Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n=321,223) and offspring birth weight (n=230,069 mothers), we identified 190 independent association signals (129 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic effects, and then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of those alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

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

“…We also constructed a type 2 diabetes (T2D) genetic score using 306 T2D SNPs (excluding SNPs overlapping or in close linkage disequilibrium with the 22 FPG SNPs) (Supplementary methods and Table S3). To examine the effect of fetal growth (as proxied by birth weight) on pregnancy outcomes and maternal blood pressure and FPG during pregnancy, we constructed genetic scores using 86 SNPs associated with birth weight with confirmed fetal effect (42).…”

“…To test the possible fetal drive of fetal growth on birth outcomes and maternal pregnancy phenotypes, we constructed genetic scores using 86 SNPs associated with birth weight with confirmed fetal effect (28) and tested their associations with birth outcomes as well as maternal blood pressure and FPG during pregnancy ( Table 2). The fetal genetic score for birth weight was significantly associated with gestational age adjusted birth weight with an R 2 = 3.1%.…”

“…Using a genome-wide association (GWA) approach, Horikoshi et al (20) (27) and a weighted linear model (WLM) approximation to separate maternal from fetal effects. Using this method, they estimated maternal and fetal genetic effects on birth weight genome-wide, and investigated associations between those genetic effects on birth weight and adult systolic blood pressure (28). We previously developed a novel MR method that utilizes non-transmitted maternal alleles as a valid genetic instrument for maternal phenotypic effects on fetal/offspring outcomes (15).…”

“…These studies have already provided novel understandings about the causal relationships between many maternal phenotypes and birth outcomes. They have also highlighted genetic contributions to life-course associations between birth weight and late onset diseases (20,28). However, previous studies have usually examined causal effects of maternal phenotypes on either birth weight or gestational duration separately despite the strong association between them (29,30).…”

Birth weight associations with psychiatric and physical health, cognitive function, and DNA methylation differences in an adult population

“…The theory's main proponent, David Barker, originally relied on birth weight as an index of foetal nutrition -an assumption that has been contested by the awareness that multiple factors can influence birth weight [2]. Maternal stress, illness, and socioeconomic status [3][4][5] are among modifiable influences over offspring birth weight; in addition, maternal-specific genetic variation has been found to influence birth weight, acting through the intrauterine environment [6]. Thus, birth weight can be seen as an index of the general foetal experience.…”