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

Nuytemans, K.; LipkinVasquez, M.; Wang, L.; Van Booven, D.; Griswold, A. J.; Rajabli, F.; Celis, K.; Oron, O.; Hofmann, N.; Rolati, S.; Garcia-Serje, C.; Zhang, S.; Jin, F.; Argenziano, M.; Grant, S. F.; Chesi, A.; Brown, C. D.; Young, J. I.; Dykxhoorn, D. M.; Pericak-Vance, M. A.; Vance, J. M.

doi:10.1101/2021.08.23.457375

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bioRxiv · 10.1101/2021.08.23.457375

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

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Abstract

INTRODUCTIONThe difference in APOE{varepsilon}4 risk for Alzheimer disease (AD) between different populations is associated with APOE{varepsilon}4 local ancestry (LA). We examined LA SNPs with significant frequency differences between African and European/Japanese APOE{varepsilon}4 haplotypes for areas of differential regulation. METHODSWe 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. RESULTSThe 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. DISCUSSIONBoth 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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Nuytemans, K., LipkinVasquez, M., Wang, L., Van Booven, D., Griswold, A. J., Rajabli, F., Celis, K., Oron, O., Hofmann, N., Rolati, S., Garcia-Serje, C., Zhang, S., Jin, F., Argenziano, M., Grant, S. F., Chesi, A., Brown, C. D., Young, J. I., Dykxhoorn, D. M., Pericak-Vance, M. A., Vance, J. M.. 2021-08-24. Converging evidence for differential regulatory control of APOEε4 on African versus European haplotypes. https://doi.org/10.1101/2021.08.23.457375

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