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

Frank Soldner, Yonatan Stelzer, Chikdu S. Shivalila, Brian J. Abraham, Jeanne C. Latourelle, M. Inmaculada Barrasa, Johanna Goldmann, Richard H. Myers, Richard A. Young, Rudolf Jaenisch

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216 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)95-99
Number of pages5
JournalNature
Volume533
Issue number7601
DOIs
StatePublished - May 5 2016
Externally publishedYes

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Cite this

Soldner, F., Stelzer, Y., Shivalila, C. S., Abraham, B. J., Latourelle, J. C., Barrasa, M. I., Goldmann, J., Myers, R. H., Young, R. A., & Jaenisch, R. (2016). Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature, 533(7601), 95-99. https://doi.org/10.1038/nature17939