Abstract
Purpose: Birth weight has a profound long-term impact on individual’s 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. Materials and methods: Mendelian randomization using multiple genetic instruments associated with birth weight was performed to explore the causal relationship between birth weight and adult diseases. The causal relationship between birth weight and 21 adult diseases as well as 38 other complex traits was examined based on data collected from 37 large-scale genome-wide association studies with 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, bias calculation, and simulations. Results: Among the 21 adult diseases, three were identified to be inversely causally affected by birth weight after the Bonferroni correction. The measurement unit of birth weight was defined as its standard deviation (i.e., 488 g), 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], 1.30 (95% CI 1.13–1.51), 1.41 (95% CI 1.15–1.73), and 1.54 (95% CI 1.25–1.89), 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 reverse causation. In addition, analysis on 38 additional complex traits did not identify candidate traits that may mediate the causal association between birth weight and CAD/MI/T2D. 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.
Highlights
Birth weight is a widely used surrogate measurement of intrauterine exposure (Peck et al, 2003) and early life development (Scharf et al, 2016), and is an indicator of intergenerational influences (Hackman et al, 1983)
We first selected a set of 47 SNPs from a large-scale GWAS for birth weight based on 143,677 individuals to serve as instrumental variables for birth weight (Table 1 and Figure S1)
We examined the causal relationship between birth weight and 21 adult diseases through Mendelian randomization (MR) analysis using the selected instruments
Summary
Birth weight is a widely used surrogate measurement of intrauterine exposure (Peck et al, 2003) and early life development (Scharf et al, 2016), and is an indicator of intergenerational influences (Hackman et al, 1983). Exemplary birth weight-associated cancers include renal cell cancer (Bergstrom et al, 2001), colorectal cancer (Sandhu et al, 2002), primary central nervous system tumor (Georgakis et al, 2017), prostate cancer (Zhou et al, 2016), bone tumor (Chen et al, 2015), and breast cancer (Xu et al, 2009) It remains unclear whether the identified associations between birth weight and the aforementioned adult diseases represent truly causal relationship, or are merely spurious associations caused by common confounding factors that occur during prenatal life (Barker, 1990; Leon, 1998; Law, 2002; Ruiz-Narvaez et al, 2014; Kahn et al, 2017) or confounding due to pleiotropy and shared genetic components (Lawlor et al, 2017). It is not completely clear to what extent the fetal origins of adult diseases hypothesis holds and it is not completely clear what types of adult diseases are causally affected by birth weight (Law, 2002; Kahn et al, 2017)
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