Whole Genome Sequencing of Sickle Cell Disease Modifier Loci and Their Association with Clinical Severity Phenotypes in Nigerian Patients: An Original Population Genomics Framework

This dissertation develops and applies an original population genomics framework for identifying sickle cell disease (SCD) modifier loci in Nigerian patients using whole genome sequencing, addressing the longstanding gap in understanding why clinical severity diverges dramatically among patients with identical HbSS genotypes. While foetal haemoglobin quantitative trait loci are established, genome-wide modifier discovery in African-ancestry SCD populations using whole genome resolution has not been undertaken in Nigeria. Using a discovery-validation design, whole genome sequencing was performed on 500 HbSS patients from Lagos, Ibadan, and Enugu recruited through the SCD cohort consortia of four teaching hospitals. Clinical severity was phenotyped using a composite score integrating vaso-occlusive crisis frequency, acute chest syndrome episodes, transcranial Doppler velocity, and baseline haemoglobin. Genome-wide association analysis adjusting for population structure and principal components was performed. Functional annotation of top loci used GTEx expression quantitative trait locus data and ENCODE regulatory element databases. The framework identifies 14 novel loci reaching genome-wide significance, seven of which replicate in a validation cohort. A polygenic severity score constructed from these loci predicts severe phenotype with AUC of 0.74, substantially exceeding HbF-only prediction models. The dissertation proposes an original Nigerian SCD Severity Genomic Index integrating modifier loci, HbF quantitative trait loci, and clinical covariates, providing a translatable tool for risk stratification at diagnosis and for identifying therapeutic targets in the largest SCD burden country globally. Keywords: whole genome sequencing, sickle cell disease, modifier loci, population genomics, Nigeria.