High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction

Gang Li, Marta Martínez-Bonet, Di Wu, Yu Yang, Jing Cui, Hung N. Nguyen, Pierre Cunin, Anaïs Levescot, Ming Bai, Harm Jan Westra, Yukinori Okada, Michael B. Brenner, Soumya Raychaudhuri, Eric A. Hendrickson, Richard L. Maas, Peter A. Nigrovic

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.

Original languageEnglish (US)
Pages (from-to)1180-1188
Number of pages9
JournalNature Genetics
Issue number8
StatePublished - Aug 1 2018

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© 2018, The Author(s).


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