Phenome-wide association study of ovarian cancer identifies common comorbidities and reveals shared genetics with complex diseases and biomarkers

BackgroundOvarian cancer (OC) is commonly diagnosed among older women who have comorbidities. This hypothesis-free phenome-wide association study (PheWAS) aimed to identify comorbidities associated with OC, as well as traits that share a genetic architecture with OC. MethodsWe used data from 181,203 white British female UK Biobank participants and analysed OC and OC subtype-specific genetic risk scores (OC-GRS) for an association with 889 diseases and 43 other traits. We conducted PheWAS and colocalisation analyses for individual variants to identify evidence for shared genetic architecture. ResultsThe OC-GRS was associated with 10 diseases, and the clear cell OC-GRS was associated with five diseases at the FDR threshold (p =5.6x10-4). Mendelian randomisaiton analysis (MR) provided robust evidence for the association of OC with higher risk of "secondary malignant neoplasm of digestive systems" (OR 1.64, 95% CI 1.33, 2.02), "ascites" (1.48, 95% CI 1.17, 1.86), "chronic airway obstruction" (1.17, 95% CI 1.07, 1.29), and "abnormal findings on examination of the lung" (1.51, 95% CI 1.22, 1.87). Analyses of lung spirometry measures provided further support for compromised respiratory function. PheWAS on individual OC variants identified five genetic variants associated with other diseases, and seven variants associated with biomarkers (all, p [≤]4.5x10-8). Colocalisation analysis identified rs4449583 as the shared causal variant for OC and seborrheic keratosis. ConclusionsOC is associated with digestive and respiratory comorbidities. Several variants affecting OC risk were associated with other diseases and biomarkers, with this study identifying a novel genetic locus shared between OC and skin conditions.