Background: Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates.
Methods: We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF. We then performed a genome-wide association study (GWAS) of the predicted AF risk and compared it with an AF GWAS and a GWAS of risk estimates from a clinical variable model.
Results: In the ECG-AI GWAS, we identified 3 signals ( P <5×10 -8 ) at established AF susceptibility loci marked by the sarcomeric gene TTN and sodium channel genes SCN5A and SCN10A . We also identified 2 novel loci near the genes VGLL2 and EXT1 . In contrast, the clinical variable model prediction GWAS indicated a different genetic profile. In genetic correlation analysis, the prediction from the ECG-AI model was estimated to have a higher correlation with AF than that from the clinical variable model.
Conclusions: Predicted AF risk from an ECG-AI model is influenced by genetic variation implicating sarcomeric, ion channel and body height pathways. ECG-AI models may identify individuals at risk for disease via specific biological pathways.
Competing Interests: Disclosures Dr Lubitz is a full-time employee of Novartis as of July 18, 2022. Dr Lubitz has received sponsored research support from Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, Fitbit, Medtronic, Premier, and IBM, and has consulted for Bristol Myers Squibb, Pfizer, Blackstone Life Sciences, and Invitae. Dr Anderson receives sponsored research support from Bayer AG and Massachusetts General Hospital and has consulted for ApoPharma. Dr Weng receives sponsored research support from IBM to the Broad Institute. Dr Ho has received sponsored research support from Bayer AG and research supplies from EcoNugenics, Inc. Dr Ellinor has received sponsored research support from Bayer AG and IBM Health, and he has consulted for Bayer AG, Novartis and MyoKardia. Drs Batra, Reeder, and Friedman have received sponsored research support from Bayer AG and IBM Health, and Dr Batra has consulted for Novartis and Prometheus Biosciences. The other authors report no conflicts.