Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in $\small \textit{BRCA1}$ and $\small \textit{BRCA2}$ Mutation Carriers

Abstract

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in $\small \textit{BRCA1}$ and $\small \textit{BRCA2}$ mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in $\small \textit{BRCA1}$ and $\small \textit{BRCA2}$ mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) $\small \textit{BRCA1}$ and 8,211 (631 ovarian cancer cases) $\small \textit{BRCA2}$ mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in $\small \textit{BRCA1}$ and $\small \textit{BRCA2}$ mutation carriers respectively, within a retrospective cohort analytical framework. In $\small \textit{BRCA1}$ mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of $\small \textit{BNC2}$. In $\small \textit{BRCA2}$ mutation carriers one region, up to 45 kb upstream of $\small \textit{BNC2}$, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in $\small \textit{BRCA1}$ mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the $\small \textit{BNC2}$ transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in $\small \textit{BRCA1}$ mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.