• Maddalena Ardissino, Kiran Haresh Kumar Patel, Bilal Rayes, Rohin K Reddy, Greg J Mellor, and Fu Siong Ng.
• National Heart and Lung Institute, Imperial College London, London, United Kingdom.
• PLoS Med. 2023 Aug 1; 20 (8): e1004275e1004275.

BackgroundObservational studies suggest that electrocardiogram (ECG) indices might be influenced by obesity and other anthropometric measures, though it is difficult to infer causal relationships based on observational data due to risk of residual confounding. We utilized mendelian randomization (MR) to explore causal relevance of multiple anthropometric measures on P-wave duration (PWD), PR interval, QRS duration, and corrected QT interval (QTc).Methods And FindingsUncorrelated (r2 < 0.001) genome-wide significant (p < 5 × 10-8) single nucleotide polymorphisms (SNPs) were extracted from genome-wide association studies (GWAS) on body mass index (BMI, n = 806,834), waist:hip ratio adjusted for BMI (aWHR, n = 697,734), height (n = 709,594), weight (n = 360,116), fat mass (n = 354,224), and fat-free mass (n = 354,808). Genetic association estimates for the outcomes were extracted from GWAS on PR interval and QRS duration (n = 180,574), PWD (n = 44,456), and QTc (n = 84,630). Data source GWAS studies were performed between 2018 and 2022 in predominantly European ancestry individuals. Inverse-variance weighted MR was used for primary analysis; weighted median MR and MR-Egger were used as sensitivity analyses. Higher genetically predicted BMI was associated with longer PWD (β 5.58; 95%CI [3.66,7.50]; p = < 0.001), as was higher fat mass (β 6.62; 95%CI [4.63,8.62]; p < 0.001), fat-free mass (β 9.16; 95%CI [6.85,11.47]; p < 0.001) height (β 4.23; 95%CI [3.16, 5.31]; p < 0.001), and weight (β 8.08; 95%CI [6.19,9.96]; p < 0.001). Finally, genetically predicted BMI was associated with longer QTc (β 3.53; 95%CI [2.63,4.43]; p < 0.001), driven by both fat mass (β 3.65; 95%CI [2.73,4.57]; p < 0.001) and fat-free mass (β 2.08; 95%CI [0.85,3.31]; p = 0.001). Additionally, genetically predicted height (β 0.98; 95%CI [0.46,1.50]; p < 0.001), weight (β 3.45; 95%CI [2.54,4.36]; p < 0.001), and aWHR (β 1.92; 95%CI [0.87,2.97]; p = < 0.001) were all associated with longer QTc. The key limitation is that due to insufficient power, we were not able to explore whether a single anthropometric measure is the primary driver of the associations observed.ConclusionsThe results of this study support a causal role of BMI on multiple ECG indices that have previously been associated with atrial and ventricular arrhythmic risk. Importantly, the results identify a role of both fat mass, fat-free mass, and height in this association.Copyright: © 2023 Ardissino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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