Abstract
Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.
Highlights
Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition characterized by symptoms of inattention, impulsivity, and hyperactivity (American Psychiatric Association, 2013)
Interaction Between expressionbased polygenic risk score (ePRS)-5-HTT in the Amygdala and Postnatal Adversity Score Moderates the Behavior in Children In MAVAN children, we found a significant effect of interaction between the adversity score and the amygdala-based ePRS-5-HTT on domains of the Child Behavior Checklist (CBCL) related to attentional problems and hyperactivity: ADHD Problems at 48 months (β = –71.19, p = 0.0009) and 60 months
We demonstrated that the expression-based polygenic risk score reflecting the function of an amygdala 5-HTT gene network interacts with postnatal adversity exposure, influencing attention and hyperactivity problems in different cohorts and different ages
Summary
Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition characterized by symptoms of inattention, impulsivity, and hyperactivity (American Psychiatric Association, 2013). The 5-HTT gene, known as SLC6A4, is localized in the long arm of chromosome 17 This gene encodes an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons, and represents a primary mechanism for the regulation of serotonergic activity (Heils et al, 2002). Genetic variation in SLC6A4 associates with individual differences in DNA methylation, a functional epigenetic modification of DNA, and SLC6A4 gene expression. Such genetic effects on DNA methylation emerged as a function of exposure to adversity early in life (Beach et al, 2010; Vijayendran et al, 2012); highlighting the importance of the interplay between the genome and the environment in the regulation of SLC6A4 gene expression
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