Gene Predicts Outcome as Cortex Normalizes in Teens with ADHD/Doctor
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August 6, 2007
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 factors."
Shaw, Judith Rapoport M.D., and colleagues report on their magnetic
resonance imaging (MRI) study in the August 2007 Archives of General
Psychiatry.
"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.
[Time-Line graphic of brain development]
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