Behavioral and neuropsychiatric traits are genetically complex and associated primarily with non-coding variants located in regulatory regions that control gene expression. While thousands of candidate enhancer elements have been mapped in the human brain, the functional validation of these candidate regions in brain cells remains challenging. We have recently carried out a high-throughput CRISPRi screen of enhancers in human primary astrocytes, and uncovered key properties of enhancer-mediated gene expression regulation, as well as novel relationships between genetic variants and gene expression in astrocytes, with implications for the interpretation of disease-associated non-coding variants. I will also discuss our recent data showing that ZMYND8, a regulator of enhancer activity, is associated with intellectual disability and is critical for brain development.