Abstract
BackgroundGreater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal.MethodsWe undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs).ResultsMV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size.ConclusionsOur results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.
Highlights
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear
MV and Mendelian randomisation (MR) consistently showed a positive association between maternal body mass index (BMI) and birth weight (BW), supporting a moderate causal effect
Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the generation
Summary
Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Evidence from animal experiments suggests that such associations are plausibly due to causal biological effects in the intrauterine period [9, 10] If true, this could have important implications for obesity prevention policy, because interventions to reduce maternal obesity before pregnancy might reduce offspring obesity risk in later life [1, 2, 6]. In order to avoid bias due to genetic inheritance, the primary analysis in the most recent MR study [23] was adjusted for an offspring weighted allele score, and simulations suggest that the use of a weighted allele score may not be the optimal approach to avoid bias (Personal communication, Wang G, Warrington N, Evans DM, 2020) Both previous studies [14, 23] were unable to adjust for paternal genetic variants, which may be necessary to avoid collider bias [24]. It is important to conduct further MR investigations with improved methods, in order to obtain more precise estimates that are not subject to the aforementioned biases
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