Ancestry-related differences in chromatin accessibility and gene expression ofAPOE4are associated with Alzheimer disease risk

Abstract

AbstractBackgroundEuropean local ancestry (ELA) surroundingAPOE4is associated with a higher risk for Alzheimer Disease (AD) compared to African local ancestry (ALA). We previously demonstrated significantly higherAPOE4expression in ELA vs ALA in the frontal cortex ofAPOE4/4AD patients. Differences in chromatin accessibility could contribute to these differences inAPOE4expression.MethodsWe performed single nuclei Assays for Transposase Accessible Chromatin sequencing (snATAC-seq) and single nuclei RNA sequencing (snRNA-seq) from frozen frontal cortex of six ALA and six ELA AD patients, all homozygous for local ancestry andAPOE4.ResultsWe demonstrated thatAPOE4, including its promoter area, has greater chromatin accessibility in ELA vs ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility and expression in ELA in astrocytes were enriched for synaptic function, cholesterol processing and astrocyte reactivity.ConclusionOur results suggest that increased chromatin accessibility ofAPOE4in astrocyte with the ELA contributes to the observed elevatedAPOE4expression, corresponding to the increased AD risk in ELA vs ALAAPOE4/4carriers.