Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Abstract

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Intermediate confounding in trio relationships: The importance of complete data in effect size estimation

“…The estimation of maternal and paternal effects on child phenotypes has long been of interest to statistical geneticists, with advancements in molecular genotyping now allowing the effects of specific variants to be tested or modeled through polygenic scores (Bates et al, 2018; Evans, Moen, Hwang, Lawlor, & Warrington, 2019; Kong et al, 2018; Warrington et al, 2019). Ultimately, parents may influence the phenotype of their child through genetic transmission, when the child receives half of each parents' genetic material, or through cultural transmission, where the environment provided by the parents affects the child's developmental outcomes.…”

“…Cultural transmission effects may also be partially attributable to parental genetics, a phenomena termed “genetic nurture” by Kong et al (2018). The most obvious example of the effects of maternal genetic nurture, mediated by the maternally provided intrauterine environment, may be those which act on perinatal outcomes (Evans et al, 2019; Warrington et al, 2019). However, there is also evidence that both maternal and paternal genes have environmentally mediated effects on later‐life traits like education attainment (Bates et al, 2018; Kong et al, 2018).…”

Hypertension and Reproduction

“…The possible link between early life factors and increased cardiovascular risk in the offspring of pregnant women with poor nutrition, unhealthy lifestyle (smoking, alcohol intake) or impaired placental function has remained controversial. Some researchers argue that genetic factors may explain the link between hypertension in the mother, SGA of the newborn, and development of hypertension in the offspring in adult life [25].…”

Cardiac imaging of aortic valve area from 26,142 UK Biobank participants reveal novel genetic associations and shared genetic comorbidity with multiple disease phenotypes

“…Supplementary Figure 2 shows significant correlations at a false discovery rate of p=0.05 separately for published research studies (non-UK Biobank) and UK Biobank GWAS results (http://www.nealelab.is/uk-biobank, which is complicated by phenotypic and sample overlap between the lab GWAS traits and e.g., aortic valve size comorbidities in subjects from the current MRI study). After correction for multiple testing, the correlation with UK Biobank Amongst the independent 258 genetic correlation coefficients, alleles related to larger aortic valve size overlap with the genetic determinants of birthweight 25,26 ( Supplementary Table S3).…”