and rs17803970 in SYNE1 on 6q25.1; and rs10757272 in CDKN2B-AS1 and rs1448792 on 9p21.3.

    “GCTA identified five secondary signals including one (rs77294520 near GREB1) on 2p25.1; two (rs2206949 in ESR1 and rs17803970 in SYNE1) on 6q25.1, and two (rs10757272 in CDKN2B-AS1 and rs1448792) on 9p21.3 (Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The nine previously reported SNPs explain 0.97% of phenotypic variance on the liability scale; the 10 new SNPs explain a further 0.78%, totalling 1.75% of phenotypic variance explained for endometriosis.

    “On the basis of the fixed-effect GWA meta-analysis results including all endometriosis cases from European studies, the nine previously reported SNPs explain 0.97% of the phenotypic variance on the liability scale19. The 10 new SNPs identified in this study together explain a further 0.78%, totalling to 1.75% of the phenotypic variance explained for endometriosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Risch, N. J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Of the 14 distinct loci, 6 showed evidence of between-study heterogeneity in fixed-effect meta-analysis including all endometriosis cases; after modelling the observed heterogeneity in the RE2 model, these associations remained genome-wide significant.

    “Of the 14 distinct loci, 6 (2p14, 2q35, 4q12, 6q25.1 (SYNE1), 7p15.2 and 12q22) showed evidence of between-study heterogeneity (Phet<0.05; I2: 13.30–20.33) in fixed-effect meta-analysis including all endometriosis cases; however, after appropriately modelling the observed heterogeneity in the RE2 model, these associations remained genome-wide significant (Supplementary Data 2).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The RE2 model's assumption of no heterogeneity under the null hypothesis of no association holds.

  • May combine two claims.

    Findingnone given

    SNP rs17761446 is monomorphic in Europeans and is in weak LD (r2<0.16) in Japanese with the SNPs implicated in the current study.

    “SNP rs17761446 is monomorphic in Europeans and is also in weak LD (r2<0.16) in Japanese with the SNPs implicated in the current study”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Results from the current study provide genome-wide evidence for the FN1 locus in Grade B endometriosis, thereby highlighting the importance of subgroup analysis and phenotype definition.

    “Results from the current study provide genome-wide evidence for the FN1 locus in Grade B endometriosis, thereby highlighting the importance of subgroup analysis and phenotype definition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This study robustly associated the FN1 locus with endometriosis, in particular with moderate-to-severe disease.

    “This study robustly associated the FN1 locus with endometriosis, in particular with moderate-to-severe disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In addition to confirming the previously identified association signal at the 2p25.1 locus, the results provide evidence for secondary association with risk of endometriosis.

    “In addition to confirming the previously identified association signal at this locus, our results provide evidence for secondary association with risk of endometriosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Of the 11 European SNP risk loci, eight SNPs have been replicated and robustly implicated as susceptibility loci for endometriosis, with exceptions rs1519761, rs17773813 and rs519664.

    “Of the 11 European SNP risk loci, eight SNPs have been replicated and robustly implicated as susceptibility loci for endometriosis1012, the exceptions being rs1519761 (2q23.3), rs17773813 (4q12) and rs519664 (TTC39B) that are yet to be examined in an independent study.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1012]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Endometriosis has an estimated total heritability of 0.47-0.51 based on twin studies and a common SNP-based heritability of 0.26.

    “The condition has an estimated total heritability of 0.47–0.51 based on twin studies13, and a common SNP-based heritability of 0.26 (ref. 4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010). source

      Not checked in the free run.

    • cites [4] Lee, S. H. et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum. Mol. Genet. 22, 832–841 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous GWA studies of endometriosis have implicated WNT signalling, oestrogen responsive genes and genes involved in the actin cytoskeleton and cellular adhesion.

    “Previous GWA studies of endometriosis have implicated WNT signalling, oestrogen responsive genes and genes involved in the actin cytoskeleton and cellular adhesion1233.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Rahmioglu, N. et al. Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets. Hum. Reprod. Update 20, 702–716 (2014). source

      Not checked in the free run.

