Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression

Genome-wide association studies (GWAS) have identified genomic loci associated with complex diseases but mechanistic insights are impeded by the lack of understanding of how specific risk variants functionally contribute to diseases. Here we describe an experimental strategy to robustly identify cis-acting effects of genetic variants in regulatory elements on gene expression by combining genome-wide epigenetic information with CRISPR/Cas genome editing in human pluripotent cells. Using this genetically controlled system, we identify a common Parkinson’s disease (PD)-associated risk variant in a non-coding distal enhancer element that regulates the expression of SNCA, a key gene implicated in the pathogenesis of PD. We provide data suggesting that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. Our work provides a general experimental strategy to functionally connect genetic variation with disease relevant phenotypes. ChIP-Seq for H3K27ac and H3K4me1 in hES-derived neurons with and without modified SNCA enhancer alleles