Maternal and Fetal Genetic Control of Mid-Gestational and Neonatal Levels of Markers of Immune Function
The immune system plays an important role in neurodevelopment, and increasing evidence suggests a link between immune system dysregulation and autism spectrum disorder (ASD). Animal models show that maternal immune activation during gestation impacts fetal brain development and subsequent behavior, potentially driven by alterations in levels of cytokines and chemokines which serve as Soluble Immune Mediators (SIMs). We therefore aimed to assess whether levels of SIMs during pregnancy or at birth might be determined by maternal and/or fetal genetics, and thus influence ASD risk beyond the presence of infection.
To determine whether maternal and neonatal immune markers are regulated by genetics in addition to environmental immune stimulation.
We utilized a multi-ethnic genotyped population-based nested case-control study of 790 women and 764 of their newborns (390 ASD cases, 400 controls) in the EMA (Early Markers of Autism) study (Croen, Autism Res 2008; Tsang, PLoS ONE 2013). Mid-gestational levels of 22 SIMs were measured in maternal serum, and 42 in neonatal bloodspots. We first estimated the maternal and neonatal genome-wide SNP-based heritability (h2g) for each SIM and then performed GWAS using linear regression to identify specific loci contributing to individual SIMs. Finally, we assessed the relationship between genetic SIM determinants and ASD outcome.
Levels of two maternal SIMs showed > 80% maternal heritability (P<0.05, each) and the levels of 4 separate neonatal SIMs showed > 50% neonatal heritability in a SNP-based model (Yang, Nat Genet 2010) adjusted for genetic ancestry, maternal sociodemographic confounding factors as well as offspring affection status. Genome-wide association revealed 19 independent loci associated with 27 SIMs (P<5x10-8): 3 maternal alleles were associated with maternal SIMs, 3 maternal alleles were associated with neonatal SIMs, 1 neonatal allele was associated with maternal sIL2Ra, and 12 neonatal alleles were associated with neonatal SIMs. Thus, not only can maternal genetics influence immune markers during pregnancy and in her infant, but fetal genetics can influence maternal immune markers mid-gestation as well as neonatal immune markers immediately after birth. The specific genetic loci highlight the pleiotropic contribution of a neonatal locus mapping to PLCL2, (Pmin=8x10-21), previously associated with autoimmune diseases. Maternal CCL2 and maternal and neonatal IL-8 were nominally associated with offspring affection status (P<0.05, each). Of these, neonatal IL-8 showed a suggestively associated locus that interacts with ASD status and maps to chromosome 2 (with no nearby genes) (rs55823040; P=4x10-7). Thus, association between neonatal IL-8 levels and ASD outcome appears only within one genotype class at this IL-8 associated SNP.
Our results demonstrate strong mutual contribution of both maternal and neonatal genetics to maternal and neonatal SIMs, however further research is required to elucidate roles in the development of ASD.