Opposite causal effects of birthweight on myocardial infarction and atrial fibrillation and the distinct mediating pathways: a Mendelian randomization study

Fig. 1. Overview of the MR study design. This MR study consisted of two analysis phases. In Phase 1, the causal associations of birthweight with MI and AF were estimated using UVMR, and the MR estimates showed that birthweight had opposite effects on MI and AF. In Phase 2, two-step MR was applied to screen for 52 candidate mediators that may lie in the pathways between birthweight and MI or AF and quantify the mediation proportions for qualified mediators. AF atrial fibrillation, EGG Early Growth Genetics, IV instrumental variable; MR Mendelian randomization; MI myocardial infarction, MVMR multivariable Mendelian randomization, UVMR univariable Mendelian randomization

Fig. 2. Selection process for mediators in the causal associations of birthweight with MI and AF. Three criteria were applied to screen for the mediators in the causal associations of birthweight with MI and AF: [1] birthweight is causally associated with the mediator; [2] the mediator has a direct causal effect on the outcome independently of birthweight; and [3] the total effect of birthweight on the outcome and the mediating effect of the mediator are in the same direction. Eventually, a total of 17 and 5 qualified mediators met all criteria and were included in the mediation analyses to quantify their individual mediating proportions in the causal associations of birthweight with MI and AF, respectively. The full MR estimates are shown in Additional file 1: Table S5, Table S7. AF atrial fibrillation, ApoA-I Apolipoprotein A-I, ApoB Apolipoprotein B, BMI body mass index, CI confidence interval, CKD Chronic kidney disease, CRP C-reactive protein, DBP diastolic blood pressure; DHA docosahexaenoic acid, eGFR estimated glomerular filtration rate, HbA1c glycated hemoglobin, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, SBP…

Fig. 3. Mediating role of each mediator in the causal associations of birthweight with MI and AF. Two-step MR was used to evaluate the mediating role of each mediator in the causal associations of birthweight with MI (A) and AF (B). Left: UVMR estimates for the causal effect of birthweight on each mediator. Middle: MVMR estimates for the causal effect of each mediator on MI or AF with adjustment for birthweight. Right: mediation proportion of each mediator in the causal association between birthweight and MI or AF. Negative mediation proportions were truncated at a lower limit of 0%, as it is the lowest threshold to determine a mediation proportion. AF atrial fibrillation, ApoB Apolipoprotein B, BMI body mass index, CI confidence interval, HbA1c Glycated hemoglobin, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction, MVMR multivariable Mendelian randomization, SBP systolic blood pressure, UVMR univariable Mendelian randomization, WC Waist circumference