CHAS, a deconvolution tool, infers cell type-specific signatures in bulk brain histone acetylation studies of neurological and psychiatric disorders

Acetylation of histone H3 lysine 27 (H3K27ac) has emerged as an informative disease-associated epigenetic mark. However, cell type-specific contributions to epigenetic dysregulation in disease are unclear as studies have often used bulk brain tissue. Therefore, methods for the deconvolution of bulk H3K27ac profiles are critical. Here we developed the Cell type-specific Histone Acetylation Score (CHAS), a computational tool for inferring cell type-specific signatures in bulk brain H3K27ac profiles. We applied CHAS to > 300 H3K27ac ChIP-seq samples from studies of Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, schizophrenia, and bipolar disorder in bulk post-mortem brain tissue. In addition to recapitulating known disease-associated shifts in cellular proportions, we identified novel cell type-specific biological insights into brain disorder associated regulatory variation. In most cases, genetic risk and epigenetic dysregulation targeted different cell types, thus suggesting independent mechanisms. For instance, Alzheimer’s disease genetic risk was exclusively enriched within microglia, while epigenetic dysregulation predominantly fell within oligodendrocyte-specific H3K27ac regions. In addition, reanalysis of the original datasets using CHAS enabled identification of biological pathways associated with each neurological and psychiatric disorder at cellular resolution.