Multiple SCN5A variant enhancers modulate its cardiac gene expression and the QT interval

Proc Natl Acad Sci U S A. 2019 May 28;116(22):10636-10645. doi: 10.1073/pnas.1808734116. Epub 2019 May 8.


The rationale for genome-wide association study (GWAS) results is sequence variation in cis-regulatory elements (CREs) modulating a target gene's expression as the major cause of trait variation. To understand the complete molecular landscape of one of these GWAS loci, we performed in vitro reporter screens in cardiomyocyte cell lines for CREs overlapping nearly all common variants associated with any of five independent QT interval (QTi)-associated GWAS hits at the SCN5A-SCN10A locus. We identified 13 causal CRE variants using allelic reporter activity, cardiomyocyte nuclear extract-based binding assays, overlap with human cardiac tissue DNaseI hypersensitive regions, and predicted impact of sequence variants on DNaseI sensitivity. Our analyses identified at least one high-confidence causal CRE variant for each of the five sentinel hits that could collectively predict SCN5A cardiac gene expression and QTi association. Although all 13 variants could explain SCN5A gene expression, the highest statistical significance was obtained with seven variants (inclusive of the five above). Thus, multiple, causal, mutually associated CRE variants can underlie GWAS signals.

Keywords: GWAS; QT interval; SCN5A; cis-regulatory variants; enhancers.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Cell Line
  • Electrocardiography
  • Gene Expression Regulation / genetics*
  • Genetic Variation / genetics
  • Genome-Wide Association Study
  • Heart / physiopathology*
  • Humans
  • Mice
  • Myocardium / chemistry
  • Myocardium / metabolism*
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • Quantitative Trait Loci / genetics
  • Regulatory Sequences, Nucleic Acid / genetics


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human