    • cites [33] Nyholt, D. R. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 44, 1355–1359 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Symptoms occur after puberty and oestrogen action contributes to pathological processes including growth of lesions and inflammation, and to symptoms including pain.

    “Symptoms occur after puberty and oestrogen action contributes to pathological processes including growth of lesions and inflammation, and to the symptoms including pain4142.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Bulun, S. E. et al. Role of estrogen receptor-beta in endometriosis. Semin. Reprod. Med. 30, 39–45 (2012). source

      Not checked in the free run.

    • cites [42] Burney, R. O. & Giudice, L. C. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril. 98, 511–519 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KDR is responsive to steroid hormones; expression of KDR in endometrial stromal cells isolated from proliferative phase endometrium was significantly increased by oestrogen and medroxyprogesterone acetate in vitro.

    “KDR is responsive to steroid hormones; expression of KDR in endometrial stromal cells isolated from proliferative phase endometrium was significantly increased by oestrogen and medroxyprogesterone acetate in vitro39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Sugino, N., Kashida, S., Karube-Harada, A., Takiguchi, S. & Kato, H. Expression of vascular endothelial growth factor (VEGF) and its receptors in human endometrium throughout the menstrual cycle and in early pregnancy. Reproduction 123, 379–387 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During the premenstrual phase in both humans and macaques, KDR expression was significantly increased in the stromal cells of the endometrium.

    “During the premenstrual phase in both humans and macaques, KDR expression was significantly increased in the stromal cells of the endometrium40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Brenner, R. M., Nayak, N. R., Slayden, O. D., Critchley, H. O. & Kelly, R. W. Premenstrual and menstrual changes in the macaque and human endometrium: relevance to endometriosis. Ann. NY Acad. Sci. 955, 60–74 discussion 86-8, 396-406 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    For rs2268177, there was no significant evidence of heterogeneity (PHEIDI=0.065) in effect sizes of dependent SNPs, and therefore it is very likely that rs2268177 contributes to both endometriosis risk and the expression level of CDC42.

    “For rs2268177, there was no significant evidence of heterogeneity (PHEIDI=0.065) in effect sizes of dependent SNPs at this associated region and therefore it is very likely that rs2268177 contributes to both endometriosis risk and the expression level of CDC42.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The genetic variants used as instruments in SMR affect endometriosis risk only through gene expression (no horizontal pleiotropy).

  • May combine two claims.

    Premisecitation

    The index SNP associated with endometriosis on chromosome 2p25.1 is a common splice variant in GREB1 and SNPs associated with endometriosis on chromosome 12q22 increase expression of VEZT in RNA from blood and endometrium.

    “The index SNP associated with endometriosis on chromosome 2p25.1 is a common splice variant in the oestrogen-responsive growth regulation by oestrogen in breast cancer 1 (GREB1) gene3337 and SNPs associated with endometriosis on chromosome 12q22 increase expression of the transmembrane adherens junctions protein coding gene vezatin (VEZT) in RNA from blood and endometrium38.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [33] Nyholt, D. R. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 44, 1355–1359 (2012). source

      Not checked in the free run.

    • cites [37] Fung, J. N. et al. Functional evaluation of genetic variants associated with endometriosis near GREB1. Hum. Reprod. 30, 1263–1275 (2015). source

      Not checked in the free run.

    • cites [38] Holdsworth-Carson, S. J. et al. Endometrial vezatin and its association with endometriosis risk. Hum. Reprod. 31, 999–1013 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The index SNP for endometriosis at the WNT4 locus on chromosome 1p36.12 is also the index SNP for ovarian cancer and the risk mechanism likely acts through inverse regulation of CDC42 and LINC00339.

