Brain cell type–specific enhancer–promoter interactome maps and disease <b>-</b> risk association

TLDR

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. The study defines noncoding regulatory regions for major brain cell types to better understand common genetic variation associated with brain diseases. The authors constructed interactome maps linking disease‑risk variants in cell‑type‑specific enhancers to promoters, revealing an extended microglia gene network in AD. The study found that psychiatric disorders are linked to neuronal enhancer and promoter variants, while sporadic AD variants are mainly in microglia enhancers; deleting a microglia enhancer containing AD‑risk variants eliminated BIN1 expression in microglia, leading to a revised and expanded list of genes influenced by noncoding variants in AD and indicating the relevant cell types.

Abstract

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.