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.