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Nucleic Acids Res. 2018 Apr 20;46(7):3517-3531. doi: 10.1093/nar/gky166.

A screen for deeply conserved non-coding GWAS SNPs uncovers a MIR-9-2 functional mutation associated to retinal vasculature defects in human.

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Department of Psychiatry and Behavioral Sciences, Stanford Center for Sleep Sciences and Medicine, Stanford, CA 94305, USA.
Department of Computer Science, Stanford, CA 94305, USA.
Department of Developmental Biology, Stanford, CA 94305, USA.
Division of Medical Genetics, Department of Pediatrics, Stanford, CA 94305, USA.
INSERM 1024, Ecole Normale Supérieure Paris, 75005, France.


Thousands of human disease-associated single nucleotide polymorphisms (SNPs) lie in the non-coding genome, but only a handful have been demonstrated to affect gene expression and human biology. We computationally identified risk-associated SNPs in deeply conserved non-exonic elements (CNEs) potentially contributing to 45 human diseases. We further demonstrated that human CNE1/rs17421627 associated with retinal vasculature defects showed transcriptional activity in the zebrafish retina, while introducing the risk-associated allele completely abolished CNE1 enhancer activity. Furthermore, deletion of CNE1 led to retinal vasculature defects and to a specific downregulation of microRNA-9, rather than MEF2C as predicted by the original genome-wide association studies. Consistent with these results, miR-9 depletion affects retinal vasculature formation, demonstrating MIR-9-2 as a critical gene underpinning the associated trait. Importantly, we validated that other CNEs act as transcriptional enhancers that can be disrupted by conserved non-coding SNPs. This study uncovers disease-associated non-coding mutations that are deeply conserved, providing a path for in vivo testing to reveal their cis-regulated genes and biological roles.

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