Genetics of Atrial Fibrillation in 2020: GWAS, Genome Sequencing, Polygenic Risk, and Beyond

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Abstract

Atrial fibrillation is a common heart rhythm disorder that leads to an increased risk for stroke and heart failure. Atrial fibrillation is a complex disease with both environmental and genetic risk factors that contribute to the arrhythmia. Over the last decade, rapid progress has been made in identifying the genetic basis for this common condition. In this review, we provide an overview of the primary types of genetic analyses performed for atrial fibrillation, including linkage studies, genome-wide association studies, and studies of rare coding variation. With these results in mind, we aim to highlighting the existing knowledge gaps and future directions for atrial fibrillation genetics research.

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Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway

Yusuke Ebana, Yihan Sun, Xiaoxi Yang … (2019)

Background Genome-wide association studies (GWAS) have identified numerous loci associated with diseases and traits. However, the elucidation of disease mechanisms followed by drug development has remained a challenge owing to complex gene interactions. We performed pathway analysis with MAGENTA (Meta-Analysis Geneset Enrichment of variaNT Associations) to clarify the pathways in genetic background of AF. Methods The existing GWAS data were analyzed using MAGENTA. A microarray analysis was then performed for the identified pathways with human atrial tissues, followed by Gene-Set Enrichment Analysis (GSEA). Results MAGENTA identified two novel candidate pathways for AF pathogenesis, the CTCF (CCCTC-binding factor, p = 1.00 × 10−4, FDR q = 1.64 × 10−2) and mTOR pathways (mammalian target of rapamycin, p = 3.00 × 10−4, FDR q = 3.13 × 10−2). The microarray analysis with human atrial tissue using the GSEA indicated that the mTOR pathway was suppressed in AF cases compared with non-AF cases, validating the MAGENTA results, but not CTCF pathway. Conclusions MAGENTA identified a novel pathway, mTOR, followed by GSEA with human atrial tissue samples. mTOR pathway is a key interface that adapts the change of environments by pressure overload and metabolic perturbation. Our results indicate that the MTOR pathway is involved in the pathogenesis of AF, although the details of the basic mechanism remain unknown and further analysis for causal-relationship of mTOR pathway to AF is required. CTCF pathway is essential for construction of chromatin structure and transcriptional process. The gene-set components of CTCF overlap with those of mTOR in Biocarta.