DNA methylation of imprint control regions associated with Alzheimer's disease in non-Hispanic Blacks and non-Hispanic Whites

Abstract

Alzheimer's disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain_track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs.

Keywords: Alzheimer’s disease; Computational analysis; DNA methylation; Epigenetics; Imprint control regions.

Fig. 1

AD-associated candidate ICRs in NHBs and NHWs. a DMRs that differed in DNA methylation (≥ 10%) between AD cases and controls in NHBs and NHWs were determined by WGBS. b Venn diagram of ICRs from ALL [40], NHB [81] and NHW [27] when DNA methylation differed by ≥ 10% between AD cases and controls. c Venn diagram of ICRs from ALL [10], NHB [32] and NHW [10] when DNA methylation differed by ≥ 15% between AD cases and controls. Created with BioRender.com

Fig. 2

Race/ethnicity dependent ICRs in AD. a ICR_20 (CASZ1) and b ICR_1027 (RBFOX3) differed by ≥ 10% in DNA methylation between AD cases and controls only in NHBs. Candidate ICRs (horizontal red boxes) are delineated by vertical dashed red lines. The candidate ICRs were previously defined by having 5 or more consecutive CpGs with methylation levels of 50% ± 15% (green dots) for tissues in all three germ layers (i.e. brain, kidney, and liver); methylation levels for sperm and oocytes are also shown (i.e. ≥ 90% methylation—yellow dots and ≤ 10% methylation—blue dots) [35]

Fig. 3

Race/ethnicity independent ICRs in AD. a ICR_481 (MEST/MESTIT1) and b ICR_987 (NLRP1) differed by ≥ 10% in DNA methylation between AD cases and controls in both NHBs and NHWs. Candidate ICR (horizontal red box) and a known ICR (horizontal yellow box) is delineated by vertical dashed red lines. The candidate ICR was previously defined by having 5 or more consecutive CpGs with methylation levels of 50% ± 15% (green dots) for tissues in all three germ layers (i.e., brain, kidney, and liver); methylation levels for sperm and oocytes are also shown (i.e., ≥ 90% methylation—yellow dots and ≤ 10% methylation—blue dots) [35]

Fig. 4

Experimental workflow. The steps used to identify DMRs in AD cases vs controls, overlapping ICRs, and closest genes. Created with BioRender.com