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Large\u2010scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome\u2010wide association analyses for HPV16, HPV18 and HPV16\/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case\u2010control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and\/or HPV18 seropositivity (at 6p21.32). MAGMA gene\u2010based analysis identified <jats:italic>HLA\u2010DQA1<\/jats:italic> and <jats:italic>HLA\u2010DQB1<\/jats:italic> as genome\u2010wide significant (GWS) genes. In validation genotyping, the genome\u2010wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR\u2009=\u20090.86, <jats:italic>p<\/jats:italic>\u2009=\u20090.004, 95% CI\u2009=\u20090.78\u20130.95, <jats:italic>n<\/jats:italic>\u2009=\u20093710) and HPV16 positive invasive cancer (OR\u2009=\u20090.73, <jats:italic>p<\/jats:italic>\u2009=\u20090.005, 95% CI\u2009=\u20090.59\u20130.91, <jats:italic>n<\/jats:italic>\u2009=\u20091431). This variant was found to be a robust eQTL for <jats:italic>HLA\u2010DRB1<\/jats:italic>, <jats:italic>HLA\u2010DQB1\u2010AS1<\/jats:italic>, <jats:italic>C4B<\/jats:italic>, <jats:italic>HLA\u2010DRB5<\/jats:italic>, <jats:italic>HLA\u2010DRB6<\/jats:italic>, <jats:italic>HLA\u2010DQB1<\/jats:italic>, and <jats:italic>HLA\u2010DPB1<\/jats:italic> in a series of cervical epithelial tissue samples. We additionally genotyped twenty\u2010four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type\u2010specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.<\/jats:p>","DOI":"10.1002\/jmv.70195","type":"journal-article","created":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T07:59:26Z","timestamp":1738396766000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genome\u2010Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer"],"prefix":"10.1002","volume":"97","author":[{"given":"Theresa","family":"Beckhaus","sequence":"first","affiliation":[{"name":"Gynaecology Research Unit, Department of Gynecology and Obstetrics Hannover Medical School Hannover 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