Abstract 4367179: Eight Novel Atrial Fibrillation Candidate Genes Identified and Validated in a De Novo UK Biobank GWAS

Background: Despite advances in large-scale GWAS and multi-ancestry meta-analyses, not all genetic contributors to atrial fibrillation (AF) have been fully identified. Foundational studies published between 2018 and 2019 established key AF risk loci but may have missed additional associations due to limitations in design, phenotype definition, or population structure. Using individual-level UK Biobank data, we conducted a de novo GWAS to identify novel AF-associated genes not reported in these earlier efforts. Hypothesis: We hypothesized that a de novo GWAS leveraging individual-level UK Biobank data would reveal novel AF susceptibility genes that were missed in prior large-scale summary-level GWAS, highlighting the added resolution provided by individual-level analyses. Methods: We performed a genome-wide association study (GWAS) of atrial fibrillation in approximately 500,000 UK Biobank participants. After standard quality control, genotypes were imputed to the Haplotype Reference Consortium panel. Association testing was conducted using mixed-effects logistic regression models adjusted for age, sex, genotyping array, and principal components of ancestry. Genome-wide significance was defined as P < 5 x 10^-7. We compared genome-wide significant loci with those reported in three foundational AF GWAS from 2018–2019 to identify novel findings. Functional annotations were obtained using OMIM and curated cardiovascular gene ontology resources. Results: We identified 18 genome-wide significant loci associated with AF (P < 5 x 10^-7). Of these, eight loci—mapped to ESR2, ITPR2, KANSL1, KLHL3, OBSCN, PLEKHM1, RARS2, and ZBTB7B—had not been reported as genome-wide significant in the foundational GWAS. These genes demonstrated robust statistical association and biologically plausible links to AF. Functional annotations implicated them in calcium signaling (ITPR2), sarcomeric integrity (OBSCN), transcriptional regulation (ESR2, ZBTB7B), and ion homeostasis (KLHL3), supporting their candidacy as novel AF susceptibility genes. Conclusions: This de novo GWAS of atrial fibrillation in the UK Biobank identified 18 genome-wide significant loci, including eight novel candidate genes not previously reported in foundational studies. These findings underscore the power of individual-level genetic analysis in uncovering previously unrecognized AF risk loci and lay the groundwork for future investigations integrating transcriptomics, proteomics, and therapeutic discovery.