Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study

Abstract

Background: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls.

Methods: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer.

Findings: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10^-9) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10^-9), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10^-28), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10^-17), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10^-28), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10^-6). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10^-7), and HLA-DQA1 (rs9272050; p=7·90 × 10^-8). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer.

Interpretation: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions.

Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.

Figure 1

Analysis plans for the discovery (UK Biobank) and replication (FinnGen release 5) datasets GWAS=genome-wide association study. CIN3=cervical intraepithelial neoplasia grade 3. SNP=single-nucleotide polymorphism. eQTL=expression quantitative trait loci.

Figure 2

Regional plots of sentinel SNPs from conditional analysis associated with CIN3 and invasive cervical cancer in PAX8 (chromosome 2; A), CLPTM1L (chromosome 5; B), and HLA (chromosome 6; C and D) The p value of the association between variant and the cervical cancer status is represented by the log₁₀ scale (y-axis) in function of the genetic location. SNPs are colour coded in relation to their correlation (as measured by their recombination rate [r₂]) with the sentinel SNP (shown in red) in the region. In the lower panel of each plot, gene annotations are provided according to the 1000 Genomes project 2014. SNP=single nucleotide polymorphism. CIN3=cervical intraepithelial neoplasia grade 3.

Figure 3

Mendelian randomisation analysis of exposures associated with CIN3 and invasive cervical cancer (A) Forest plot shows inverse variance weighted mendelian randomisation for all identified known environmental risk or protective factors for cervical cancer with available GWAS, to determine effect sizes by OR and 95% CI (x-axis; n=3). (B) Three mendelian randomisation exposures (x-axis, lifetime smoking index; number of sexual partners; age of first pregnancy) found to have a significant association with cervical cancer (y-axis). Each blue point represents a genetic variant used as an instrumental variable in the mendelian randomisation analysis and error bars show standard errors of genetic associations. The dark blue trendline represents the causal effect estimate from the inverse variance weighting mendelian randomisation on the β scale. CIN3=cervical intraepithelial neoplasia grade 3. GWAS=genome-wide association study. OR=odds ratio.