Polygenic Risk Scores for Venous Thromboembolism in Nigerian Adults: Developing an Original African-Ancestry Calibrated Model Integrating Genetic, Clinical, and Environmental Factors

This dissertation develops and validates an original African-ancestry calibrated polygenic risk score (PRS) for venous thromboembolism (VTE) in Nigerian adults, addressing the critical limitation that existing European-derived VTE genetic risk models perform poorly when applied to African-ancestry populations due to population-specific linkage disequilibrium patterns and allele frequency differences. VTE causes significant preventable mortality in Nigerian hospitals, and a genetically informed risk stratification tool would substantially advance prophylaxis targeting. A three-stage design enrolled 800 VTE cases and 1,600 matched controls from six tertiary hospitals spanning all six geopolitical zones. Genome-wide SNP genotyping was performed using the H3Africa SNP array. An original VTE PRS calibrated for the Nigerian population was constructed using a penalised regression approach (LDpred2-auto) applied to genome-wide association summary statistics from both an African-ancestry meta-analysis and a novel Nigeria-specific GWAS conducted as part of the dissertation. Clinical and environmental predictors were integrated into a joint model using multivariate logistic regression. The Nigerian-calibrated PRS showed significantly improved discrimination (AUC 0.73) compared to a directly applied European PRS (AUC 0.58) in the Nigerian cohort. Incorporating the PRS into a clinical prediction model (Wells score plus PRS) improved VTE prediction to AUC 0.81. A novel interaction between high BMI, oestrogen exposure, and high PRS produced 5.4-fold elevated VTE risk versus each factor alone. The original Nigerian VTE Polygenic Risk Model is provided as an open-access clinical decision tool. Keywords: polygenic risk score, venous thromboembolism, African ancestry, genetic risk, Nigeria.