Causal Association between Birth Weight and Adult Diseases: Evidence from a Mendelian Randomisation Analysis

Background It has long been hypothesized that birth weight has a profound long-term impact on individual predisposition to various diseases at adulthood: a hypothesis commonly referred to as the fetal origins of adult diseases. However, it is not fully clear to what extent the fetal origins of adult diseases hypothesis holds and it is also not completely known what types of adult diseases are causally affected by birth weight. Determining the causal impact of birth weight on various adult diseases through traditional randomised intervention studies is a challenging task.

Methods Mendelian randomisation was employed and multiple genetic variants associated with birth weight were used as instruments to explore the relationship between 21 adult diseases and 38 other complex traits from 37 large-scale genome-wide association studies up to 340,000 individuals of European ancestry. Causal effects of birth weight were estimated using inverse-variance weighted methods. The identified causal relationships between birth weight and adult diseases were further validated through extensive sensitivity analyses and simulations.

Results Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight with a statistical significance level passing the Bonferroni corrected significance threshold. The measurement unit of birth weight was defined as its standard deviation (i.e. 488 grams), and one unit lower birth weight was causally related to an increased risk of coronary artery disease (CAD), myocardial infarction (MI), type 2 diabetes (T2D) and BMI-adjusted T2D, with the estimated odds ratios of 1.34 [95% confidence interval (CI) 1.17 - 1.53, p = 1.54E-5], 1.30 (95% CI 1.13 - 1.51, p = 3.31E-4), 1.41 (95% CI 1.15 - 1.73, p = 1.11E-3) and 1.54 (95% CI 1.25 - 1.89, p = 6.07E-5), respectively. All these identified causal associations were robust across various sensitivity analyses that guard against various confounding due to pleiotropy or maternal effects as well as inverse causation. In addition, analysis on 38 additional complex traits found that the inverse causal association between birth weight and CAD/MI/T2D was not likely to be mediated by other risk factors such as blood-pressure related traits and adult weight.

Conclusions The results suggest that lower birth weight is causally associated with an increased risk of CAD, MI and T2D in later life, supporting the fetal origins of adult diseases hypothesis.