GWAS meta-analysis and gene expression data link reproductive tract development, immune response and cellular proliferation/apoptosis with cervical cancer and clarify overlap with other cervical phenotypes

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 up to 9,229 cases and 490,304 controls for cervical cancer from diverse ancestries. 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 GRS that associates with cervical cancer (HR=3.7 for top 5% vs lowest 5%), and with other HPV- and immune-system related diagnoses in a PheWAS analysis. Our results propose valuable leads for further functional studies and the presented GRS offers an additional opportunity for risk stratification together with conventional screening strategies.