Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development

Abstract

Background: The genetic basis of left ventricular (LV) image-derived phenotypes, which play a vital role in the diagnosis, management, and risk stratification of cardiovascular diseases, is unclear at present.

Methods: The LV parameters were measured from the cardiovascular magnetic resonance studies of the UK Biobank. Genotyping was done using Affymetrix arrays, augmented by imputation. We performed genome-wide association studies of 6 LV traits-LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection fraction, LV mass, and LV mass to end-diastolic volume ratio. The replication analysis was performed in the MESA study (Multi-Ethnic Study of Atherosclerosis). We identified the candidate genes at genome-wide significant loci based on the evidence from extensive bioinformatic analyses. Polygenic risk scores were constructed from the summary statistics of LV genome-wide association studies to predict the heart failure events.

Results: The study comprised 16 923 European UK Biobank participants (mean age 62.5 years; 45.8% men) without prevalent myocardial infarction or heart failure. We discovered 14 genome-wide significant loci (3 loci each for LV end-diastolic volume, LV end-systolic volume, and LV mass to end-diastolic volume ratio; 4 loci for LV ejection fraction, and 1 locus for LV mass) at a stringent P<1×10^-8. Three loci were replicated at Bonferroni significance and 7 loci at nominal significance (P<0.05 with concordant direction of effect) in the MESA study (n=4383). Follow-up bioinformatic analyses identified 28 candidate genes that were enriched in the cardiac developmental pathways and regulation of the LV contractile mechanism. Eight genes (TTN, BAG3, GRK5, HSPB7, MTSS1, ALPK3, NMB, and MMP11) supported by at least 2 independent lines of in silico evidence were implicated in the cardiac morphogenesis and heart failure development. The polygenic risk scores of LV phenotypes were predictive of heart failure in a holdout UK Biobank sample of 3106 cases and 224 134 controls (odds ratio 1.41, 95% CI 1.26 - 1.58, for the top quintile versus the bottom quintile of the LV end-systolic volume risk score).

Conclusions: We report 14 genetic loci and indicate several candidate genes that not only enhance our understanding of the genetic architecture of prognostically important LV phenotypes but also shed light on potential novel therapeutic targets for LV remodeling.

Keywords: genome-wide association study; heart failure; left ventricle.

Figure 1.

Flowchart of analysis strategy. GCTA indicates genome-wide complex trait analysis; GWAS, genome-wide association study; INFO, imputation quality score; INT, inverse-normal rank transformation; LD, linkage disequilibrium; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; LVMVR, left ventricular mass to end-diastolic volume ratio; LVSV, left ventricular stroke volume; MAF, minor allele frequency; MESA, Multi-Ethnic Study of Atherosclerosis; Nmax, maximum sample size; REML, restricted maximal likelihood; SBP, systolic blood pressure; and SNV, single nucleotide variant.

Figure 2.

SNP heritability and genotypic and phenotypic correlations between LV traits. The upper triangle of correlogram represents the degree of genotypic correlation, and the lower triangle represents the degree of phenotypic correlation. Heritability estimated from genotyped SNPs is presented on the right-hand side of the figure. *P<0.0001; #P>0.05; All other correlation estimates had P<1×10^–16. LV indicates left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; LVMVR, left ventricular mass to end-diastolic volume ratio; LVSV, left ventricular stroke volume; and SNP, single nucleotide polymorphism.

Figure 3.

Genomic loci associated with CMR-LV phenotypes. Circular Manhattan plot depicting the genome-wide association study results of all LV traits. The red line indicates the genome-wide significant threshold at P<1×10^-8. No genome-wide significant locus was found for LVSV. The significant genomic loci are denoted by the red dots. CMR indicates cardiovascular magnetic resonance; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; LVMVR, left ventricular mass to end-diastolic volume ratio; and LVSV, left ventricular stroke volume.

Figure 4.

Venn diagram of left ventricular loci. The locus name indicates the nearest annotated gene. LVEDV indicates left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; and LVMVR, left ventricular mass to end-diastolic volume ratio.

Figure 5.

Summary of genes associated with left ventricular traits. Genes are ranked based on the supporting evidence summarized in Table XI in the online-only Data Supplement based on the presence of nonsynonymous variant, gene expression data, chromatin interaction analyses, literature review, and knockout models. LVEDV indicates left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVM, left ventricular mass; and LVMVR, left ventricular mass to end-diastolic volume ratio. *Coding variant gene, †knockout phenotype, ‡previously reported cardiovascular biology or strong functional rationale, §expression quantitative trait locus gene, ‖Hi-C long-range interaction gene. The illustration used elements with permission from Servier Medical Art.