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NAAIJEN, J., Bralten, J., Poelmans,
G., The IMAGE consortium, Glennon. J.C., Franke, B., Buitelaar, J. K.,
[incl. Oades (RDO) & Christiansen (HC)]
Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity
disorder: association to overlapping traits in ADHD and autism.
Translational
Psychiatry, 7 (1), e999 .(open
access)
Abstract
ADHD & autism spectrum disorders (ASD) often co-occur. Both are
highly heritable; -- however, it has been difficult to discover genetic
risk variants.
Glutamate & GABA are main excitatory & inhibitory neurotransmitters
in the brain; their balance is essential for proper brain development
& function.
0/ In this study we investigated the role
of glutamate and GABA genetics in ADHD severity, autism symptom severity
and inhibitory performance, based on gene set analysis, an approach
to investigate multiple genetic variants simultaneously.
-- Common variants within glutamatergic
and GABAergic genes were investigated using the MAGMA software in an
ADHD case-only sample (n=931), in which we assessed ASD symptoms and
response inhibition on a Stop task.
-- Gene set analysis for ADHD symptom severity,
divided into inattention and hyperactivity/impulsivity symptoms, autism
symptom severity and inhibition were performed using principal component
regression analyses.
-- Subsequently, gene-wide association
analyses were performed.
1/ The glutamate gene set showed an association
with severity of hyperactivity/impulsivity (P=0.009), which was robust
to correcting for genome-wide association levels.
2/ The GABA gene set showed nominally significant
association with inhibition (P=0.04), but this did not survive correction
for multiple comparisons.
3/ None of single gene or single variant
associations was significant on their own.
By analysing multiple genetic variants within candidate gene sets together,
we were able to find genetic associations supporting the involvement
of excitatory and inhibitory neurotransmitter systems in ADHD and ASD
symptom severity in ADHD
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