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

Sapkota, Yadav; Steinthórsdóttir, Valgerður; Morris, Andrew P.; Fassbender, Amelie; Rahmioğlu, Nilüfer; Vivo, Immaculata De; Buring, Julie E.; Zhang, Futao; Edwards, Todd L.; Jones, Sarah; Dorien, O; Peterse, Daniëlle; Rexrode, Kathryn M.; Ridker, Paul M.; Schork, Andrew J.; MacGregor, Stuart; Martin, Nicholas G.; Becker, Christian M.; Adachi, Sosuke; Yoshihara, Kosuke; Enomoto, Takayuki; Takahashi, Atsushi; Kamatani, Yoichiro; Matsuda, Koichi; Kubo, Michiaki; Þorleifsson, Guðmar; Geirsson, Reynir Tómas; Þorsteinsdóttir, Unnur; Wallace, Leanne; Yang, Jian; Edwards, Digna R. Velez; Nyegaard, Mette; Low, Siew‐Kee; Zondervan, Krina T.; Missmer, Stacey A.; D’Hooghe, Thomas; Montgomery, Grant W.; Chasman, Daniel I.; Stefánsson, Kāri; Tung, Joyce Y.; Nyholt, Dale R.

doi:10.1038/ncomms15539

Cited by 261 publications

(340 citation statements)

References 70 publications

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“…It is important to distinguish whether these overlaps are coincident or true shared causal variants. We used summary data-based Mendelian randomization (SMR) analysis (41,47) to test for association between RANKL expression and BMD GWAS signals at six eQTL SNPs. The SMR identified RANKL as the causal gene underlying BMD GWAS association (p < 5 Â 10 -5 ), and there was no significant heterogeneity underlying the eQTL signals (p HEIDI > 0.05) (Supporting Table 5), suggesting that the same causal SNPs contributed to both osteoporosis risk and RANKL expression at 13q14.11.…”

Section: Cis-eqtl Analyses Identified Six Regulatory Snps At 13q1411mentioning

confidence: 99%

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Zhu

Chen

et al. 2018

Journal of Bone and Mineral Research

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RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genomewide association studies (GWASs) have identified multiple intergenic single-nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (high-throughput chromosome conformation capture [Hi-C]), epigenetic annotation, and a series of functional assays. The eQTL analysis identified six potential functional SNPs (rs9533090, rs9594738, r8001611, rs9533094, rs9533095, and rs9594759) exclusively correlated with RANKL gene expression (p < 0.001) at 13q14.11. Co-localization analyses suggested that eQTL signal for RANKL and BMD-GWAS signal shared the same causal variants. Hi-C analysis and functional annotation further validated that the first five osteoporosis SNPs are located in a super-enhancer region to regulate the expression of RANKL via long-range chromosomal interaction. Particularly, dual-luciferase assay showed that the region harboring rs9533090 in the super-enhancer has the strongest enhancer activity, and rs9533090 is an allele-specific regulatory SNP. Furthermore, deletion of the region harboring rs9533090 using CRISPR/Cas9 genome editing significantly reduced RANKL expression in both mRNA level and protein level. Finally, we found that the rs9533090-C robustly recruits transcription factor NFIC, which efficiently elevates the enhancer activity and increases the RANKL expression. In summary, we provided a feasible method to identify regulatory noncoding SNPs to distally regulate their target gene underlying the pathogenesis of osteoporosis by using bioinformatics data analyses and experimental validation. Our findings would be a potential and promising therapeutic target for precision medicine in osteoporosis. © 2018 American Society for Bone and Mineral Research.

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Section: Cis-eqtl Analyses Identified Six Regulatory Snps At 13q1411mentioning

confidence: 99%

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Zhu

Chen

et al. 2018

Journal of Bone and Mineral Research

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“…Causes of endometriosis remain largely unknown, but the condition has an estimated heritability of ∼ 50% [3, 4] with ∼26% estimated to be due to common genetic variation [5]. In total eight genome-wide association studies (GWAS) in women of European and East Asian ancestry have been published to date [6], the largest of which comprised 17,045 cases and 191,596 controls and identified 19 distinct signals at 14 loci [7], leaving many loci yet to be uncovered. Although positional evidence had suggested potential involvement of sex-steroid hormone, WNT signalling, cell adhesion/migration, cell growth/carcinogenesis and inflammation-related pathways, the regulatory effects of most of these variants have yet to be determined in tissues relevant to endometriosis.…”

Section: Introductionmentioning

confidence: 99%

Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Nilufer¹,

Karina²,

Paraskevi³

et al. 2018

Preprint

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Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5×10−8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28×103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

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“…Women with endometriosis have a lower monthly fecundity rate than fertile controls [3]. A meta-analysis of 22 published studies showed that women with endometriosis undergoing in vitro fertilization (IVF) had significantly reduced oocyte retrieval, fertilization, and implantation rates, as well as a significantly lower chance of achieving pregnancy, compared to patients with tubal factor [4].…”

Section: Introductionmentioning

confidence: 99%

“…Endometriosis is a complex trait, with both genetic and environmental factors contributing to the pathophysiology of the disease. The heritability of endometriosis is estimated to be 47-51% [14,15], but the 13 loci identified by previous genome-wide association studies (GWASs) only explain 1.75% of the phenotypic variance [16][17][18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association studies on endometriosis and endometriosis-related infertility

Galarneau¹,

Fontanillas

Clementi³

et al. 2018

Preprint

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Endometriosis affects ~10% of women of reproductive age. It is characterized by the growth of endometrial-like tissue outside the uterus and is frequently associated with severe pain and infertility. We performed the largest endometriosis genome-wide association study (GWAS) to date, with 37,183 cases and 251,258 controls. All women were of European ancestry. We also performed the first GWAS of endometriosis-related infertility, including 2,969 cases and 3,770 controls. Our endometriosis GWAS study replicated, at genome-wide significance, seven loci identified in previous endometriosis GWASs (CELA3A-CDC42, SYNE1, KDR, FSHB-ARL14EP, GREB1, ID4, and CEP112) and identified seven new candidate loci with genome-wide significance (NGF, ATP1B1-F5, CD109, HEY2, OSR2-VPS13B, WT1, and TEX11-SLC7A3). No loci demonstrated genome-wide significance for endometriosis-related infertility, however, the three most strongly associated loci (MCTP1, EPS8L3-CSF1, and LPIN1) were in or near genes associated with female fertility or embryonic lethality in model organisms. These results reveal new candidate genes with potential involvement in the pathophysiology of endometriosis and endometriosis-related infertility. Conflicts of InterestPF, JYT, and members of the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe. GG, THS, DEP, PYB and members of the Celmatix Research Team are employees of Celmatix Inc., and hold stock or stock options in Celmatix Inc. Data availabilityThe full GWAS summary statistics for the 23andMe data sets will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit research.23andMe.com/collaborate for more information and to apply to access the data.Genome-wide significant loci in endometriosis case-control GWAS

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

Cited by 261 publications

References 70 publications

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Multiple Functional Variants at 13q14 Risk Locus for Osteoporosis Regulate RANKL Expression Through Long-Range Super-Enhancer

Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions

Genome-wide association studies on endometriosis and endometriosis-related infertility

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