Abstract
BackgroundThe immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control.MethodsThis is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome.ResultsWe show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype.ConclusionsOur results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders.
Highlights
The immune system plays a fundamental role in development during pregnancy and early life
Maternal immune mediators To assess our ability to identify genetic contributions of circulating maternal immune mediators, we first analysed distributions of the log-transformed concentrations of 16 cytokines and six chemokines surveyed in mid-gestational maternal blood
We identified a total of 17 specific maternal and fetal loci contributing to one or more cytokine and chemokine status at the two different time points
Summary
The immune system plays a fundamental role in development during pregnancy and early life. A recent study [8] identified 27 specific loci associated with circulating levels of 41 cytokines/chemokines, mainly in genes that encode the proteins and/or their receptors, and that were associated with inflammatory and autoimmune diseases. Despite this strong evidence for genetic control of immune system status, no study has analysed the genetic regulation of maternal immune mediator levels during pregnancy, neonatal levels at birth, or the intersection of genetic determinants of either with chronic disorders
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