Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother–infant pairs

by Jing Chen, Jonas Bacelis, Pol Sole-Navais, Amit Srivastava, Julius Juodakis, Amy Rouse, Mikko Hallman, Kari Teramo, Mads Melbye, Bjarke Feenstra, Rachel M. Freathy, George Davey Smith, Deborah A. Lawlor, Jeffrey C. Murray, Scott M. Williams, Bo Jacobsson, Louis J. Muglia, Ge Zhang

Many maternal traits are associated with a neonate’s gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved.

Based on 10,734 mother–infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10⁻⁴). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10⁻¹⁷). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10⁻⁴). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10⁻³), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10⁻² and p = 4.5 × 10⁻³, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10⁻⁶); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10⁻³). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10⁻³) and a stronger fetal effect (p = 1.3 × 10⁻⁵). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10⁻⁴) and increased maternal systolic BP during pregnancy (p = 2.2 × 10⁻²). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits.

We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk–increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.