Multi-Omics Integration Framework for Understanding Type 2 Diabetes Pathogenesis in the Nigerian Population: A Systems Genetics Approach

Type 2 diabetes mellitus (T2DM) is a paradigmatic complex disease resulting from the interplay of genomic, epigenomic, transcriptomic, proteomic, and metabolomic variation modulated by environmental exposures. Multi-omics integration provides a holistic systems-level view of T2DM pathogenesis that single-omic analyses cannot capture. Despite the substantial T2DM burden in Nigeria, no multi-omics integration study has been conducted in a Nigerian population. This dissertation develops and applies a multi-omics integration framework for T2DM pathogenesis in Nigeria using a deeply phenotyped cohort from Ogun, Lagos, and Plateau States. Four hundred participants (200 T2DM, 200 normoglycaemic controls) underwent genome-wide SNP genotyping (H3Africa array), whole blood transcriptomics (RNA-seq), plasma proteomics (Olink proximity extension assay), serum metabolomics (LC-MS), and targeted epigenomics (EPIC methylation array). An analytical pipeline integrating sparse canonical correlation analysis, multi-omics factor analysis (MOFA+), and causal inference through Mendelian randomisation was developed and applied. A novel T2DM-relevant multi-omic signature was identified, implicating mitochondrial one-carbon metabolism, branched-chain amino acid catabolism, and interferon gamma signalling as converging pathogenic axes. This framework represents the most comprehensive molecular investigation of T2DM in a Nigerian cohort and offers a replicable systems genetics methodology for complex disease research in Africa. Keywords: multi-omics, type 2 diabetes, systems genetics, Nigeria, MOFA