TY - JOUR
T1 - GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer
AU - Koel, Mariann
AU - Võsa, Urmo
AU - Jõeloo, Maarja
AU - Läll, Kristi
AU - Gualdo, Natàlia P.
AU - Laivuori, Hannele
AU - Lemmelä, Susanna
AU - Estonian Biobank Research Team
AU - FinnGen
AU - Daly, Mark
AU - Palta, Priit
AU - Mägi, Reedik
AU - Laisk, Triin
N1 - Funding Information:
This study was supported by European Union through Horizon 2020 research and innovation programme under grant agreement No 101016775 (INTERVENE), the Estonian Research Council grants (PRG687, PRG1291, PRG1911 and PSG776), and by MATER Marie Sklodowska-Curie, which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. Computational analyses of EstBB data were performed in the High-Performance Computing Centre, University of Tartu. U.V. was funded by the European Regional Development Fund and the programme Mobilitas Pluss (MOBTP108).
Funding Information:
This study was supported by European Union through Horizon 2020 research and innovation programme under grant agreement No 101016775 (INTERVENE), the Estonian Research Council grants (PRG687, PRG1291, PRG1911 and PSG776), and by MATER Marie Sklodowska-Curie, which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 813707. Computational analyses of EstBB data were performed in the High-Performance Computing Centre, University of Tartu. U.V. was funded by the European Regional Development Fund and the programme Mobilitas Pluss (MOBTP108).
Publisher Copyright:
© The Author(s) 2023.
PY - 2023/6
Y1 - 2023/6
N2 - Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging the latest computational methods and gene expression data, we refine the association signals for cervical cancer and propose potential causal variants and genes at each locus. We prioritise PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1 and GSDMB as the most likely candidate genes for cervical cancer signals, providing insights into cervical cancer pathogenesis and supporting the involvement of reproductive tract development, immune response and cellular proliferation/apoptosis. We construct a genetic risk score (GRS) that is associated with cervical cancer [hazard ratios (HR) = 3.1 (1.7–5.6) for the top 15% vs lowest 15% of individuals], and with other HPV- and immune-system-related diagnoses in a phenome-wide association study analysis. Our results propose valuable leads for further functional studies and present a GRS for cervical cancer that allows additional risk stratification and could potentially be used to personalise the conventional screening strategies for groups more susceptible to cervical cancer.
AB - Genome-wide association studies (GWAS) have successfully identified associations for cervical cancer, but the underlying mechanisms of cervical biology and pathology remain uncharacterised. Our GWAS meta-analyses fill this gap, as we characterise the genetic architecture of cervical phenotypes, including cervical ectropion, cervicitis, cervical dysplasia, as well as up to 9229 cases and 490 304 controls for cervical cancer from diverse ancestries. Leveraging the latest computational methods and gene expression data, we refine the association signals for cervical cancer and propose potential causal variants and genes at each locus. We prioritise PAX8/PAX8-AS1, LINC00339, CDC42, CLPTM1L, HLA-DRB1 and GSDMB as the most likely candidate genes for cervical cancer signals, providing insights into cervical cancer pathogenesis and supporting the involvement of reproductive tract development, immune response and cellular proliferation/apoptosis. We construct a genetic risk score (GRS) that is associated with cervical cancer [hazard ratios (HR) = 3.1 (1.7–5.6) for the top 15% vs lowest 15% of individuals], and with other HPV- and immune-system-related diagnoses in a phenome-wide association study analysis. Our results propose valuable leads for further functional studies and present a GRS for cervical cancer that allows additional risk stratification and could potentially be used to personalise the conventional screening strategies for groups more susceptible to cervical cancer.
U2 - 10.1093/hmg/ddad043
DO - 10.1093/hmg/ddad043
M3 - Article
C2 - 36929174
AN - SCOPUS:85162263416
SN - 0964-6906
VL - 32
SP - 2103
EP - 2116
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 12
ER -
