Direct and Indirect Genetic Effects of Birthweight Predisposition on Child DNA Methylation at Birth

BackgroundBirthweight is heritable and strongly associated with epigenetic differences at birth. It is unclear whether a genetic birthweight score is associated with DNA methylation (DNAm) and, if so, whether through direct genetic effects (i.e., child genotype) or indirect genetic effects (i.e., parental genotype, independent of child genotype), which are suspected to be mediated by the prenatal environment (e.g. metabolic factors). MethodsWe constructed polygenic scores (PGS) for birthweight predisposition in mothers and children using an existing pre-adjusted GWAS assessing maternal indirect effects (maternal genotype on offspring birthweight, correcting for offspring genotype) or fetal effects (offspring genotype on offspring birthweight, correcting for maternal genotype) in 2116 families from the Generation R Study. Offspring DNAm levels at 829 birthweight-related sites were then regressed on both maternal and fetal effect PGS. Additionally, we aggregated 829 DNAm sites into a methylation profile score for birthweight (MPS-BW) and tested which pregnancy health factors (n=13) might mediate genetic effects. FindingsWe identified six DNAm sites associated with maternal indirect effects and the birthweight MPS revealed indirect genetic associations, as well. Gestational age partly mediated maternal indirect effects on DNAm, but no other mediators were identified. Results did not depend on offspring sex. InterpretationThis study presents first evidence of maternal genetic effects on offspring birthweight being associated with offspring epigenetic patterns at birth. Paternal genotype was not associated with offspring methylation in this study but was limited by lower sample size and lack of existing GWAS on paternal indirect effects. FundingEuropean Union Research in contextO_ST_ABSEvidence before this studyC_ST_ABSBirthweight is a moderately heritable trait and prior genome-wide association studies have identified multiple genetic variants associated with fetal growth. Genetic variants may impact birthweight via direct and indirect genetic routes of transmission. Indirect genetic effects occur when parental genetics still associate with child outcomes independent of genetic transmission to offspring, suggesting involvement of environmental mechanisms. For example, maternal genetic predispositions may shape the intrauterine environment in ways that accelerate or slow fetal growth. Indirect genetic effect may explain up to 22% of birthweight variance. Additionally, epigenetic modifications, particularly differences in DNA methylation (DNAm) at birth, have been linked to birthweight. Recent studies have identified over 900 CpG sites associated with birthweight. However, it is unknown whether the direct and indirect genetic effects on birthweight are reflected in DNAm variation, as well. Added value of this studyWe found that especially indirect maternal genetic effects on offspring birthweight are associated with offspring DNAm patterns at birth. We have linked six DNAm sites with indirect maternal effects in contrast to only one site with direct genetic transmission. A methylation profile score for birthweight associated similarly with direct and indirect effects, with a trend for stronger association with indirect effects. Implications of all the available evidenceThe results shed new light on how the interplay between genetics and environment on epigenetics may impact birthweight. This study confirms that maternal genetics partly affect offspring birthweight indirectly, independent of direct transmission. Importantly, our results imply that DNAm levels in cord blood partly reflect these indirect maternal genetic effects. This in turn raises the possibility that DNAm is an important mechanism mediating indirect maternal genetic effects on birthweight, but more research is needed to investigate causality.