Understanding the genetic basis of complex brain disorders is critical for identifying individuals at risk, designing prevention strategies, and developing rational therapeutics. In the last 50 years, twin studies have shown that psychiatric disorders, neurological diseases, and cognitive traits are strongly influenced by genetic factors, explaining a mean of ~50% of the variance in liability 1, and GWAS have identified thousands of highly significant loci 2–5. However, interpretation of GWAS results remains challenging. First, >90% of the identified variants are located in non-coding regions 6, complicating precise identification of risk genes and mechanisms. Second, extensive linkage disequilibrium present in the human genome confounds efforts to pinpoint causal variants and the genes they influence. Finally, it remains unclear in which tissues and cell types these variants are active, and how they disrupt specific biological networks to impact disease risk.
