Influence of birth weight on later life cardiovascular structure, function and disease: unpacking influences from direct genetic effects versus intrauterine programming
Authors: Ardissino M , Slob E A W , Rayes B , Morley A P , Raisi-Estabragh Z , De Marvao A , Williamson C , Rogne T , Burgess S , Ng F S 
Published: November 2023

Abstract

Aims
The cardinal risk factors for cardiovascular disease in adulthood are well-recognised. In addition to these, observational studies have suggested that intrauterine and early developmental factors might play a role. However, observational associations are liable to influence by residual confounding and bias. Additionally, observational and genetic studies to date have not been able to isolate the fetal versus maternal influences.

Purpose
We aim to explore the causal relevance of birth weight on cardiovascular disease and cardiac structure and function using Mendelian randomization (MR), and specifically investigate the role of fetal genetic effects (reflecting the direct causal influence of birth weight) versus maternal genetic effects (reflecting the influence of the intrauterine environment).

Methods
Uncorrelated (r2&lt;0.001), genome-wide significant (p&lt;5x10-8) SNPs were extracted from genome-wide association study summary statistics for gestational age-adjusted birth weight overall, and after isolating the indirect maternal versus direct fetal genetic effects. Inverse-variance weighted Mendelian randomisation (MR) was utilised for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 15 measures of cardiac structure and function indexed to body surface area. Multivariable MR was utilised to explore potential mediation of effects observed on cardiovascular outcomes by cardiometabolic risk factors. P-values were FDR-adjusted to account for multiple testing.

Results
Higher genetically-predicted birth weight was associated with higher risk of atrial fibrillation (OR 1.26 [1.15-1.39], p&lt;0.001), but lower risk of coronary artery disease (OR 0/78 [0.71-0.86] p&lt;0.001). These associations were driven predominantly by direct fetal genetic effects. For the association with atrial fibrillation, there was no evidence of mediation through body mass index or height. For the association with coronary artery disease, there was at least partial mediation through systolic blood pressure (Figure 1). Higher genetically-predicted birth weight was associated with a greater chamber volumes, but lower ejection fraction (Figure 2), driven by direct fetal genetic effects.

Conclusion
The results of this study suggest that lower birthweight is associated with higher risk of coronary artery disease, partly mediated by a higher systolic blood pressure. Conversely, a greater birth weight was associated with higher risk of atrial fibrillation, and this was not mediated by body mass index or height. Higher birth weight was also associated with greater chamber volumes and lower ejection fraction. The associations were in all cases predominantly driven by direct fetal effects, suggesting a causal relevance of birth weight itself, and not of the intrauterine environment, on later life cardiovascular disease.Figure 1Figure 2