Fetal and Maternal Genes’ Influence on Gestational Age in a Quantitative Genetic Analysis of 244,000 Swedish Births

Abstract

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Consistent with this finding, segregation analysis shows that maternal genome effects in both the mother and the fetus are much more prominent than paternal effects (13). A comparison of the offspring of twins, full siblings, and half siblings estimated that 13% of the variation in gestational age at delivery was explained by fetal genetic factors, and 21% was accounted for by maternal genetic factors (14). As reviewed recently, human candidate gene studies in both maternal and fetal genomes have been inconsistent in demonstrating associations across populations, although the most robust evidence suggests a role for interleukin-6 (IL-6) in the maternal genome and for coagulation protein Factor V in both maternal and infant genomes (15,16).…”

Resolving the Effects of Maternal and Offspring Genotype on Dyadic Outcomes in Genome Wide Complex Trait Analysis (“M-GCTA”)

“…For outcomes that depend markedly on age, such as pre- and peri-natal outcomes or assessments of early development, studies have focused on the phenotypes of collateral relatives such as offspring related through mothers of different degrees of genetic relationship, e.g., maternal and paternal half siblings and offspring of male and female twins and siblings (Corey and Nance 1978; York et al 2009, 2010, 2013). Although such approaches can estimate direct ( G ) and maternal effects (M + Q ), instances where intergenerational phenotypic data are not available preclude the resolution of maternal effects (M) from those of genotype-environmental covariance ( Q ).…”

“…Such models have been implemented in extended animal pedigrees and, most recently, have been applied by York et al (2010, 2013) to gestational age in large samples of Swedish and American births from female twin, sibling and half-sibling mothers and the spouse of male twins, sibling and half-siblings.…”

“…There is an extensive theoretical and empirical literature on modeling maternal effects in human kinships and resolving them from the direct effects of the offspring genotype. Such models have been especially important in resolving the contributions of maternal and fetal genotype to pre- and peri-natal outcomes (Corey and Nance 1978; York et al 2009, 2010, 2013). Our extension of GCTA to include the effects of the maternal genotypes builds on much of this classical work.…”

CXCR3 Polymorphism and Expression Associate with Spontaneous Preterm Birth

“…According to large population-based studies and genetic modeling studies, preterm birth and/or variation in gestational age (GA) are affected by maternal genetic factors (11,13,14,(16)(17)(18)(19); some of these studies suggest that fetal genes also play a role (16,17,19). SPTB is a multifactorial phenotype that is influenced by multiple interacting factors, with the potential involvement of extensive gene-gene and gene-environmental interactions (20).…”