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

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

Author information

1
The Whitehead Institute, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
2
Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, Massachusetts 02139, USA.
3
Department of Neurology, Boston University School of Medicine, Boston, Masssachusetts 02118, USA.

Abstract

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.

PMID:
27096366
PMCID:
PMC5042324
DOI:
10.1038/nature17939
[Indexed for MEDLINE]
Free PMC Article
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