Functional Genomics in Human iPSC-Derived Sinoatrial Node Cells Reveals Shared Regulatory Determinants of Heart Rate and Atrial Fibrillation

Human model systems for functional genomics of heart rhythm are needed to translate genome wide association studies into biological insight and actionable targets. Here we develop a human induced pluripotent stem cell sinoatrial node system that recapitulated the transcriptional and epigenetic heterogeneity of primary human pacemaker tissue, permitting exploration of heart rhythm-associated single nucleotide polymorphisms (SNPs) in a cell subtype-specific manner. Using self-transcribing active regulatory region sequencing (STARR-seq), we experimentally validated numerous enhancers containing heart rhythm associated variants. We demonstrated the utility of this platform for fine mapping of candidate causal SNPs by identifying an AF-associated variant at the ATXN1 locus that affects signal responsiveness of an enhancer, and a variant at the GNB4 locus that regulates cardiac autonomic sensitivity, leading to a pleiotropic effect on heart rate and atrial fibrillation. Taken together, these data establish a robust human cellular system to explore the mechanistic basis of heart rhythm heritability.