3D chromatin structure in human macrophages and iPSC‐derived microglia identifies putative Alzheimer’s Disease risk genes

Alzheimer’s disease (AD) genome‐wide association studies (GWAS) identified 75 disease‐associated loci. The vast majority of risk variants are located in non‐coding genomic regions, suggesting a regulatory function (i.e. enhancer activity). Enhancers can regulate distal genes via DNA loops, bringing elements millions of base pairs away into close physical proximity in three‐dimensional (3D) space. Mapping 3D chromatin contact frequencies using Hi‐C can reveal enhancer‐promoter connections and assign disease‐associated variants to putative causal genes. Because enhancer and 3D chromatin structures are cell‐type specific, it is critical to map these features in the relevant cell type and biological context. Genetic risk factors for AD are located within microglia and macrophages chromatin‐accessible regions. The aim of this work was to map 3D chromatin structures in human microglia and macrophages and intersect them with AD GWAS to identify novel genes regulated by non‐coding AD risk variants.