Variation in enhancer activity across brain regions defines neurological disease risk and shapes cellular pathology

Genetic variants associated with neurological traits are enriched in enhancers active in neurons. However, there are many types of neurons with varying functions across the brain, making it difficult to pinpoint insights into disease pathology. We set out to investigate whether cell type and brain region specificity of transcriptional enhancers could reveal new insights into the cellular pathology of neurological traits. We performed H3K27ac ChIP-seq on neurons and glia sorted from post-mortem tissue for six brain regions in triplicate and integrated these datasets with existing single-cell ATAC-seq data. While 87% of neuronal enhancers had similar activity across brain regions, we identified 40,049 neuronal regulatory elements that vary in activity across brain regions, which we termed Brain Region Variable Elements (BRVEs). Some BRVEs reflect differences in cell composition, such as a high proportion of medium spiny neurons (MSNs) in the nucleus accumbens, whereas others capture developmental trajectories, including enhancers with robust activity across telencephalic regions that are inactive in the diencephalic hypothalamus. Genetic variants within BRVEs are disproportionately enriched for the heritability of neurological traits, capturing far more heritability than neuronal enhancers with uniform activity across the brain. Additionally, genes linked to BRVEs are also more likely to be implicated in neuropsychiatric disorders by differential expression studies. Finally, we present a new method, GWAS-LOCATE, that leverages variation in enhancer activity across the brain to assign 23,494 GWAS loci to specific cell types and brain regions, including 9.8% linked to MSNs. This includes a BMI risk locus linked to the transcription factor ISL1. ISL1 knockdown in iPSC-derived MSNs revealed differentially expressed genes enriched for BMI heritability, supporting a role for ISL1-mediated MSN pathways with BMI. Collectively, these findings demonstrate that the enhancer specificity across the brain provides a powerful framework for dissecting complex trait biology and revealing cellular pathology.