|Gene Predicts Better Outcome as Cortex Normalizes
in Teens with ADHD
Brain areas that control attention were thinnest in children with
attention deficit hyperactivity disorder (ADHD) (http://www.nimh.nih.gov/healthinformation/adhdmenu.cfm)
who carried a particular version of a gene in a study by the National
Institutes of Health’s (NIH) National Institute of Mental Health
(NIMH). However, the areas, on the right side of the brain’s outer
mantle, or cortex, normalized in thickness during the teen years
in these children, coinciding with clinical improvement. Although
this particular gene version increased risk for ADHD, it also predicted
better clinical outcomes and higher IQ than two other common versions
of the same gene in youth with ADHD.
“Since this gene version had similar structural effects in healthy
children as in children with the disorder, our findings suggest
that ADHD is at the far end of a continuum of normal traits,” said
Philip Shaw, M.D., NIMH Child Psychiatry Branch, who led the research. “ADHD
likely stems from interactions between several such genes and non-genetic
Shaw, Judith Rapoport M.D., and colleagues report on their magnetic
resonance imaging (MRI) study in the August 2007 Archives of
“This study provides us with a first glimpse of how variation
in a specific gene influences both brain development and clinical
prognosis in ADHD,” said NIMH Director Thomas R. Insel, M.D.
When the NIMH researchers first reported (http://www.nimh.nih.gov/press/adhdmirror.cfm)
last year that normalization of right cortex thickening was associated
with better clinical outcomes in ADHD, there were few hints of
a genetic connection. Yet evidence from several previous studies
led them to suspect involvement of an ADHD-implicated version of
a gene that codes for a receptor protein that binds to the brain
chemical messenger dopamine.
This version of the dopamine D4 receptor gene, called the 7-repeat
variant, accounts for about 30 percent of the genetic risk for
ADHD, making it by far the strongest candidate gene implicated
in the disorder. It’s called the 7-repeat because it contains the
same repeating sequence in its genetic code seven times. Everyone
inherits two copies of the D4 receptor gene, one from each parent,
so some people have two copies of the same version while others
may carry two different versions.
For the current study, the researchers scanned and determined
the D4 gene types of 105 children with ADHD and 103 healthy controls
and re-scanned them through their teen years.
They found that nearly one-fourth of youth with ADHD and in about
one-sixth of the healthy controls had at least one copy of the
7-repeat version. Nearly two thirds of the ADHD youth and three-fourths
of the healthy controls had the most common 4-repeat version; fewer
than one-tenth in each group had a 2-repeat version.
While the 7-repeat version was linked to thinner attention-controlling
cortex in both ADHD and healthy subjects, it appeared to confer
advantage only among youth with ADHD. For example, participants
with ADHD who lacked at least one copy of this 7-repeat variant
had significantly lower IQs, and more than half of them still had
pronounced ADHD symptoms when followed-up about six years later,
compared to only 21 percent of those with at least one copy of
the 7-repeat variant. There was also a trend toward better overall
functioning among those with at least one copy of the 7-repeat
variant at follow-up.
The MRI scans revealed that 7-repeat carriers with ADHD started
out with the thinnest cortex areas important for controlling attention
(right orbitofrontal and posterior parieto-occipital). The next
thinnest were children with ADHD who did not have the 7-repeat
version, followed by healthy children with the 7-repeat. Healthy
children lacking the 7-repeat had the thickest cortex, but this
did not appear to affect their IQ. However, the researchers note
that other studies have found correlations between cortex thickness
and certain measures of memory and intelligence.
In 7-repeat carriers with ADHD, the attention-controlling areas
thickened to normal by age 16 (see time-lapse image below). Gene
variants of two other dopamine system components showed few such
anatomic correlates, confirming that the findings were specific
to the D4 receptor gene.
“Some genes have a good side, even though they’re linked to disorder,” said
Shaw, who noted that other traits linked to the 7-repeat version,
such as novelty seeking and impulsiveness, might confer advantage
in some settings. “Evidence suggests that the 7-repeat may be a
relatively new variant that may have been favored through evolution
because such traits proved adaptive for survival.”
The researchers are following up with studies on the relationship
between cortex thickness and cognitive features of ADHD, such as
working memory and the ability to inhibit responses.
Also participating in the research were: Jay Giedd, Michele Gornick,
Jason Lerch, Anjene Addington, Jeffrey Seal, Deanna Greenstein,
Wendy Sharp, NIMH; Alan Evans, McGill University; F. Xavier Castellanos,
New York University.
Children with ADHD who had the 7-repeat version of the dopamine
D4 receptor gene had thinner-than-normal areas in their brain’s
out mantle, the cerebral cortex, which normalized during the
teen years. This thickening in areas that control attention paralleled
clinical improvement. Composite 3-D MRI scan data for youth,
ages 8-16. Colored areas are those in which cortex thickness
varied between ADHD patients and healthy controls, with brighter
colors indicating greater differences. Source: Philip Shaw,
M.D., NIMH Child Psychiatry Branch
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the burden of mental and behavioral disorders through research
on mind, brain, and behavior. More information is available at
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