Deciphering the functional impact of Alzheimer’s Disease-associated variants in resting and proinflammatory immune cells [crispr]

Genome-wide association studies have identified loci associated with Alzheimer’s Disease (AD), but identifying the exact causal variants and genes at each locus is challenging due to linkage disequilibrium and their largely non-coding nature. To address this, we performed a massively parallel reporter assay of 3,576 AD-associated variants in THP-1 macrophages in both resting and proinflammatory states and identified 47 expression-modulating variants (emVars). To understand the endogenous chromatin context of emVars, we built an activity-by-contact model using epigenomic maps of macrophage inflammation and inferred condition-specific enhancer-promoter pairs. Intersection of emVars with enhancer-promoter pairs and microglia expression quantitative trait loci allowed us to connect 39 emVars to 76 putative AD risk genes enriched for AD-associated molecular signatures. CRISPR-mediated validation of emVars confirmed the predicted variant-gene relationship. Overall, systematic characterization of AD-associated variants enhances our understanding of the regulatory mechanisms underlying AD pathogenesis.