Allele‐specific histone acetylation in Alzheimer’s disease brain

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AbstractBackgroundAlzheimer’s disease (AD) is associated with cell type‐specific H3K27ac signatures, an epigenetic modification that marks active enhancers and promoters. Genomic regions marked by H3K27ac, particularly enhancers, are enriched for AD genetic risk. We aim to identify nearby genetic variants regulating histone acetylation to better understand the link between genetic risk and disease.MethodFor the first time we have performed allelic specific analysis of histone epigenetic modifications in AD. We used H3K27ac ChIP‐seq data from human post‐mortem entorhinal cortex samples from AD cases (n = 24) and controls (n = 23) (Marzi et al., 2018) to differentiate the histone acetylation signal originating from both alleles in an individual.ResultsWe identified 844 significant loci with allele‐specific histone acetylation by testing individual samples, and 344 by testing across samples. Both sets featured an FDR‐significant acetylation imbalance in a region predicted to be regulating SETD1B, a histone lysine methyltransferase previously found to be elevated in AD patients (Cao et al., 2020). Using linear regression, we also identified 329 SNPs associated with histone acetylation levels. Cell type deconvolution of the overlap between the SNP‐associated H3K27ac regions and genomic regions differentially acetylated in AD highlighted multiple brain cell types. In addition, there was an enrichment for biological processes involving myelination, and cell type‐specific regions were enriched for oligodendrocytes.ConclusionGenetic variants are associated with levels of H3K27ac in genomic regions regulating disease‐related processes.