Genome-wide association studies of cardiac electrical phenotypes

Abstract

The genetic basis of cardiac electrical phenotypes has in the last 25 years been the subject of intense investigation. While in the first years, such efforts were dominated by the study of familial arrhythmia syndromes, in recent years, large consortia of investigators have successfully pursued genome-wide association studies (GWAS) for the identification of single-nucleotide polymorphisms that govern inter-individual variability in electrocardiographic parameters in the general population. We here provide a review of GWAS conducted on cardiac electrical phenotypes in the last 14 years and discuss the implications of these discoveries for our understanding of the genetic basis of disease susceptibility and variability in disease severity. Furthermore, we review functional follow-up studies that have been conducted on GWAS loci associated with cardiac electrical phenotypes and highlight the challenges and opportunities offered by such studies.

Keywords: Arrhythmias.

Figure 1

Genetic architecture of human disease. Genome-wide association studies for atrial fibrillation, ECG traits, and other complex traits have explored common variants (MAF >5%) and established many associations with modest to low effect size on disease risk. Whole-exome and -genome sequencing studies seek to further identify low-frequency (MAF 1–5%) and rare variants within genes or across the entire genome, respectively. The effect sizes of less common and rare variants are greater than for more common variants. The figure is adapted from Manolio et al., permissions obtained.

Figure 2

Genomic regions associated with phenotype through GWAS. Causal variants have a direct biological effect and therefore a direct effect on the phenotype. Causal variants are responsible for the association signal at a locus, although the association may be identified by using other non-causal variants in LD with the causal variant. The genotyped SNP will be statistically associated with disease as a surrogate for the disease SNP through an indirect association. The figure is adapted from Bush et al., permissions obtained.

Figure 3

From GWAS to polygenic risk scores (PRS). (A) An approach that is likely to favour the identification of genetic variants that impact on risk for cardiac electrical phenotypes is testing genetic variants that have been shown to be associated with phenotypes that are considered as risk factors (endophenotypes). Genetic modifiers of these endophenotypes are thus expected to also determine the risk of the cardiac electrical phenotypes. For instance, slowed conduction is an established mediator of arrhythmia and therefore genetic factors that modulate the QRS-interval may also affect arrhythmia risk. (B) Summary how GWAS findings provides a unique opportunity for direct investigation of results from GWAS to clinical populations. The use of the endophenotype approach in the dissection of genetics of cardiac electrical phenotypes may increase the chances of genetic locus discovery as it considers candidate SNPs in pathways that are biological plausible for these disorders. The PRS summarizes risk-associated variation across the genome by counting the number of disease-associated alleles. Endophenotypes that are correlated with the disease phenotype because of overlapping genetic causes would be expected to be correlated with PRS for the disease as well. PRS can differentiate cases from controls on a population level, cases are expected to have a significantly higher mean PRS than controls. GWAS, genome-wide association study; PRS, polygenic risk score.

Figure 4

From GWAS locus to gene and mechanism. (A and B) Follow-up studies on loci identified in GWAS. In the absence of a candidate coding region variant that can be tested directly in functional studies (C), studies on non-coding putatively regulatory genetic variation may involve experimental approaches (e.g. eQTL, CHiP-seq, circularized chromosome conformation capture, and non-coding RNA analyses) to uncover the genetic mechanism and the regulated gene (D). GWAS, genome-wide association study; LD, linkage disequilibrium, SNP, single nucleotide polymorphism; CHIP-Seq, chromatin immunoprecipitation sequencing. The figure is adapted from Bezzina et al., permissions obtained.