Analysis of Two Polymorphisms On the Serotonin Transporter Gene and Their Interaction with Environmental Stressors During Pregnancy

Background:  

While genetics has been shown to have a strong influence in the etiology of Autism Spectrum Disorder (ASD), other factors must also contribute to this disorder. Our previous research has shown a significant increase in prenatal stress in mothers of children with ASD with a peak at weeks 21-32 of gestation. However, not all mothers that encounter stressful situations during pregnancy have children with ASD. It is possible that genetics may play a role in stress tolerance in the development of ASD. The serotonergic system holds particular interest in this regard. The serotonergic system has been implicated as a possible contributing factor to the development of ASD. Moreover, an insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, SLC6A4, has been associated with anxiety and stress reactivity, and some studies have suggested an association with ASD in carriers of the short allele. Additionally, the 3’ polyadenylation site of the serotonin transporter has been shown to have a polymorphism that has a stronger association panic disorder than the insertion/deletion polymorphism in the promoter.  

Objectives:  

Our aim is to discover which of these stress-reactive polymorphisms found on the serotonin transporter gene may interact with environmental stressors during the pregnancy to produce a higher risk for the development of ASD in the child.

Methods:  

Blood was collected from families with children diagnosed with ASD for genetic analysis. DNA was isolated using Flexigene (Qiagen, Valencia, CA) kit following manufacturer specifications. PCR was performed using previously documented protocols. Products were then analyzed via gel electrophoresis. Mothers were asked to complete several questionnaires regarding their history of stress exposure during pregnancy, and the timing of the stressors.

Results:  

Early evidence suggests that the 44 base-pair deletion in the 5-HTTLPR is the critical polymorphism interacting with environmental stressors to increase the risk for ASD in the developing child. Mothers with the 5-HTTLPR short allele have higher numbers of stressors and stressor severity during pregnancy, predominantly during the critical period of pregnancy identified in our previous work, when compared to carriers of the long allele. Furthermore, when compared to the polyadenylation polymorphism, the short allele in the 5-HTTLPR is associated with more stressors and stress severity.

Conclusions:  

This study is beginning to suggest a gene and environment interaction in the development of ASD. Our study continues to show the significance of stress during gestation in the etiology of ASD particularly during weeks 21-32. More importantly, this evidence further identifies a specific potential gene that appears to interact with prenatal stress exposure in association with this risk. While the polyadenylation site is linked with panic disorders it does not appear to be interacting with environmental stressors to increase the risk for ASD in the child. Further analysis needs to be conducted to completely understand this gene and environment interaction.