GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer

Koel, Mariann; Võsa, Urmo; Jõeloo, Maarja; Läll, Kristi; Pujol-Gualdo, Natàlia; Laivuori, Hannele; Lemmelä, Susanna; Daly, Mark J.; Palta, Priit; Mägi, Reedik; Laisk, Triin

doi:10.1093/hmg/ddad043

Cited by 14 publications

(2 citation statements)

References 62 publications

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“…Details of EstBB genotyping procedure have been described previously ( Laisk et al , 2021 ; Pujol-Gualdo et al , 2022 ; Koel et al , 2023 ). Briefly, all EstBB participants were genotyped using Illumina GSAv1.0, GSAv2.0, and GSAv2.0_EST arrays at the Core Genotyping Lab of the Institute of Genomics, University of Tartu.…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy

Pujol Gualdo,

Mägi,

Laisk

2023

Human Reproduction

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STUDY QUESTION Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives? SUMMARY ANSWER We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene. WHAT IS KNOWN ALREADY Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far. STUDY DESIGN, SIZE, DURATION A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study. PARTICIPANTS/MATERIALS, SETTING, METHODS We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition. MAIN RESULTS AND THE ROLE OF CHANCE We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32×10−9) and 10 (rs11598956, P = 2.41×10−8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations. LARGE SCALE DATA The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883). LIMITATIONS, REASONS FOR CAUTION The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings. WIDER IMPLICATIONS OF THE FINDINGS This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation. STUDY FUNDING/COMPETING INTEREST(S) N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests.

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Section: Methodsmentioning

confidence: 99%

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy

Pujol Gualdo,

Mägi,

Laisk

2023

Human Reproduction

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“…Koel et al. (2023) ( 71 ) performed a genome-wide association study (GWAS) to identify genomic variants associated with the full spectrum of cervical disorders, including ectropion, cervicitis, dysplasia, and CC. The variants that were mainly identified overlapped between cervicitis, dysplasia, and cancer and appeared different for ectropion.…”

Section: New Advances In Molecular Characterization Of Cervical Cancermentioning

confidence: 99%

Molecular aspects of cervical cancer: a pathogenesis update

Vallejo-Ruiz,

Gutiérrez-Xicotencatl,

Medina-Contreras

et al. 2024

Front. Oncol.

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Cervical cancer (CC) is a significant health problem, especially in low-income countries. Functional studies on the human papillomavirus have generated essential advances in the knowledge of CC. However, many unanswered questions remain. This mini-review discusses the latest results on CC pathogenesis, HPV oncogenesis, and molecular changes identified through next-generation technologies. Interestingly, the percentage of samples with HPV genome integrations correlates with the degree of the cervical lesions, suggesting a role in the development of CC. Also, new functions have been described for the viral oncoproteins E5, E6, and E7, resulting in the acquisition and maintenance of cancer hallmarks, including proliferation, immune response evasion, apoptosis, and genomic instability. Remarkably, E5 oncoprotein affects signaling pathways involved in the expression of interferon-induced genes and EGFR-induced proliferation, while E6 and E7 oncoproteins regulate the DNA damage repair and cell cycle continuity pathways. Furthermore, next-generation technologies provide vast amounts of information, increasing our knowledge of changes in the genome, transcriptome, proteome, metabolome, and epigenome in CC. These studies have identified novel molecular traits associated with disease susceptibility, degree of progression, treatment response, and survival as potential biomarkers and therapeutic targets.

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Methylation, Gene Expression, and Risk Genotypes at the TERT‐CLPTM1L Locus in Cervical Cancer

Ramachandran,

Mao,

Liao

et al. 2024

Molecular Carcinogenesis

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The reverse transcriptase subunit of telomerase, TERT, is frequently activated in high‐grade dysplasia and invasive cancers of the uterine cervix. Telomerase activation through hypomethylation of the TERT promoter holds promise as a biomarker for cervical cancer progression, however, specific CpG sites involved in cervical cancer risk remain to be fully defined. A recent genome‐wide association study on cervical cancer identified genetic polymorphisms at 5p13.33 (close to TERT‐CLPTM1L) but the underlying mechanisms are undetermined. We investigated 529 CpG sites within the TERT promoter region and 3 CpG islands nearby, and 21 CpG sites within CLPTM1L in 190 bisulfite‐converted cervical tumor DNA samples from BioRAIDs (NCT02428842). We identified eight CpG sites within TERT intron 2 where methylation was significantly associated with the genotypes of cervical cancer risk variants rs27070 and rs459961 in cervical tumors after multiple testing correction (p < 9.4 × 10E−5). Hypermethylation at chr5:1289663 correlated with decreased TERT mRNA levels. In an independent series of 188 normal or dysplastic cervical tissues, rare alleles of rs27070 and rs459961 were associated with low basal CLPTM1L levels and with the absence of TERT mRNA in HPV‐negative samples, consistent with their proposed role as protective variants for cervical cancer. HPV infection was associated with increased CLPTM1L and TERT levels. Collectively, our results provide a link between cervical cancer risk variants, methylation, and gene expression and implicate both TERT and CLPTM1L as genes modulated by genomic background and HPV infection during cervical cancer development.

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GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer

Cited by 14 publications

References 62 publications

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy

Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy

Molecular aspects of cervical cancer: a pathogenesis update

Methylation, Gene Expression, and Risk Genotypes at the TERT‐CLPTM1L Locus in Cervical Cancer

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