Converging evidence for differential regulatory control of APOEε4 on African versus European haplotypes

INTRODUCTION The difference in APOEε4 risk for Alzheimer disease (AD) between different populations is associated with APOEε4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOEε4 haplotypes for areas of differential regulation. METHODS We performed two enhancer Massively Parallel Reporter Assay (MPRA) approaches, supplemented with single fragment reporter assays. We utilized Capture C analyses to support interactions with the APOE promoter. RESULTS The TOMM40 intron 2 and 3 region showed increased enhancer activity in the European/Japanese versus African LA haplotypes in astrocytes and microglia. This region overlaps with APOE promoter interactions as assessed by Capture C analysis. Single variant analyses pinpoints rs2075650/rs157581, and rs59007384 as functionally different on these haplotypes. DISCUSSION Both differential regulatory function and Capture C data support an intronic region in TOMM40 as contributing to the differential APOE expression between African and European/Japanese LA.