Children with the 7-repeat variant had thin attention-controlling areas of the brain that normalized by age 16.

NIMH researchers report that a particular version of the dopamine D4 receptor gene increased risk for attention deficit hyperactivity disorder (ADHD) but also predicted better clinical outcomes and higher IQ than two other common versions of the same gene in youth with ADHD.

“This study provides us with a first glimpse of how variation in a specific gene influences both brain development and clinical prognosis in ADHD,” remarks NIMH Director Thomas R. Insel, M.D.

The scientists observed that brain areas that control attention were thinnest in children with ADHD who carried the 7-repeat variant. However, these areas on the right side of the brain’s outer mantle, or cortex, normalized in thickness during the teen years in this subset of children, coinciding with clinical improvement.

The 7-repeat variant accounts for about 30% of the genetic risk for ADHD, according to the researchers. It’s called the 7-repeat because it contains the same repeating sequence in its genetic code seven times.

The NIMH team scanned and determined the D4 gene types of 105 children with ADHD and 103 healthy controls and rescanned them through their teen years.

They found that nearly one-fourth of youth with ADHD and 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 areas in both ADHD and healthy subjects, it appeared to confer advantage among those with ADHD. For example, participants with ADHD who lacked at least one copy of this 7-repeat variant had significantly lower IQs. Sixty-seven subjects with ADHD had follow-up clinical evaluations after six years. More than 50% of them had pronounced ADHD symptoms when followed-up, compared to only 21% 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. 

“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,” says 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.”

In 7-repeat carriers with ADHD, the attention-controlling areas thickened to normal by age 16. Gene variants of two other dopamine system components, dopamine transporter 1 and dopamine D1 receptor genes, showed few such anatomic correlates, suggesting that the findings were specific to the D4 receptor gene.

The study is published in the August 2007 Archives of General Psychiatry.

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