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New Attention to ADHD Genes

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Science  11 Jul 2003:
Vol. 301, Issue 5630, pp. 160-161
DOI: 10.1126/science.301.5630.160

Researchers are trying to tease apart the genetic and environmental contributions to childhood's most common mental disorder

“Passionate, deviant, spiteful, and lacking inhibitory volition.” That's how one pediatrician, George Frederick Still, described children with symptoms of attention deficit hyperactivity disorder (ADHD). The year was 1902, and Still puzzled over his young patients in The Lancet. What was their disorder, exactly—and what caused it?

A century later, scientists would still like to know. As skyrocketing numbers of children are diagnosed with ADHD and prescribed drugs, researchers are falling under increasing pressure to explain the disorder (Science, 14 March, p. 1646). Is ADHD the result of faulty brain wiring? Which genes are to blame? And how much does environment matter? Emerging studies, harnessing genome scans and other high-tech tools, promise new insights. But as Judith Rapoport, chief of child psychiatry at the National Institute of Mental Health (NIMH) puts it, “there's been no home run yet.”

Like any complex disorder, ADHD is a one-two punch of susceptibility genes and environmental risks. Together they cause severe inattention, hyperactivity, or both, says clinical psychologist Stephen Faraone of Harvard University. “My hope is that once we've discovered those genes, we'll be able to do a prospective study of kids at high versus low genetic risk,” Faraone says. “That's when you'll see environmental factors at work.” Eventually, he adds, environmental changes could play an important role in treating some ADHD patients.

In the family

Since the 1800s, doctors have labeled some children as overwhelmingly distracted or fidgety. Depending on the diagnosis of the day, they suffered from “childhood hyperactivity,” “hyperkinetic syndrome,” or “minimal brain dysfunction.”

In the 1980s, the American Psychiatric Association defined ADHD in the Diagnostic and Statistical Manual of Mental Disorders (DSM) for the first time. According to the current, revised DSM definition, a person with ADHD has been severely inattentive (forgetful, careless, distracted, etc.) or hyperactive/impulsive (restless, impatient, aggressive, etc.) for at least 6 months. To qualify as ADHD, those symptoms must emerge before 7 years of age, be maladaptive and inconsistent with developmental level, and impair social or work routines in at least two settings, usually home and school.

According to NIMH, ADHD is the most commonly diagnosed mental disorder in childhood, estimated to affect 3% to 5% of school-age children. The proportion of children diagnosed with ADHD has risen steadily over the past 15 years, but researchers argue over whether this represents a real increase, overdiagnosis, or better recognition of ADHD after years of underdiagnosing the condition.

Skeptics still question whether ADHD is an authentic disorder and not simply a pathological label for normal, if exasperating, childhood behavior. But most scientists who study the condition are convinced. Over the past decade, more than 10 studies of twins in far-flung locations have suggested that ADHD has a strong genetic component. Heritability for ADHD—meaning that if one identical twin has it, the other will, too—ranges from 65% to 90%, comparable to schizophrenia and bipolar disorder, Faraone says.

In fact, researchers know more about ADHD genes than those behind several other complex behavioral disorders, such as Tourette's syndrome, asserts molecular geneticist Cathy Barr of Toronto Western Hospital. “We've made good progress, replicating studies on several genes,” Barr says. “At the very least, this new research contributes to the idea that ADHD is biologically based—that there's something here.”

That “something” likely includes the neurotransmitter dopamine. Paradoxically, stimulants, including methylphenidate (Ritalin), calm rather than excite children with ADHD. Researchers have long suspected that such drugs work by indirectly regulating dopamine levels in the brain. Based on that hunch, they are hunting genes that affect dopamine communication, notably a receptor (DRD4), a transporter (DAT), and a protein called synaptosomal-associated protein 25 (SNAP-25) that helps trigger the release of neurotransmitters from nerve cells. Genetic linkage studies of each gene have associated variants with ADHD symptoms. But more research is needed to explain the underlying biochemistry.

Some researchers even suggest that ADHD may be too much of a good thing. Last year in the Proceedings of the National Academy of Sciences, for instance, Robert Moyzis of the University of California, Irvine, and his colleagues reported that one variety of the DRD4 gene associated with ADHD—the so-called seven-repeat allele, or DRD4 7R—appears to have been selected for in human evolution, suggesting that it supported an adaptive trait.

“Kids with this gene version may have inherited faster reaction times or different attention spans, and now we're calling this a disorder,” Moyzis says. “Maybe all you need to do is steer those kids into a different educational situation.”

Scanning scores.

Researchers led by Susan Smalley of UCLA are scanning whole genomes for ADHD genes. One such gene may lie on chromosome 16, roughly 20 to 30 centimorgans from the tip of the chromosome's short arm. Here, three curves represent samples of sibling pairs with ADHD, with the strongest genetic linkage (shown by high peaks) in this chromosomal region. The banded chromosome 16 picture (bottom) shows the possible ADHD risk gene, illustrated by the black band near region 16p13.

CREDIT: S. SMALLEY/UCLA

One thing seems clear: No matter how these purported ADHD genes affect dopamine, they cannot cause the disorder by themselves. So far, scientists estimate that each gene confers a very low added risk—roughly 1% to 3%—of developing ADHD. How are other neurotransmitters involved? Some scientists are investigating genes that regulate norepinephrine and nicotine levels in the brain. At Washington University in St. Louis, Missouri, for instance, molecular geneticist Richard Todd and his colleagues report that twins with ADHD often share a form of nicotinic acetylcholine receptor alpha 4, although the link is preliminary.

Scanning the future

Meanwhile, a few researchers are betting that critical ADHD genes, contributing far greater risk, remain undiscovered. They've begun using genome scans to randomly hunt for these susceptibility genes. Genome scans compare hundreds of known DNA markers between two siblings sharing the disorder. Any DNA regions with unusually high (more than 50%) similarity between those siblings may contain risk genes.

Susan Smalley, a geneticist at the University of California, Los Angeles, recently led the first genome scans of siblings sharing ADHD. “We're operating on the idea that a couple of genes may add 10% to 25% of ADHD risk,” Smalley says. In the May issue of the American Journal of Human Genetics, Smalley's group described scanning the genomes of 270 sibling pairs with ADHD. They found hints of ADHD genes on chromosomes 5, 6, 16, and 17.

“What's intriguing is that several of these gene regions overlap with those implicated in autism and dyslexia,” Smalley says. She suspects that these disorders may share a neurological glitch that disrupts the brain's “executive function” system—neural networks that govern tasks such as problem-solving, planning, and attention. Faraone calls the study a “very impressive” step toward isolating promising genes.

In the same journal issue, medical geneticist Richard Sinke of the University Medical Center in Utrecht, the Netherlands, and colleagues reported an ADHD genome scan with fewer children. It mostly highlighted different chromosomal regions but overlapped with the site that Smalley's team found on chromosome 5. Now the two teams are analyzing their data together.

Environmental risks, researchers predict, will be even harder to pin down than genes contributing to ADHD. They've begun linking ADHD symptoms to lifestyle factors, from maternal smoking during pregnancy to chronic family conflict. But because such adversities boost the risk of many disorders, the links are hard to interpret.

Still, genes promise an analytical starting point. In the next 10 years, Faraone and others hope to use genetic tests to identify preschoolers at high or low risk of ADHD. Tracking both sets of children, they could look for specific environmental factors that trigger ADHD symptoms. “How do genes work in different environments?” muses Smalley. “How do genes lead to impairment? That's the next step.”

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