    “The most strongly associated (index) SNP for endometriosis at the WNT4 locus on chromosome 1p36.12 is also the index SNP for ovarian cancer35 and the risk mechanism likely acts through inverse regulation of CDC42 and LINC00339 (ref. 36).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Kuchenbaecker, K. B. et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat. Genet. 47, 164–171 (2015). source

      Not checked in the free run.

    • cites [36] Powell, J. E. et al. Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Hum. Mol. Genet. 25, 5046–5058 (2016).

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    A reference population with a similar proportion of European and Japanese individuals to the meta-analysis was used to calculate the LD for conditional analysis.

    “we used a reference population with similar proportion of European and Japanese individuals to calculate the LD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Gene-based approaches can be more powerful than single SNP analyses, in part because they account for allelic heterogeneity and LD between SNPs and restrict to genic regions, reducing the multiple-testing problem of traditional GWA studies.

    “Gene-based approaches can be more powerful than single SNP analyses, in part due to accounting for allelic heterogeneity (if present) and LD between SNPs, and restricting to genic regions thereby reducing the multiple-testing problem of traditional GWA study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Regulation of GREB1 transcription by oestrogen receptor α (ERα) is mediated through three oestrogen response elements (EREs) located 20 kb upstream of the gene.

    “Regulation of GREB1 transcription by oestrogen receptor α (ERα) is mediated through three oestrogen response elements (EREs) located 20 kb upstream of the gene5051.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Deschenes, J., Bourdeau, V., White, J. H. & Mader, S. Regulation of GREB1 transcription by estrogen receptor alpha through a multipartite enhancer spread over 20 kb of upstream flanking sequences. J. Biol. Chem. 282, 17335–17339 (2007). source

      Not checked in the free run.

    • cites [51] Sun, J., Nawaz, Z. & Slingerland, J. M. Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. Mol. Endocrinol. 21, 2651–2662 (2007). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Best-guess genotypes of well-imputed (minimac r2>0.8) SNPs in the QIMRHCS 1000 Genomes imputed data were quality-controlled to exclude SNPs with Hardy-Weinberg Equilibrium P<1 × 10−6 in controls, MAF<0.01 and >5% missingness.

    “Best guess genotypes of well-imputed (minimac r2>0.8) SNPs in the QIMRHCS 1,000 Genomes imputed data were then subjected to quality control to exclude SNPs with Hardy-Weinberg Equilibrium P<1 × 10−6 in controls, MAF<0.01 and >5% missingness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    FSHB encodes the beta polypeptide of FSH, a glycoprotein hormone that plays a central role in ovarian folliculogenesis.

    “FSHB encodes the beta polypeptide of FSH, a glycoprotein hormone that plays a central role in ovarian folliculogenesis46.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Gougeon, A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann. Endocrinol. (Paris) 71, 132–143 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All samples were collected with informed consent and study protocols were approved by the relevant local institutional ethics committees.

    “All samples were collected with informed consent and study protocols were approved by the relevant local institutional ethics committees”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Imputed genotypes with low imputation quality (<0.3 for minimac and <0.4 for IMPUTE2) in each data set were excluded from downstream analysis.

    “Imputed genotypes with low imputation quality (<0.3 for minimac and <0.4 for IMPUTE2) in each data set were excluded from the downstream analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Association between rs1250248, which is in very high LD (r2=0.95) with the lead SNP rs1250241 at the FN1 locus, was first reported by the earlier European GWA study led by us, but was not replicated in an independent sample.

    “Association between rs1250248, which is in very high LD (r2=0.95) with our lead SNP rs1250241 at this locus, was first reported by the earlier European GWA study led by us, but was not replicated in an independent sample7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Painter, J. N. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat. Genet. 43, 51–54 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SNPs at the chromosome 9p21 locus are also associated with a number of other diseases, including coronary artery disease, in which ANRIL has previously been implicated.

