全基因组关联研究(GWAS)已成功地鉴定出宫颈癌的相关联，但宫颈生物学和病理学的潜在机制仍未被描述。我们GWAS荟萃分析填补了这个空白，因为我们描述了宫颈表型的遗传结构，包括宫颈外翻，宫颈炎，宫颈上皮内瘤变，以及来自各种族祖先的9229例宫颈癌病例和490,304个对照组。利用最新的计算方法和基因表达数据，我们精炼了宫颈癌的关联信号，并在每个位点提出了潜在的致病变异体和基因。我们优先选择PAX8 / PAX8-AS1、LINC00339、CDC42、CLPTM1L、HLA-DRB1和GSDMB作为最可能的宫颈癌信号候选基因，从而提供了关于宫颈癌发病机制的见解，并支持生殖道发育、免疫应答和细胞增殖/凋亡的参与。我们构建了一个与宫颈癌相关的GRS(HR = 3.1 (1.7-5.6)，适用于个体中前15%与最低15%的人群），并在pheWAS分析中与其他HPV和免疫系统相关的诊断相关联。我们的结果为进一步的功能研究提供了有价值的线索，并提出了一个宫颈癌的GRS，可以在额外的风险分层方面使用，并有可能用于个性化的常规筛查策略，以便针对更容易患上宫颈癌的人群进行筛查。 ©作者(们)2023。由牛津大学出版社发表。

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 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 GRS that associates with cervical cancer (HR = 3.1 (1.7-5.6) for top 15% vs lowest 15% of individuals), and with other HPV- and immune-system related diagnoses in a pheWAS 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.© The Author(s) 2023. Published by Oxford University Press.