Genome-wide association study identifies 18 novel loci associated with left atrial volume and function

Abstract

Aims: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data.

Methods and results: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14].

Conclusion: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.

Keywords: GWAS; Left atrium; UK Biobank; Cardiac magnetic resonance.

Genome-wide association study on left atrial volume and function based on cardiac magnetic resonance imaging. Imaging data from 35 658 individuals were exposed to machine learning algorithms to annotate five left atrial traits. A total of 18 novel genetic loci were associated with left atrial volume and function. Of these, 15 constituted unique loci. Genes marked with bold have previously been associated with cardiomyopathy.

Figure 1

Sample inclusion flowchart. Please note that some individuals may fulfil multiple exclusion criteria and can be listed multiple times in the exclusion boxes, e.g. having both extreme BMI and MI. BMI, body mass index; CMR, cardiac magnetic resonance; GWAS, genome-wide association study; HF, heart failure; LA, left atrial; LAAEF, left atrial active emptying fraction; LAPEF, left atrial passive emptying fraction; LATEF, left atrial total emptying fraction; LAV, left atrial volume; MAF, minor allele frequency; MI, myocardial infarction.

Figure 2

Genome-wide associations. Manhattan plots with the −log10(P-value) plotted on the y-axis and chromosomal position on the x-axis. Each locus is labelled with name of nearest gene to sentinel SNP. All sentinel SNPs are listed in Supplementary material online, Data S3. LA, left atrial; LAAEF, left atrial active emptying fraction; LAPEF, left atrial passive emptying fraction; LATEF, left atrial total emptying fraction; SNP, single nucleotide polymorphism.

Figure 3

Genetic correlation between left atrial traits and cardiovascular phenotypes using LDSC. Sample sizes of external genome-wide association studies are shown in Supplementary material online, Data S2. Phenotypes with negative log10(P) are displayed on the y-axis. X-axis shows genetic correlation (r_g). Point estimates shown as dots with thick lines indicate mean and standard error (SE) and thin lines 95% confidence intervals (1.96xSE). Nominal significance (P < 0.05) is denoted with bright colour and non-significant correlations with faded colour. Standard errors and P-values were derived using block jackknife resampling.