Impact of autism-associated genetic variants in interaction with environmental factors on ADHD comorbidities: an exploratory pilot study

Attention-deficit/hyperactivity disorder (ADHD) is determined by genetic and environmental factors, and shares genetic risk with ASD. Functional single-nucleotide polymorphisms of the metabotropic glutamatergic signaling pathway are reported to increase the risk for ASD. The aim of this pilot study was to explore the main effects of respective ASD variants as well as their interaction effects with well-replicated ADHD environmental risk factors on the risk for ADHD, ADHD symptom severities, and comorbidities. We included 318 children with ADHD, aged 5-13 years, and their parents (N = 164 trios, N = 113 duos, N = 41 singletons). Interaction of ASD risk variants CYFIP1-rs7170637, CYFIP1-rs3693, CAMK4-rs25925, and GRM1-rs6923492 with prenatal biological and lifetime psychosocial risk factors was explored in a subsample with complete environmental risk factors (N = 139 trios, N = 83 duos, two singletons) by transmission disequilibrium test and stepwise regression analyses. We identified nominally significant (alpha < 0.05) GxE interactions of acute life events with CYFIP1-rs3693 on ADHD diagnosis (p = 0.004; fdr = 0.096) but no significant association of any single marker. Further results suggest that the risk for comorbid disruptive disorders was significantly modulated by GxE interactions between familial risk factors and CAMK4-rs25925 (p = 0.001; fdr = 0.018) and prenatal alcohol exposure with CYFIP1-rs3693 (p = 0.003; fdr = 0.027); both findings survived correction for multiple testing (fdr value < 0.05). Nominal significant GxE interactions moderating the risk for anxiety disorders have also been identified, but did not pass multiple testing corrections. This pilot study suggests that common ASD variants of the glutamatergic system interact with prenatal and lifetime psychosocial risk factors influencing the risk for ADHD common comorbidities and thus warrants replication in larger samples.