Increased<i>APOEε4</i>expression is associated with reactive A1 astrocytes and the difference in Alzheimer Disease risk from diverse ancestral backgrounds

Griswold, Anthony J.; Celis, Katrina; Bussies, Parker L.; Rajabli, Farid; Whitehead, Patrice; Hamilton‐Nelson, Kara L.; Beecham, Gary W.; Dykxhoorn, Derek M.; Nuytemans, Karen; Wang, Liyong; Gardner, Olivia K.; Dorfsman, Daniel A.; Bigio, Eileen H.; Mesulam, Marek-Marsel; Weıntraub, Sandra; Geula, Changiz; Gearing, Marla; Martinez-McGrath, Elisa; Dalgard, Clifton L.; Scott, William K.; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Young, Juan I.; Vance, Jeffery M.

doi:10.1101/2020.03.09.983817

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“…Recently, using single nuclei RNAseq on frozen frontal cortex, we found that APOEε4 homozygotes lying on a European local ancestry had significantly higher expression of APOEε4 than APOEε4 homozygotes lying on an African local ancestry 39 , suggesting a significant difference in the regulatory composition of this regions between ancestries. This supports the importance of determining potential regulatory variants differing in the regulatory architecture between local ancestries.…”

Section: Discussionmentioning

confidence: 98%

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

Nuytemans

Lipkin-Vasquez

Wang

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 98%