GWAS meta-analyses clarify the genetics of cervical phenotypes and inform risk stratification for cervical cancer.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
05 06 2023
05 06 2023
Historique:
received:
21
11
2022
revised:
22
02
2023
accepted:
06
03
2023
medline:
8
6
2023
pubmed:
18
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36929174
pii: 7078905
doi: 10.1093/hmg/ddad043
pmc: PMC10244231
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2103-2116Informations de copyright
© The Author(s) 2023. Published by Oxford University Press.
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