Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort

Abstract

There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother-offspring pairs (and 19,792 father-offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

Fig. 1. Four credible ways in which maternal single nucleotide polymorphism (SNP)s can be related to offspring birthweight and offspring cardiometabolic risk factors.

a Maternal SNPs produce an adverse in utero environment that leads to fetal growth restriction and subsequently low offspring birthweight and developmental compensations that produce increased risk of offspring cardiometabolic disease in later life. b Maternal SNPs produce an adverse in utero environment that leads to fetal growth restriction and low offspring birthweight. Low offspring birthweight in turn is causal for increased risk of offspring cardiometabolic disease. c Maternal SNPs produce an adverse in utero environment that leads to fetal growth restriction and reduced birthweight. The same SNPs are transmitted to the offspring and pleiotropically influence offspring cardiometabolic risk through the offspring genome. d Maternal SNPs produce an adverse in utero environment that leads to fetal growth restriction and reduced offspring birthweight. SNPs that exert maternal effects on offspring birthweight also pleiotropically influence offspring cardiometabolic disease through the postnatal environment. The star on the arrows denotes the act of conditioning on maternal or offspring genotype blocking the association between maternal and offspring variables. The dotted paths indicate paths in which the maternal genotype can be related to offspring phenotype that are not to do with intrauterine growth restriction. Finally, we note that some offspring SNPs may also exert direct effects on offspring birthweight (these not shown). The presence of direct effects from offspring genotype on offspring birthweight is inconsequential so long as the relevant analyses are conditional on offspring genotype.

Fig. 2. Path diagram of the relationship between maternal Genetic Risk Score (GRS), offspring GRS, the intrauterine environment, offspring birthweight and an offspring cardiometabolic risk factor.

Variables within square boxes represent observed variables, whereas variables in circles represent latent unobserved variables. Unidirectional arrows represent causal relationships from tail to head, whilst two headed arrows represent correlational relationships. Greek letters on one headed arrows represent path coefficients which quantify the expected causal effect of one variable on the other. Greek letters on two headed arrows represent covariances between variables. The two epsilon variables represent residual latent factors (both environmental and genetic) that are not modeled in the study. The coefficient Θ represents the covariance between the residual terms. We assume that all variables are standardized to have unit variance. Consequently, the residual variance of the offspring GRS is set to 0.75 since ¼ of the variance comes from the maternal genotype. For the purposes of the power calculation described in the discussion, we assume that maternal single nucleotide polymorphism (SNP)s that affect offspring birthweight do so through a single latent intrauterine factor, and that this factor also exerts long term effects on the offspring cardiometabolic risk factor of interest.

Fig. 3. Flowchart showing the number of individuals (N) participating in the analysis and the exclusion criteria for each analysis.

A total of 69,716 genotyped HUNT participants were recruited from either HUNT2 or HUNT 3. Of these 46,428 parent–offspring relationships were identified using the King software. Parent–offspring pairs with ≤15 years difference in birth year were removed leaving 26,058 mother–offspring pairs and 19,792 father–offspring pairs for the main analysis. Birthweight was only available for offspring born after 1967. Additionally, for analyses involving birthweight as an outcome, offspring were excluded if they were part of a multiple birth, had congenital malformation, were born where the birth was induced or performed with C-section, their birthweight ≤1000 g, or were born before 258 days of gestation.