Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants

Cell Rep Med. 2021 Apr 20;2(4):100250. doi: 10.1016/j.xcrm.2021.100250.


Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, SCN5A-SCN10A. Our analysis reveals 5 common 7-SNV haplotypes (Hap1-5) with 2 combinations associated with life-threatening arrhythmia-Brugada syndrome (the risk Hap1/1 and protective Hap2/3 genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition.

Keywords: Brugada syndrome; GWAS; SNV redundancy; common SNV; haplotype block; long-read sequencing; non-coding SNV; protective haplotype; risk haplotype; sudden cardiac death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Brugada Syndrome / diagnosis
  • Brugada Syndrome / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing / methods
  • Genome-Wide Association Study / methods
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Linkage Disequilibrium / genetics*
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci / genetics