Assessment of the causal relevance of ECG parameters for risk of atrial fibrillation: A mendelian randomisation study

Abstract

Background: Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR).

Methods and findings: Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 × 10-4 and OR 0.94; 95% CI: 0.93-0.96, P = 2 × 10-19, respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank.

Conclusions: In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.

Fig 1. Associations between genetic scores and 12-lead ECG parameters in UK Biobank.

Association between quintiles of genetic scores for ECG parameters (defined in non-AF cases) and 12-lead ECG parameters in 13,314 participants in UK Biobank. Boxes represent mean values with their size inversely proportional to variance, and lines represent 95% CIs. A constant representing the population mean nongenetically predicted ECG interval was added to all genetic score values (the population mean of measured 12-lead ECG parameter excluding the genetic contribution; 93.2 ms for P-wave duration, 93.5 ms for PR interval, and 360.7 ms for QT interval) for display purposes. P calculated across the genetic score using linear regression adjusting for sex, genotyping array, and 40 principal components of ancestry. AF, atrial fibrillation; CI, confidence interval; ECG, electrocardiographic.

Fig 2. Effects of genetically predicted ECG parameters on risk of AF in UK Biobank.

ORs for AF per quintile of genetic score (defined in non-AF cases) in 278,792 participants in UK Biobank. Boxes represent effect estimates with their size inversely proportional to variance. Solid lines represent 95% CIs calculated using floating absolute risks. ORs are adjusted for genotyping array, sex, and 40 principal components of ancestry. P calculated across continuous genetic score values adjusting for sex, genotyping array, and 40 principal components of ancestry. AF, atrial fibrillation; CI, confidence interval; OR, odds ratio.

Fig 3. Effects of genetically predicted ECG parameters on the risk of lone AF and SVT in UK Biobank.

Effects of genetically predicted ECG parameters on risk of (A). “Lone” AF and (B). SVTs in UK Biobank. Ion channel scores for each ECG parameter include only genetic variants annotated to known ion channel genes. Boxes represent point estimates of effect per 5 ms higher ECG score with sizes inversely proportional to their variance, and lines represent 95% CIs. ORs are adjusted for genotyping array, sex, and 40 principal components of ancestry. AF, atrial fibrillation; CI, confidence interval; ECG, electrocardiographic; OR, odds ratio; SVT, supraventricular tachycardia.

Fig 4. Effects of genetically predicted ECG parameters on risk of AF in UK Biobank and AFGen.

Ion channel scores for each ECG parameter include only genetic variants annotated to known ion channel genes. Boxes represent point estimates of effect per 5 ms higher ECG score, diamonds represent meta-analysis estimates, with sizes inversely proportional to their variance, and lines represent 95% CIs. UK Biobank derived ORs are adjusted for sex, genotyping array, and 40 principal components of ancestry. ORs for AFGen were calculated using inverse variance weighted fixed-effects methods from published summary data. AF, atrial fibrillation; CI, confidence interval; ECG, electrocardiographic; OR, odds ratio.