Abstract

Objective
Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination.

Methods
A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8–۹ from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD.

Results
Perinatal inflammation (β [SE], 0.263 [0.017]; P < 0.001), ADHD-PRS (β [SE], 0.116[0.042]; P = 0.006), and an interaction between the two (β [SE], 0.031[0.011]; P = 0.010) were associated with ADHD symptoms. The association between perinatal inflammation and ADHD symptoms measured by ADHD-PRS was evident only in the two higher genetic risk groups (β [SE], 0.623[0.122]; P < 0.001 for the medium-high risk group; β [SE], 0.664[0.152]; P < 0.001 for the high-risk group).

Conclusion
Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8–۹ with genetically higher risk for ADHD.

Introduction

Attention Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder in childhood. While the heritability of ADHD is reported to be as high as 75%, both genetic and environmental factors play an important role in its development (Kim et al., 2020). It has been proposed that common genetic variants have a greater impact on the development of ADHD than rare ones and a recent large-scale, genome-wide association study (GWAS) of ADHD identified several genomic regions as being associated with ADHD (Demontis et al., 2019).

Polygenic risk scores (PRS) have been developed to explain the genetic liability of individuals for certain diseases or phenotypes using common genetic variants examined in GWAS (Rai et al., 2018). So far, a positive correlation between PRS for ADHD (henceforward ADHD-PRS) and ADHD symptoms has been reported, not only in diagnosed clinical cases (Hamshere et al., 2013), but also in the general population (Martin et al., 2014).

Although several environmental factors, such as maternal psychological stress, dietary intake, and adiposity (Faraone et al., 2021), are known risk factors for ADHD, recent evidence suggests that maternal inflammation during pregnancy is also associated with ADHD symptoms in offspring (Kim et al., 2020). Gustafasson et al. showed that maternal inflammation in the 3rd trimester of pregnancy, measured in plasma concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1, also known as C–C Motif Chemokine Ligand 2, or CCL2), is a promising marker of ADHD symptoms at age 6 (Gustafsson et al., 2020). The authors further speculated that maternal inflammation elevates the risk for ADHD in children by inducing neuroinflammation in their brain (Dunn et al., 2019). However, the potential interaction of perinatal inflammation and genetic liability for ADHD has not been explored to date.

Conclusion

Inflammation in the perinatal period both directly elevated ADHD symptoms and magnified the impact of genetic vulnerability on ADHD risk particularly among children aged 8–۹ with genetically higher risk for ADHD.