Low birthweight and risk of type 2 diabetes: a Mendelian randomisation study

Abstract

Aims/hypothesis: Low birthweight has been associated with a high risk of type 2 diabetes mellitus in observational studies. However, it remains unclear whether this relation is causal.

Methods: The present study included 3627 individuals with type 2 diabetes and 12,974 control participants of European ancestry from the Nurses' Health Study and the Health Professionals Follow-Up Study. A genetic risk score (GRS) was calculated based on five low-birthweight-related single nucleotide polymorphisms (SNPs). We assessed the evidence for causality first by examining the association of the GRS and the individual SNPs with type 2 diabetes, and second by performing a Mendelian randomisation analysis to estimate the potentially causal effect size of low birthweight on type 2 diabetes.

Results: In a meta-analysis of the two studies, each 1 point increment in the GRS was associated with a 6% (95% CI 3%, 9%) higher risk of type 2 diabetes. CCNL1 rs900400 and 5q11.2 rs4432842 showed dose-response associations with risk of type 2 diabetes; the corresponding ORs and 95% CIs were 1.09 (1.03, 1.16) and 1.09 (1.02, 1.16), respectively. Furthermore, we observed an overall Mendelian randomisation OR of 2.94 (95% CI 1.70, 5.16; p < 0.001) for type 2 diabetes per 1 SD lower genetically determined birthweight.

Conclusions/interpretation: A genetically lowered birthweight was associated with increased susceptibility to type 2 diabetes. Our findings support a potential causal relation between birthweight and risk of type 2 diabetes, providing new evidence to support the role of intrauterine exposures in the pathogenesis of type 2 diabetes.

Keywords: Birthweight; Mendelian randomisation; Type 2 diabetes.

Fig. 1

Schematic representation of the Mendelian randomisation analysis. β₁ is the effect size estimate of each low-birthweight-related SNP on birthweight derived from the GWAS of birthweight reported by Horikoshi et al [11]. β₂ is the log_e OR estimate of the type 2 diabetes for each SNP derived from the NHS and HPFS using inverse-variance-weighted, fixed-effects meta-analysis (all p for heterogeneity >0.05). β₃ is calculated from β₁ and β₂ for each SNP: β₃=β₂/β₁. The SE of β₃ is given by: ${\mathrm{S}}_3=\sqrt{\frac{1}{{{\mathrm{\beta }}_1}^2{{\mathrm{S}}_2}^{-2}}}$, where S₂ is the SE of β₂. We then combined β₃ estimates for all five SNPs analysed using inverse-variance-weighted, fixed-effects meta-analysis to obtain an overall estimate of the relation between genetically determined low birthweight and type 2 diabetes. In a Mendelian randomisation study, the overall β₃ estimate would be considered to be an estimate of the causal association between low birthweight and type 2 diabetes. The OR for type 2 diabetes associated with each 1 SD lower genetically determined birthweight can be given by exp(overall β₃)

Fig. 2

Relationship between the low-birthweight GRS and type 2 diabetes. Data are ORs (solid lines) and 95% CIs (dashed lines), based on the combined data of the NHS and HPFS, adjusting for age and sex. p for linearity=0.001

Fig. 3

Mendelian randomisation estimate of the association of low birthweight with risk of type 2 diabetes. The forest plot shows β₃ estimates (log_e-ORs) of the effect of low birthweight on the risk of type 2 diabetes for each low-birthweight-related SNP. The overall β₃ estimate was obtained by using inverse-variance-weighted, fixed-effects meta-analysis (p for heterogeneity = 0.318), and can be interpreted as an OR of 2.94 (95% CI 1.70, 5.16) for type 2 diabetes per 1 SD lower genetically determined birthweight (p<0.001)