    “SNPs at the chromosome 9p21 locus are also associated with a number of other diseases, including coronary artery disease (CAD)—a disease in which ANRIL has previously been implicated55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Holdt, L. M. & Teupser, D. From genotype to phenotype in human atherosclerosis–recent findings. Curr. Opin. Lipidol. 24, 410–418 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functional studies in mammalian cells show that ANRIL overexpression accelerated proliferation, increased adhesion and decreased apoptosis.

    “Functional studies in mammalian cells show that ANRIL overexpression accelerated proliferation, increased adhesion and decreased apoptosis5456.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Nakaoka, H. et al. Allelic Imbalance in Regulation of ANRIL through Chromatin Interaction at 9p21 Endometriosis Risk Locus. PLoS Genet. 12, e1005893 (2016). source

      Not checked in the free run.

    • cites [56] Chen, H. H., Almontashiri, N. A., Antoine, D. & Stewart, A. F. Functional genomics of the 9p21.3 locus for atherosclerosis: clarity or confusion? Curr. Cardiol. Rep. 16, 502 (2014). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Variants at the 6q25.1 locus have recently been associated with overall breast cancer and its sub-phenotypes including tumour subtypes, mammographic density and tumour grade.

    “Variants at this locus have recently been associated with overall breast cancer and its sub-phenotypes including tumour subtypes, mammographic density and tumour grade27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Dunning, A. M. et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat. Genet. 48, 374–386 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromatin conformation capture in human vascular endothelial cells identified short-range interactions between sequences at the 9p21.3 locus and sequences near CDKN2A, CDKN2B and MTAP, and long-range interactions with IFNW1 and IFNA21 approximately one million base pairs upstream on chromosome 9.

    “Chromatin conformation capture in this region in human vascular endothelial cells identified short-range interactions between sequences at the 9p21.3 locus and sequences in the vicinity of the genes encoding CDKN2A, CDKN2B, and MTAP, and long-range interactions with IFNW1 and IFNA21 approximately one million base pairs upstream on chromosome 9 (ref. 56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Chen, H. H., Almontashiri, N. A., Antoine, D. & Stewart, A. F. Functional genomics of the 9p21.3 locus for atherosclerosis: clarity or confusion? Curr. Cardiol. Rep. 16, 502 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While effects of individual risk SNPs are small, the results suggest that risk variants acting on several genes in the same pathway act to increase sensitivity to oestrogen and increase the risk of endometriosis.

    “Moreover, GREB1 functions as an essential component of the oestrogen receptor transcription complex52, and while effects of individual risk SNPs are small, the results suggest that risk variants acting on several genes in the same pathway act to increase sensitivity to oestrogen and increase the risk of endometriosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Mohammed, H. et al. Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell Rep. 3, 342–349 (2013). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Imputed genotypes in the 23andMe data set were analysed adjusting for age and the top five principal components.

    “Imputed genotypes in the 23andMe data set were analysed by adjusting for age and the top five principal components”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The allele(s) associated with increased risk of endometriosis are also associated with shorter menstrual cycles, earlier age at menopause, increased dizygotic twinning and polycystic ovarian syndrome.

    “The allele(s) associated with increased risk of endometriosis are also associated with shorter menstrual cycles, earlier age at menopause, increased dizygotic twinning and polycystic ovarian syndrome24454748.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Ruth, K. S. et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur. J. Hum. Genet. 24, 284–290 (2016). source

      Not checked in the free run.

    • cites [45] Ruth, K. S. et al. Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health. Hum. Reprod. 31, 473–481 (2016). source

      Not checked in the free run.

    • cites [47] Jones, M. R. & Goodarzi, M. O. An update on the genetics of polycystic ovary syndrome: progress and future directions. Fertil. Steril. 106, 25–32 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    Association analysis of deCODE data was performed using logistic regression and included adjustment for age and population substructures.

    “Association analysis of deCODE data was performed using logistic regression9, and included adjustment for age and population substructures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Steinthorsdottir, V. et al. Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nat. Commun. 7, 12350 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 6q25.1 region is a well-established susceptibility locus for breast cancer in both Europeans and Asians.

