Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression

Abstract

While many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology.

Early environmental influences on the development of children's brain structure and function

“…38 Serotonin is known to affect the development of brain pathways and networks 44 and, as mentioned previously, childhood trauma dysregulates serotonin neurotransmission. 45 We showed that the serotonin transporter gene expression-based polygenic score significantly interacts with a cumulative prenatal adversity score on measures of childhood cognitive-emotional problems, suggesting again that serotonin function is involved in the long-term effects of prenatal adversity on child socioemotional outcomes. 45 We showed that the serotonin transporter gene expression-based polygenic score significantly interacts with a cumulative prenatal adversity score on measures of childhood cognitive-emotional problems, suggesting again that serotonin function is involved in the long-term effects of prenatal adversity on child socioemotional outcomes.…”

“…21 We recently created a hippocampal-specific, expression-based polygenic score reflecting variations in the function of the serotonin transporter gene network, using a novel process for genome profiling. 45 We showed that the serotonin transporter gene expression-based polygenic score significantly interacts with a cumulative prenatal adversity score on measures of childhood cognitive-emotional problems, suggesting again that serotonin function is involved in the long-term effects of prenatal adversity on child socioemotional outcomes. 45…”

“…45 We showed that the serotonin transporter gene expression-based polygenic score significantly interacts with a cumulative prenatal adversity score on measures of childhood cognitive-emotional problems, suggesting again that serotonin function is involved in the long-term effects of prenatal adversity on child socioemotional outcomes. 45…”

“…21 We recently created a hippocampal-specific, expression-based polygenic score reflecting variations in the function of the serotonin transporter gene network, using a novel process for genome profiling. 45 45 …”

Polygenic differential susceptibility to prenatal adversity

“…Recently in this journal, Silveira et al (2017) sought to determine whether, in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort, prenatal adversity, operationalized using a composite measure of multiple indicators (e.g., maternal health during pregnancy, socioeconomic status), interacted with a biologically informed polygenic index, based on genes coexpressed with the serotonin transporter gene in the hippocampus, in predicting a diverse set of neurodevelopmental outcomes measured at 48 and 60 months. Importantly, functional polymorphisms in the promoter region of the SLC6A4 gene moderate the influence of stressful life events and of positive environmental exposures on the development of and resilience to psychopathology at different ages (Bukh et al, 2009;Caspi et al, 2003;Eley et al, 2004;Kendler, Kuhn, Vittum, Prescott, & Riley, 2005).…”