Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Abstract

IMPORTANCE Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain.OBJECTIVE To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTSMendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population-or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included.EXPOSURES Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level.MAIN OUTCOME AND MEASURE Offspring birth weight from 18 studies.RESULTS Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10 −14 ) and −4 g (95% CI, −6 to −2g) per SBP-raising allele (P = 1×10 −5 ), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions.CONCLUSIONS AND RELEVANCE In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Using Genetic Variation to Explore the Causal Effect of Maternal Pregnancy Adiposity on Future Offspring Adiposity: A Mendelian Randomisation Study

“…Taken together, these results do not support an important causal intrauterine effect of greater maternal BMI on later offspring adiposity. This is in contrast to evidence of a causal effect of greater maternal adiposity on birth weight and ponderal index at birth identified using MR in a previous study that included both of the cohorts used here [7], potentially indicating a diminishing effect of this intrauterine exposure over the life course (Fig 3). …”

“…However, previous analysis in ALSPAC has shown that misreporting is similar for the majority of participants and is not markedly influenced by mean weight [71]. Furthermore, the magnitude of the association of the weighted allele score with maternal BMI in this study was similar to that seen for its relationship to BMI based on measured weight and height from other studies [7]. …”

“…Maternal body mass index (BMI) is positively associated with greater pregnancy-related increases in circulating glucose, lipids, and fatty acids [2,3], and in turn higher maternal gestational levels of these nutrients are associated with greater birth size [4–6]. In support of this hypothesis, strong evidence for a causal effect of greater maternal gestational adiposity and circulating fasting glucose, but not triglycerides, on birth weight and ponderal index at birth has recently been shown using a Mendelian randomisation (MR) approach [7]. As birth size is correlated with later size, it is possible that these effects will extend into later offspring postnatal life.…”

Differential methylation of genes in individuals exposed to maternal diabetes in utero

“…For differentially methylated sites, the median adjusted absolute difference in methylation between OMD and OMND was 2.2% (range 0.6-4.6%). Exposure to diabetes in utero is strongly associated with higher maternal BMI, and genetically raised maternal BMI is associated with birthweight, which in turn is associated with long-term developmental outcomes and adult diseases [22,23]. However, the additional adjustment for maternal pre-pregnancy BMI did not materially change the effect sizes of our 48 top signals.…”

Lights and Shadows on Pediatric Obesity Prevention

“…According to this obesity prevention should start even preconceptionally, and then diminishing gestational excessive weight gain, gestational diabetes and large for gestational age (>4.0 kg) newborns. These are linked to adult obesity and comorbidities [15,16]. Lifestyle, psychosocial or medical factors like maternal smoking, depression, T2D, lead to a fetal exposure to glucocorticoids that could act epigenetically as gene-specific DNA methylation levels found in umbilical cord tissue.…”