    “The 6q25.1 region is a well-established susceptibility locus for breast cancer in both Europeans and Asians274344.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Dunning, A. M. et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat. Genet. 48, 374–386 (2016). source

      Not checked in the free run.

    • cites [43] Cai, Q. et al. Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of chinese, Japanese, and European ancestry. Cancer Res. 71, 1344–1355 (2011). source

      Not checked in the free run.

    • cites [44] Zheng, W. et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat. Genet. 41, 324–328 (2009). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The smaller effect sizes in analyses including all endometriosis cases may be due to disease misclassification in self-reported endometriosis cases.

    “The smaller effect sizes in analyses including all endometriosis cases may be due to disease misclassification in self-reported endometriosis cases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The iPSYCH data were analysed adjusting for genotyping waves and the top five principal components.

    “The iPSYCH were analysed by adjusting for genotyping waves and the top five principal components.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FSH and LH play central roles in regulating follicle development in the ovary, influencing oestradiol release during the proliferative phase of the cycle and contributing to a role for estradiol in endometriosis risk.

    “They both play central roles in regulating follicle development in the ovary, influencing oestradiol release during the proliferative phase of the cycle46 and contributing to a role for estradiol in endometriosis risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Gougeon, A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann. Endocrinol. (Paris) 71, 132–143 (2010). source

      Not checked in the free run.

46 of 46

  • The authors state this as an assumption.

    A single causal variant underlies each association signal in the fine-mapping analysis.

    “We assumed a single causal variant for each association signal and constructed a 99% credible set of variants including SNPs within 500 kb of the index SNP.”

  • The authors state this as an assumption.

    The RE2 model's assumption of no heterogeneity under the null hypothesis of no association holds.

    “The RE2 model is similar to the traditional RE approach except it relaxes the conservative assumption in hypothesis testing and assumes no heterogeneity under the null hypothesis of no association.”

  • The paper relies on this without support.

    The genetic variants used as instruments in SMR affect endometriosis risk only through gene expression (no horizontal pleiotropy).

    “we used a novel method30, summary data-based Mendelian randomization (SMR), which exploits the concept of Mendelian Randomisation (MR), to test for the causative effect of an exposure (that is, gene expression) on a phenotypic outcome (that is, endometriosis) using a genetic (SNP) variant as an instrumental variable.”

  • The authors state this as an assumption.

    There is a single causal variant for each association signal.

    “We assumed a single causal variant for each association signal, calculated BF for all SNPs within 500 kb of the index SNP, and ranked the SNPs based on their BF.”

  • The authors state this as an assumption.

    The associated SNPs are not in high LD with one another.

    “Assuming associated SNPs are not in high LD, we calculated the sum of single-SNP explained variances to produce the total variance explained by a set of independent SNPs72.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recent GWAS meta-analysis of 17,045 women with endometriosis and 191,596 controls has documented five novel genome-wide significant SNPs enriched for genes involved in steroid hormone levels and activities.

    “Recent GWAS meta-analysis of 17,045 women with endometriosis and 191,596 controls has documented five novel genome-wide significant SNPs, that are enriched for a set of genes (including FN1, CCDC170, ESR1, SYNE1 and FSHB) involved in steroid hormone levels and activities.35”

    From Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone (2023) · cites this paper as [35]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • A recent meta-analysis identified five loci regulating sex steroid hormone pathways, five secondary signals, and 19 single-nucleotide polymorphisms robustly associated with endometriosis.

    “A recent meta-analysis identified five loci regulating sex steroid hormone pathways, five secondary signals, and 19 single-nucleotide polymorphisms robustly associated with endometriosis (54)”

    From Pathogenesis of endometriosis: The genetic/epigenetic theory (2019) · cites this paper as [54]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ESR1 region is assigned two chromosome bands

    Minor

    The Discussion places the ESR1 region at 6p25.1, whereas the Results places the ESR1 association at 6q25.1.

