Deciphering the Genomic Regulatory Architecture of iPSC Derived Oligodendrocytes from Diverse Ancestries for Alzheimer’s Disease Studies

Background The effect of variants associated with Alzheimer’s disease (AD) can be influenced by ancestry, which determines the genomic regulatory architecture (GRA). A global understanding of GRA in the context of AD is imperative to interpret the variability associated with AD risk genes across populations. Most studies up to date have focused on studying GRA in European ancestry, in this study we aimed at determining the GRA in African, Amerindian, and European ancestries. Since GRA is cell specific, we developed a human induced pluripotent cells (hiPSC) based model for oligodendrocytes (OLs), a cell type which has limited studies focused on AD. Method Cells from AD patients or non‐cognitively impaired controls with >90% of either Amerindian, African or European global ancestry were differentiated using a modified multi‐stage protocol that promotes the development and enrichment of oligodendrocytes in neural spheroids. After terminal differentiation, cells were collected and lysed to isolate nuclei for Multiomic profiling of chromatin accessibility and transcriptome using Single Cell ATAC and Single Cell RNA‐seq. Additionally, we examined chromatin interactions using Hi‐C analyses. Result We identified oligodendrocyte lineage cells at different stages of development ranging from dividing cells with transcriptional profiles consistent with those of oligodendrocyte precursor cells (OPC) to mature myelinating oligodendrocytes. We compared the oligodendrocytes clusters across ancestries, cases versus controls and APOE genotypes to characterize the genomic landmarks and signatures associated with AD related GWAS loci. Astrocytes and neurons were also derived within our 3D spheroids, allowing us to study ancestry‐related cell type specific changes in GRA. Conclusion Our results provide ancestry‐specific insights into oligodendrocyte chromatin structure and gene regulation in the context of AD. These results offer an integrated view of the GRA of a previously overlooked cell lineage that constitute a large population in the central nervous system and is compromised during AD in terms of abundance and function. This will expand the available functional resources for gene identification studies in African American and Hispanic/Latino studies.