Anwar Mulugeta

Protein markers of ovarian cancer and its subtypes: insights from proteome-wide Mendelian randomisation analysis

Abstract Background Ovarian cancer (OC) is often diagnosed at an advanced stage when prognosis is poor. We aimed to identify blood plasma proteins predictive of OC risk. Methods We conducted proteome-wide Mendelian randomisation (MR) analyses using summary-level protein quantitative trait locus data covering 2337 plasma proteins, and genome-wide association data on OC and its subtypes (up to 25,509 cases) from the Ovarian Cancer Association Consortium. Wald ratio or inverse-variance weighted MR analysis was used as the primary method, depending on the number of instruments. We evaluated pleiotropy using MR-Egger intercept test and leave-one-out analysis. Results From 2337 plasma proteins, 12 were associated (p < 7.4 × 10−5) with OC or its subtypes. Robust evidence linked follitropin subunit beta (FSHB) with endometrioid OC (per SD higher, OR 2.41, 95% CI 1.56, 3.71). Associations for the other 11 proteins could be explained by pleiotropy from ABO or MAPT-AS1 loci. We identified 12 suggestive associations with OC or its subtypes at nominal threshold (p < 0.05), involving 11 plasma proteins, with no evidence of pleiotropy from leave-one-out and MR-Egger intercept tests (P intercept > 0.17). Potential drug targets were identified for follitropin receptor and eight other proteins. Conclusion Our study suggests FSHB and 11 additional plasma proteins as of potential interest in OC (or subtypes) prognosis, mostly representing potentially druggable targets.

Circulating Phylloquinone and the Risk of Four Female-Specific Cancers: A Mendelian Randomization Study

Background: Observational studies have linked vitamin K and cancer, but the causality of this association remains unknown. This Mendelian randomization (MR) study aims to investigate the association between circulating phylloquinone (vitamin K1) levels and four female-specific cancers. Methods: We used four single-nucleotide polymorphisms (SNPs) to instrument phylloquinone, with the reported F-statistic 16.00–28.44 for all variants. SNP–outcome associations were obtained from consortia meta-analyses, UK Biobank, and the FinnGen database (up to 145,257/419,675, 27,446/362,324, 15,181/591,477, and 2211/320,454 cases/controls for breast, ovarian, endometrial, and cervical cancer, respectively). Analyses were conducted using five complementary MR methods including pleiotropy robust approaches. The MR Egger intercept test, MR PRESSO global test and leave-one-out analyses were used to test for and identify pleiotropic variants. Results: The relevance of the instrument was validated by positive control analyses on coagulation factor IX (p = 0.01). However, the main MR analysis and all sensitivity analyses were consistently supportive of a null association between phylloquinone and all four cancers (p > 0.05 for all analyses, across all methods). MR-PRESSO did not detect outlying variants, and there was no evidence of horizontal pleiotropy relating to any cancer outcome (pintercept > 0.26 for all). Conclusions: We found no evidence for an association between genetically predicted circulating phylloquinone levels and the risk of four female-specific cancers.

Large-scale analysis to identify risk factors for ovarian cancer

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

AbstractBackgroundOvarian 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 colocalization 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 = 5.6 × 10−4). Mendelian randomizaiton 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 ≤ 4.5 × 10−8). Colocalization analysis identified rs4449583 (from TERT locus) 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.