  • Variance explained increases by less than twofold

    Minor

    The reported variance explained rises from 0.97% for the previously reported SNPs to 1.75% with the new SNPs-approximately 1.8-fold, not more than double.

2 of 2

Cites

Flagged first, then by citations

2 of the 73 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Nyholt, D. R. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 44, 1355–1359 (2012). · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Sapkota, Y., Steinthorsdottir, V., Morris, A. P., Fassbender, A., Rahmioglu, N., De Vivo, I., Buring, J. E., Zhang, F., Edwards, T. L., Jones, S., O, D., Peterse, D., Rexrode, K. M., Ridker, P. M., Schork, A. J., MacGregor, S., Martin, N. G., Becker, C. M., Adachi, S., Yoshihara, K., Enomoto, T., Takahashi, A., Kamatani, Y., Matsuda, K., Kubo, M., Thorleifsson, G., Geirsson, R. T., Thorsteinsdottir, U., Wallace, L. M., iPSYCH-SSI-Broad Group, Werge, T. M., Thompson, W. K., Yang, J., Velez Edwards, D. R., Nyegaard, M., Low, S.-K., Zondervan, K. T., Missmer, S. A., D'Hooghe, T., Montgomery, G. W., Chasman, D. I., Stefansson, K., Tung, J. Y., & Nyholt, D. R.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Centre for Human Genetics (GB)
  • Universitair Ziekenhuis Leuven (BE)
  • Brigham and Women's Hospital (US)
  • The University of Queensland (AU)
  • Vanderbilt University Medical Center (US)
  • Vanderbilt University (US)
  • Mental Health Services (DK)
  • QIMR Berghofer Medical Research Institute (AU)
  • John Radcliffe Hospital (GB)
  • Niigata University (JP)
  • RIKEN Center for Integrative Medical Sciences (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
  • University of Iceland (IS)
  • University of Copenhagen (DK)
  • Aarhus University (DK)
  • Queensland University of Technology (AU)
Corresponding author
  • Sapkota, Yadav
  • Montgomery, Grant W.
  • Nyholt, Dale R.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-05-24
Volume
8
Issue
1
Pages
15539-15539
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15539
PMC
PMC5458088
OpenAlex
W2617005810
Semantic Scholar
43b752c493514217000f98e6381d7f65df4a71b6
Cited by
344
References
73
Citations by year
2026: 30 · 2025: 36 · 2024: 32 · 2023: 41 · 2022: 45 · 2021: 43 · 2020: 34 · 2019: 38 · 2018: 34 · 2017: 10
FWCI
5.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
  • Lirias (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Opin vísindi (Opin vísindi) (submittedVersion, cc-by)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
Funders
  • Wellcome Trust (085475, WT098017, WT084766, 339446, WTCCC2, WT084766/Z/08/Z, 076113)
  • QIMR Berghofer Medical Research Institute
  • Lundbeckfonden (R155-2014-1724, R102‐A9118, R102-A9118, R155-2014-1724)
  • Novo Nordisk
  • Novo Nordisk Fonden
  • H. Lundbeck A/S (R102-A9118, R155-2014-1724)
  • Medical Research Council (MR/K011480/1)
  • Australian Research Council (FT0991022)
  • National Health and Medical Research Council (613674, 033 and 1, 1050208, 619667, 241,944, 339,462, 389,927, 389,875, 389,891, 389,892, 389,938, 443,036, 442,915, 442,981, 496,610, 496,739, 552,485, 552,498, 1,026,033)
  • Japan Society for the Promotion of Science (17K16837, 16H06267)
  • RIKEN
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, ESR1, follicle-stimulating hormone beta subunit, FN1, SYNE1, single nucleotide polymorphisms, conditional analysis, heritability
MeSH terms
Adult, Aged, Endometriosis, Female, Genotype, Humans, Middle Aged, Gonadal Steroid Hormones, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Estrogen Receptor alpha, Metabolic Networks and Pathways, Genome-Wide Association Study, Genetic Loci

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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