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5-HTT Network and Postnatal Adversity 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.

Background: Previous studies focused on the relationship between prenatal conditions and neurodevelopmental outcomes later in life, but few have explored the interplay between gene co-expression networks and prenatal adversity conditions on cognitive development trajectories and gray matter density.Methods: We analyzed the moderation effects of an expression polygenic score (ePRS) for the Brain-derived Neurotrophic Factor gene network (BDNF ePRS) on the association between prenatal adversity and child cognitive development. A score based on genes co-expressed with the prefrontal cortex (PFC) BDNF was created, using the effect size of the association between the individual single nucleotide polymorphisms (SNP) and the BDNF expression in the PFC. Cognitive development trajectories of 157 young children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort were assessed longitudinally in 4-time points (6, 12, 18, and 36 months) using the Bayley-II mental scales.Results: Linear mixed-effects modeling indicated that BDNF ePRS moderates the effects of prenatal adversity on cognitive growth. In children with high BDNF ePRS, higher prenatal adversity was associated with slower cognitive development in comparison with those exposed to lower prenatal adversity. Parallel-Independent Component Analysis (pICA) suggested that associations of expression-based SNPs and gray matter density significantly differed between low and high prenatal adversity groups. The brain IC included areas involved in visual association processes (Brodmann area 19 and 18), reallocation of attention, and integration of information across the supramodal cortex (Brodmann area 10).Conclusion: Cognitive development trajectories and brain gray matter seem to be influenced by the interplay of prenatal environmental conditions and the expression of an important BDNF gene network that guides the growth and plasticity of neurons and synapses.

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Psychiatric and cardio-metabolic conditions are commonly comorbid, being a leading cause of disability. Early adversity is a risk factor for both conditions, however, biological pathways remain unknown. The dopamine (DA) system is sensitive to early adversity and influences the development of comorbidities. We hypothesized that early life adversity would functionally link these conditions with the mesocorticolimbic dopamine system as a critical moderator pathway. We computed a co-expression based polygenic score (ePRS) reflecting variations in the function of the dopamine transporter (DAT) gene network in the prefrontal cortex and striatum, the final targets of the mesocorticolimbic pathway. We explored the interaction effects of the ePRS with a score of early life adversity on presence of psychiatric and cardio-metabolic comorbidities in adults (UK Biobank, N= 60016) and adolescents (ALSPAC, N= 910). In adults we also explored genetic and environment effects on gray matter density variations. As predicted, the mesocorticolimbic DAT1 ePRS significantly moderated the impact of early life adversity on the risk for both psychiatric (schizophrenia, neuroticism, mood and substance use disorders) and cardio-metabolic (type 2 diabetes, atherosclerosis, cardiovascular disease) comorbidities in adults and adolescents. Brain gray matter densities in the insula and prefrontal cortex were significantly associated with SNPs from the DAT1 ePRS implicating these regions as critical dopaminergic targets for psychiatric/cardio-metabolic comorbidities. These results reveal that psychiatric and cardio-metabolic comorbidities share common developmental pathways and underlying biological mechanisms.