Increasing specificity in ADHD genetic association studies during childhood: use of the oxytocin-vasopressin pathway in attentional processes suggests specific mechanism for endophenotypes in the 2004 Pelotas birth (Brazil) cohort.

Abstract

Attentional executive functions, representing a set of self-regulatory cognitive skills, can be a potential Attention-Deficit/Hyperactivity Disorder (ADHD) endophenotype useful for exploring the huge heterogeneity associated to the disorder. Specific biological pathways like the oxytocin-vasopressin pathway (OT-AVP) can unreel ADHD polygenicity. Here, we test the association between genome-wide ADHD polygenic score (PGS) (ADHD-PGS) and both ADHD symptoms and attentional executive functions in the participants of the 2004 Pelotas (Brazil) birth cohort study (N = 4231). We also investigated whether the OT-AVP genomic pathway (OT/AVP_ADHD-PGS) is involved in the etiology of ADHD and whether it influences the specificity of attentional functions. ADHD symptoms were assessed through the Strength and Difficulties Questionnaire (SDQ) and the attentional executive functions were evaluated by the Test-of-Everyday-Attention-for-Children (TEA-Ch) at 11 years follow-up. The ADHD-PGS and OT/AVP_ADHD-PGS were constructed based on the most recent ADHD GWAS meta-analytic statistics. The OT/AVP_ADHD-PGS included only functional relevant genes for the pathway using KEGG repository. ADHD-PGS was associated with ADHD symptoms and attentional control/switching domain. OT/AVP_ADHD-PGS showed an enrichment for selective attention domain [number of targets (β = - 0.09, 95% CI = - 0.17; - 0.02, competitive-P = 0.025); attention score (β = 0.11, 95% CI = 0.001; 0.23, competitive-P = 0.050), and in attentional control/switching domain [verbal processing speed (β = 0.27, 95% CI = 0.05; 0.50, competitive-P = 0.041); attentional control (β = 0.42, 95% CI = 0.12; 0.73, competitive-P = 0.033). Our results show a specific role of the OT/AVP pathway in attentional executive functions and suggest that increasing both phenotypic and genetic specificity is of great value. These findings have clinical relevance since OT/AVP have a role in attention toward social cues and shared attentions, which are impaired in children with ADHD.