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Abstract:
The DIRAS2 gene is coding for a small Ras GTPase with so far unknown
function. In a previous study, we described the association of DIRAS2
rs1412005, as well as a haplotype containing this polymorphism and
located in the promoter region of this gene with
attentiondeficit/hyperactivity disorder (ADHD). In the present study, we
searched for rare variants within or near the DIRAS2 gene that might be
associated with ADHD using next-generation sequencing. As we were not
able to detect any rare variants associated with the disease, we sought
to establish a functional role of DIRAS2 rs1412005 on the molecular or
systems level. First, we investigated whether it has an influence on
gene expression by means of a luciferase-based promoter assay. We could
demonstrate that the minor risk allele goes along with the increased
expression of the reporter gene. Next, we aimed to identify differences
in response inhibition between risk-allele and non-risk allele carriers
in children suffering from ADHD and healthy control individuals by
analyzing event-related potentials in the electroencephalogram during a
Go/NoGo task. Risk-allele carriers showed a changed NoGo
anteriorization. Therefore, our results suggest an impact of the
investigated polymorphism on the prefrontal response control in children
with ADHD. These results imply that the promoter polymorphism is indeed
the associated as well as in itself a causal variant. Further research
is thus warranted to clarify the mechanisms linking DIRAS2 to ADHD.
