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

Nature. 2016 May 5;533(7601):95-9. doi: 10.1038/nature17939. Epub 2016 Apr 20.


Genome-wide association studies (GWAS) have identified numerous genetic variants associated with complex diseases, but mechanistic insights are impeded by a lack of understanding of how specific risk variants functionally contribute to the underlying pathogenesis. It has been proposed that cis-acting effects of non-coding risk variants on gene expression are a major factor for phenotypic variation of complex traits and disease susceptibility. Recent genome-scale epigenetic studies have highlighted the enrichment of GWAS-identified variants in regulatory DNA elements of disease-relevant cell types. Furthermore, single nucleotide polymorphism (SNP)-specific changes in transcription factor binding are correlated with heritable alterations in chromatin state and considered a major mediator of sequence-dependent regulation of gene expression. Here we describe a novel strategy to functionally dissect the cis-acting effect of genetic risk variants in regulatory elements on gene expression by combining genome-wide epigenetic information with clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9 genome editing in human pluripotent stem cells. By generating a genetically precisely controlled experimental system, we identify a common Parkinson's disease associated risk variant in a non-coding distal enhancer element that regulates the expression of α-synuclein (SNCA), a key gene implicated in the pathogenesis of Parkinson's disease. Our data suggest that the transcriptional deregulation of SNCA is associated with sequence-dependent binding of the brain-specific transcription factors EMX2 and NKX6-1. This work establishes an experimental paradigm to functionally connect genetic variation with disease-relevant phenotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Brain / metabolism
  • CRISPR-Cas Systems / genetics
  • Enhancer Elements, Genetic / genetics*
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation*
  • Genetic Engineering
  • Genetic Predisposition to Disease / genetics*
  • Genome, Human / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Models, Genetic
  • Parkinson Disease / genetics*
  • Pluripotent Stem Cells / metabolism
  • Risk
  • Transcription Factors / metabolism
  • alpha-Synuclein / genetics*


  • Homeodomain Proteins
  • NKX6-1 protein, human
  • Transcription Factors
  • alpha-Synuclein
  • empty spiracles homeobox proteins