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

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 (similar to 7%). Ten P/LP variants showed significant associations with atrial fibrillation p < 2.4 x 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.