Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation

Circ Genom Precis Med. 2018 Mar;11(3):e002107. doi: 10.1161/CIRCGEN.118.002107.

Abstract

Background: Genome-wide association studies have identified 23 loci for atrial fibrillation (AF), but the mechanisms responsible for these associations, as well as the causal genes and genetic variants, remain undefined.

Methods: To identify the effect of common genetic variants on gene expression that might explain the mechanisms linking genome-wide association loci with AF risk, we performed RNA sequencing of left atrial appendages from a biracial cohort of 265 subjects.

Results: Combining gene expression data with genome-wide single nucleotide polymorphism data, we found that approximately two-thirds of the expressed genes were regulated in cis by common genetic variants at a false discovery rate of <0.05, defined as cis-expression quantitative trait loci. Twelve of 23 reported AF genome-wide association loci displayed genome-wide significant cis-expression quantitative trait loci, at PRRX1 (chromosome 1q24), SNRNP27 (1q24), CEP68 (2p14), FKBP7 (2q31), KCNN2 (5q22), FAM13B (5q31), CAV1 (7q31), ASAH1 (8p22), MYOZ1 (10q22), C11ORF45 (11q24), TBX5 (12q24), and SYNE2 (14q23), suggesting that altered expression of these genes plays a role in AF susceptibility. Allelic expression imbalance was used as an independent method to characterize the cis-control of gene expression. One thousand two hundred forty-eight of 5153 queried genes had cis-single nucleotide polymorphisms that significantly regulated allelic expression at a false discovery rate of <0.05.

Conclusions: We provide a genome-wide catalog of the genetic control of gene expression in human left atrial appendage. These data can be used to confirm the relevance of genome-wide association loci and to direct future functional studies to identify the genes and genetic variants responsible for complex diseases such as AF.

Keywords: alleles; atrial appendage; atrial fibrillation; genomics; quantitative trait loci.

Publication types

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

MeSH terms

  • Aged
  • Alleles
  • Atrial Fibrillation / diagnosis*
  • Atrial Fibrillation / genetics
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Homeodomain Proteins / genetics
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Ribonucleoprotein, U4-U6 Small Nuclear / genetics
  • Small-Conductance Calcium-Activated Potassium Channels / genetics

Substances

  • Homeodomain Proteins
  • KCNN2 protein, human
  • PRRX1 protein, human
  • Ribonucleoprotein, U4-U6 Small Nuclear
  • SNRNP27 protein, human
  • Small-Conductance Calcium-Activated Potassium Channels