Haplotype genetic score analysis in 10,734 mother/infant pairs reveals complex maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes and adult phenotypes

Abstract

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. Based on 10,734 mother/infant duos of European ancestry, we constructed haplotype genetic scores to dissect the maternal and fetal genetic effects underlying these observed associations.We showed that maternal height and fetal growth jointly affect the duration of gestationmaternal height positively influences the gestational duration, while faster fetal growth reduces gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: tall maternal stature and higher blood glucose causally increase birth size; in the fetus, the height and metabolic risk increasing alleles can lead to increased and decreased birth size respectively; birth weight-raising alleles in fetus may reduce gestational duration and increase maternal blood pressure. These maternal and fetal genetic effects can largely 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.

Characterization of the genetic architecture of infant and early childhood body mass index

“…Taking advantage of the phasing of the children's genotypes, we could infer the parent-of-origin of the genotyped alleles as done by Chen et al 65 . This results in an alternative model that allows studying the association per haplotype in the set of unrelated trios, as detailed in equation 7.…”

Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes

“…Several studies have shown associations of preterm birth and low birth weight with developmental disabilities such as cerebral palsy, intellectual disabilities, autism spectrum disorder, attention deficit hyperactivity disorder, learning disability and future risk of type 2 diabetes mellitus and cardiovascular diseases in child [40][41][42][43][44][45] . Understanding the genetic architecture of pregnancy phenotypes will not only elucidate the genetic basis of immediate health outcomes but also shed light on the nature of their relationships with long-term health outcomes 46 .…”

Characterization of the genetic architecture of BMI in infancy and early childhood reveals age-specific effects and implicates pathways involved in Mendelian obesity

“…Taking advantage of the phasing of the children genotypes, we could infer the parent-of-origin of the genotyped alleles as done by Chen et al 59 . This results in an alternative model that allows studying the association per haplotype in the set of unrelated trios, as detailed in equation 7.…”