Early Life Adversity and Polygenic Risk for High Fasting Insulin Are Associated With Childhood Impulsivity

Abstract

While the co-morbidity between metabolic and psychiatric behaviors is well-established, the mechanisms are poorly understood, and exposure to early life adversity (ELA) is a common developmental risk factor. ELA is associated with altered insulin sensitivity and poor behavioral inhibition throughout life, which seems to contribute to the development of metabolic and psychiatric disturbances in the long term. We hypothesize that a genetic background associated with higher fasting insulin interacts with ELA to influence the development of executive functions (e.g., impulsivity in young children). We calculated the polygenic risk scores (PRSs) from the genome-wide association study (GWAS) of fasting insulin at different thresholds and identified the subset of single nucleotide polymorphisms (SNPs) that best predicted peripheral insulin levels in children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort [N = 467; pt– initial = 0.24 (10,296 SNPs), pt– refined = 0.05 (57 SNPs)]. We then calculated the refined PRS (rPRS) for fasting insulin at this specific threshold in the children from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) cohort and investigated its interaction effect with adversity on an impulsivity task applied at 36 months. We found a significant effect of interaction between fasting insulin rPRS and adversity exposure predicting impulsivity measured by the Snack Delay Task at 36 months [β = −0.329, p = 0.024], such that higher PRS [β = −0.551, p = 0.009] was linked to more impulsivity in individuals exposed to more adversity. Enrichment analysis (MetaCoreTM) of the SNPs that compose the fasting insulin rPRS at this threshold was significant for certain nervous system development processes including dopamine D2 receptor signaling. Additional enrichment analysis (FUMA) of the genes mapped from the SNPs in the fasting insulin rPRS showed enrichment with the accelerated cognitive decline GWAS. Therefore, the genetic background associated with risk for adult higher fasting insulin moderates the impact of early adversity on childhood impulsivity.

Early adversity and insulin: neuroendocrine programming beyond glucocorticoids

“…Dated candidate gene approaches have suggested that serotonin-related polymorphisms interact with early adversity modifying the risk for stress-related psychopathology [45]. A recent study [89] filtered the genetic markers identified in a genomewide association study (GWAS) for adult high fasting insulin levels by selecting those most highly associated with peripheral insulin levels in children, to calculate a polygenic risk score (PRS). This fasting insulin PRS interacted with early life adversity and predicted childhood impulsivity at 3 years of age in an independent cohort.…”

“…This fasting insulin PRS interacted with early life adversity and predicted childhood impulsivity at 3 years of age in an independent cohort. Interestingly, the markers composing the high fasting insulin PRS are mapped into genes associated with DA D2 receptor signaling, suggesting that individual variations in insulin function are related to differential effects of childhood adversity on executive functions, via DA-related mechanisms [89]. Finally, high fasting insulin genetic markers that predict childhood impulsivity in response to adversity were also significantly enriched in the accelerated cognitive decline GWAS, which may suggest that these genes are also important for long-term effects on cognition [89].…”

“…Interestingly, the markers composing the high fasting insulin PRS are mapped into genes associated with DA D2 receptor signaling, suggesting that individual variations in insulin function are related to differential effects of childhood adversity on executive functions, via DA-related mechanisms [89]. Finally, high fasting insulin genetic markers that predict childhood impulsivity in response to adversity were also significantly enriched in the accelerated cognitive decline GWAS, which may suggest that these genes are also important for long-term effects on cognition [89]. This study is an example of novel functional genomics investigations, which carry the promise to illuminate these relationships from a genome-wide perspective [84,90] (Figure 2, Key figure).…”

Novel Functional Genomics Approaches Bridging Neuroscience and Psychiatry

“…One of the biggest challenges faced by researchers studying models of disease risk prediction is to develop a methodology to accurately represent an individual’s environment in a quantitative metric. Similar to how a functional PRS can represent a restricted set of phenotype-relevant biological processes, some studies have narrowed down the environment variable to a composite score made up of clearly defined constructs [see ( 48 , 49 , 85 , 86 , 88 , 89 , 91 ) for examples]. By doing so, researchers can start investigating the interplay between genes and environments while also assessing the potential ways in which genetic and environmental effects interact ( Figure 2D ).…”

“…Essentially, SNPs with p values below an established threshold will keep the original estimate of their effect size, while SNPs with higher p values are excluded from the PRS, shrinking their effect sizes to 0. This process can be carried out iteratively, using a range of p- value thresholds, with the resulting PRSs tested for an association with the target trait in a test sample, determining the optimal p value in a forward selection method ( 48 , 49 ). Other methods for PRS calculation are based on Bayesian frameworks in which the shrinkage of all SNPs is based on a prior distribution specification [for more details, see ( 50 , 51 )].…”