A lifecourse mendelian randomization study highlights the long-term influence of childhood body size on later life heart structure

Abstract

Children with obesity typically have larger left ventricular heart dimensions during adulthood. However, whether this is due to a persistent effect of adiposity extending into adulthood is challenging to disentangle due to confounding factors throughout the lifecourse. We conducted a multivariable mendelian randomization (MR) study to separate the independent effects of childhood and adult body size on 4 magnetic resonance imaging (MRI) measures of heart structure and function in the UK Biobank (UKB) study. Strong evidence of a genetically predicted effect of childhood body size on all measures of adulthood heart structure was identified, which remained robust upon accounting for adult body size using a multivariable MR framework (e.g., left ventricular end-diastolic volume (LVEDV), Beta = 0.33, 95% confidence interval (CI) = 0.23 to 0.43, P = 4.6 × 10-10). Sensitivity analyses did not suggest that other lifecourse measures of body composition were responsible for these effects. Conversely, evidence of a genetically predicted effect of childhood body size on various other MRI-based measures, such as fat percentage in the liver (Beta = 0.14, 95% CI = 0.05 to 0.23, P = 0.002) and pancreas (Beta = 0.21, 95% CI = 0.10 to 0.33, P = 3.9 × 10-4), attenuated upon accounting for adult body size. Our findings suggest that childhood body size has a long-term (and potentially immutable) influence on heart structure in later life. In contrast, effects of childhood body size on other measures of adulthood organ size and fat percentage evaluated in this study are likely explained by the long-term consequence of remaining overweight throughout the lifecourse.

Fig 1. DAGs illustrating the different scenarios through which childhood body size may influence cardiac structure in later life.

Fig 1A illustrates the “total” effect of childhood body size on cardiac structure in adulthood. This may be due to a “direct” effect of childhood body size, which is depicted in Fig 1B or an “indirect” effect, mediated through adult body size, which is depicted in Fig 1C. DAG, directed acyclic graph.

Fig 2. Forest plots illustrating (A) univariable and (B) multivariable MR effect estimates of childhood and adult body size on measures of cardiac structure/function and abdominal organ size/fat percentage.

The estimates for child body size are in orange and the estimates for adult body size are in red. The effect estimates are per change in body size category and include the 95% CI. The data underlying this figure can be found in S3, S4, S6, and S7 Tables. CI, confidence interval; LV, left ventricular; MR, mendelian randomization; MRI, magnetic resonance imaging; SAT, subcutaneous adipose tissue; VAT, visceral adiposity tissue.