Genetic Susceptibility to Arrhythmia Phenotypes in a Middle Eastern Cohort of 14,259 Whole-Genome Sequenced Individuals

Abstract

Background: The current study explores the genetic underpinnings of cardiac arrhythmia phenotypes within Middle Eastern populations, which are under-represented in genomic medicine research. Methods: Whole-genome sequencing data from 14,259 individuals from the Qatar Biobank were used and contained 47.8% of Arab ancestry, 18.4% of South Asian ancestry, and 4.6% of African ancestry. The frequency of rare functional variants within a set of 410 candidate genes for cardiac arrhythmias was assessed. Polygenic risk score (PRS) performance for atrial fibrillation (AF) prediction was evaluated. Results: This study identified 1196 rare functional variants, including 162 previously linked to arrhythmia phenotypes, with varying frequencies across Arab, South Asian, and African ancestries. Of these, 137 variants met the pathogenic or likely pathogenic (P/LP) criteria according to ACMG guidelines. Of these, 91 were in ACMG actionable genes and were present in 1030 individuals (~7%). Ten P/LP variants showed significant associations with atrial fibrillation p < 2.4 × 10^-10. Five out of ten existing PRSs were significantly associated with AF (e.g., PGS000727, p = 0.03, OR = 1.43 [1.03, 1.97]). Conclusions: Our study is the largest to study the genetic predisposition to arrhythmia phenotypes in the Middle East using whole-genome sequence data. It underscores the importance of including diverse populations in genomic investigations to elucidate the genetic landscape of cardiac arrhythmias and mitigate health disparities in genomic medicine.

Keywords: Middle East; arrythmia; atrial fibrillation; cardiomyopathy; diverse populations; diversity; genomics; whole-genome sequencing.

Figure 1

Population structure analysis in the QBB data. Population structure analysis using PC-AiR, which is a principal component analysis that accounts for relatedness among participants. The figure shows the four major ancestry groups in the QBB data inferred using ADMIXTURE. The five major ancestries in the 1000 Genomes Project are shown with QBB subpopulations: Arabs (e.g., Gulf region, Middle East, North Africa), South Asians (e.g., Iran, India), Africans, and Admixed. (Left) Principal component 1 (PC1) vs. principal component 2 (PC2); and (Right) principal component 1 (PC1) vs. principal component 3 (PC3).

Figure 2

Summary of prioritized variants with respect to pathogenicity by ClinVar and QCII, and their link to arrhythmia phenotypes as defined in the Supplemental Materials.

Figure 3

Distribution of actionable P/LP variants that are absent from gnomAD across different ancestries by MAFs.

Figure 4

Distribution of actionable P/LP variants with frequencies more than 5-fold higher than gnomAD across different ancestries by MAFs. This figure illustrates the distribution of pathogenic/likely pathogenic (P/LP) genetic variants across various ethnic groups, with a specific focus on variants that have a frequency more than five times higher than observed in the gnomAD. The data are categorized by MAF ranges, depicted in different colors for easy reference: MAF > 10⁻², 10⁻³ < MAF < 10⁻², 10⁻⁴ < MAF < 10⁻³, 10⁻⁵ < MAF < 10⁻⁴, and MAF < 10⁻⁵. The ethnic groups analyzed include Middle Eastern (ME), Arab, South Asian, African, and Admixed populations. The figure also presents the Total ME/gnomAD ratio, representing the ratio of the MAFs in the ME population to the MAFs in the gnomAD dataset. The annotations indicate the impact of these variants, categorized as low, moderate, high, or modifier.

Figure 5

The most significant associations with atrial fibrillation. This figure illustrates a comprehensive analysis of genetic associations with atrial fibrillation (AF). (A) The left panel highlights the statistical significance of these associations, using a threshold of p < 0.05. The −log10(p) values are plotted on the X-axis, while the Y-axis details the variant’s chromosome position and associated gene name. The center panel displays the odds ratios (ORs) for each variant, offering insights into the strength of these associations. The right panel compares allele counts in cases versus controls, providing a clear view of variant prevalence in affected individuals versus the general population. (B) The table included in the figure lists the reference and alternative alleles for each variant.