microRNAs and Gene–Environment Interactions in Autism: Effects of Prenatal Maternal Stress and the SERT Gene on Maternal microRNA Expression

Abstract

Background: Genetics and environment both are critical in autism spectrum disorder (ASD), but their interaction (G × E) is less understood. Numerous studies have shown higher incidence of stress exposures during pregnancies with children later diagnosed with ASD. However, many stress-exposed mothers have unaffected children. The serotonin transporter (SERT) gene affects stress reactivity. Two independent samples have shown that the association between maternal stress exposure and ASD is greatest with maternal presence of the SERT short (S)-allele (deletion in the promoter region). MicroRNAs play a regulatory role in the serotonergic pathway and in prenatal stress and are therefore potential mechanistic targets in this setting.Design/methods: We profiled microRNA expression in blood from mothers of children with ASD, with known stress exposure during pregnancy. Samples were divided into groups based on SERT genotypes (LL/LS/SS) and prenatal stress level (high/low).Results: Two thousand five hundred mature microRNAs were examined. The ANOVA analysis showed differential expression (DE) of 119 microRNAs; 90 were DE in high- vs. low-stress groups (stress-dependent). Two (miR-1224-5p, miR-331-3p) were recently reported by our group to exhibit stress-dependent expression in rodent brain samples from embryos exposed to prenatal stress. Another, miR-145-5p, is associated with maternal stress. Across SERT genotypes, with high stress exposure, 20 significantly DE microRNAs were detected, five were stress-dependent. These microRNAs may be candidates for stress × SERT genotype interactions. This is remarkable as these changes were from mothers several years after stress-exposed pregnancies.Conclusions: Our study provides evidence for epigenetic alterations in relation to a G × E model (prenatal maternal stress × SERT gene) in ASD.

Prenatal maternal stress and the severity of autism spectrum disorder: A cross‐sectional study

“…However, this meta‐analysis did not evaluate the relationship between stressors and ASD severity. Moreover, epigenetics, specific maternal polymorphisms and gene‐environmental interaction might have a role in provoking the effect of stressors, leading to a child with ASD (Beversdorf et al., 2021; Hecht et al., 2016; Jones et al., 2010; Sandin et al., 2017; Sjaarda et al., 2017).…”

The Relationship between Maternal Antibodies to Fetal Brain and Prenatal Stress Exposure in Autism Spectrum Disorder

“…As described above, previous studies have found prenatal stress to affect behavioral and neurodevelopmental outcomes in humans, including ASD diagnosis [ 11 ]. Additionally, past research has revealed that susceptibility to stress (via SLC6A4, specifically the 5-HTTLPR region) interacts with prenatal stress, shows an increased risk of ASD [ 22 ], and is associated with a distinct miRNA profile [ 48 ]. Other G × E interactions with stress have been observed in a range of neuropsychiatric conditions [ 5 ].…”

“…Additionally, future studies should investigate the different genotypes associated with stress reactivity and maternal autoantibodies to determine if the interaction between prenatal stress and maternal autoantibodies is different for different stress-associated genes. While the sample size was small, previous studies of a similar size revealed miRNA results associated with prenatal stress in ASD [ 48 ]. However, the small sample size limits the conclusions that can be drawn from these findings.…”

“…For prenatal stress, groups were broken into high (3+ stressors) and low (2 > stressors) prenatal stress. This approach to categorizing stress exposure has been successful in previous work demonstrating the miRNA profiles of prenatal stress exposure in ASD [ 48 ]. For the presence of maternal autoantibodies, groups were divided into the presence or absence of specific sets of antibodies previously found to be associated with ASD in approximately 20% of cases [ 11 ].…”

Analysis of Gene-Environment Interactions Related to Developmental Disorders

“…For example, lncRNA is involved in the toxic response to dioxins, such as jaw malformation and pericardiac edema, by downregulating the expression of sox9b ( Mathew et al, 2008 ; Xiong et al, 2008 ; Garcia et al, 2018 ). The roles of non-coding RNA in G E associated with ASD have been actively studied ( Beversdorf et al, 2021 ; Cui et al, 2021 ).…”