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The DRD4 Gene: Psychiatry's Repeat Offender
After a chance discovery, another polymorphism in the dopamine D4 receptor gene is linked to attention deficit hyperactivity disorder
Edward R. Winstead

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The laboratory is no place to spend an evening. So Michael Jensen-Seaman sometimes prepares for routine experiments by reading genetic code at home. Sitting on his couch with a beer two years ago, he scrutinized the sequence of one of psychiatry's most studied genes—the dopamine D4 receptor, or DRD4—and made an accidental discovery. "I was just looking at the sequence when a repeat caught my eye," recalls Jensen-Seaman, then of Yale University School of Medicine. He realized he was seeing the same string of 120 letters twice.

DRD4 is one of the most variable genes, containing a relatively large number of DNA sequences that differ slightly from individual to individual. The differences are called polymorphisms, and that night Jensen-Seaman suspected he found one. The next day, a quick analysis of additional DNA samples revealed that some but not all individuals have the repeat. Jensen-Seaman and a colleague in the Yale laboratory headed by Kenneth K. Kidd found the 120/240 polymorphism in more than 30 ethnic groups worldwide. Kidd's team of researchers assembles global data on polymorphisms suspected in psychiatric and neurological disorders.

Graph of frequency of 120/240 polymorphism in world populations

The Yale group reported its discovery last December in the American Journal of Human Genetics. As they pointed out, the repeat occurs in a region of DRD4 associated with gene activity, so the 120/240 polymorphism may have a functional effect on the dopamine receptor. The brain chemical dopamine plays a role in attentiveness and activity, and research has linked polymorphisms in DRD4 to an increased risk for attention deficit hyperactivity disorder, or ADHD.

A new study—the first to focus on the 120/240 polymorphism—adds to the literature implicating the dopamine receptor in ADHD. Researchers at the University of California, Los Angeles, School of Medicine found an association between the 240-letter variant and ADHD in a population of families with two or more affected children. According to a statistical analysis of the transmission of DRD4 from parent to child, the 120/240 polymorphism may be a minor risk factor for ADHD. A paper describing the research appears in the current issue of Molecular Psychiatry.

The UCLA study actually considered two polymorphisms: the 120/240 repeat and a 48-letter sequence that repeats at varying lengths in different ethnic groups. The 48-letter polymorphism has been the focus of virtually all ADHD association studies in recent years, and those results are the reason DRD4 is generally considered to be a susceptibility gene for ADHD. The UCLA study found evidence that the 120/240 polymorphism may be more relevant to ADHD than the 48-letter polymorphism.

Graph of frequency of 48-letter polymorphism in world populations

The researchers are cautious about their results, saying that more studies of this polymorphism are needed. They don't want parents to think scientists have found the gene for ADHD. "The genetic story is likely to be quite complex," says James McCracken, who led the UCLA study. As with breast cancer, he says, many genes are likely to contribute modestly to the risk for developing ADHD. The hunt for genes is complicated by not knowing the contribution of environmental factors that influence biology and behavior.

The characteristic ADHD symptoms are inattentiveness, impulsiveness, and hyperactivity. Children tend to have one of three subtypes: the inattentive/impulsive form, the hyperactive form, or the combined form. Making a diagnosis of ADHD based on a child's behavior is not an exact science, but researchers are confident that it can be done reliably. The literature on ADHD seems to document not only the biological basis of the condition but also the fact that it runs in families.

"Children with ADHD are at the extreme of a continuum," explains Susan Smalley, an author of the UCLA study. In her view, attentiveness and activity are biological domains like IQ or height—things that normally are distributed in the population across a spectrum. Only at the extremes is any one of these a potential liability.

ADHD traits can be an asset in the working world.

Smalley adds that 'disorder' is probably not the right word. "Many of these children are extremely talented," she says. And as they grow older, some find that ADHD traits are an asset in the working world. What prevents a young boy from sitting still and concentrating in a classroom may enable him to process many things simultaneously later on in life, she says. The adult brain has more tools for managing impulsiveness and shortened attention spans, and adults tend to select environments and jobs that compensate for shortcomings.

During the nineties, researchers investigated dopamine-related genes in ADHD, schizophrenia, alcoholism, heroin addiction, and a behavioral category called novelty seeking. Most of these studies were never replicated and fell by the wayside. But by the late nineties, DRD4 was a leading gene candidate for ADHD. Interest grew as dopamine-related medications were shown to assist some children in sustaining attention to tasks that lack novelty, notes McCracken.

"It's pretty remarkable in the field of psychiatric genetics that so many studies have replicated the same finding," says James Swanson, of the University of California, Irvine, who led some of the first studies on the subject. "Usually in this field everyone finds something different."

DRD4 was ‘a gene in search of a disease’

The failed attempts to define a function for DRD4 in psychiatric and neurological conditions led some to observe that DRD4 was a 'gene in search of a disease.' "I was highly skeptical of the first DRD4 studies partly because of the methods used and the populations studied," recalls Kenneth Kidd of Yale. "But at some point one has to change one's mind. Most of the research on ADHD seems to support a role for this gene."

No one knows what that role is, however, and the relationship between dopamine and normal attention and activity is anything but clear. Researchers agree that multiple genes play a role in ADHD, but the estimates range from a half dozen to more than two dozen. And while the data seem to say that DRD4 is a susceptibility gene for ADHD, the gene has more than a dozen known polymorphisms. A single polymorphism may confer risk for ADHD, or it may do so in combination with other polymorphisms or other genes. The trouble with association studies is that there's no way to know which effects are due to what polymorphism(s).

"The bottom line is we don't know which variation leads to the dopamine receptor changing in function," says Susan Smalley of UCLA. She is scanning the genomes of individuals in the current study to identify regions that may contain additional gene candidates. The initial work is focusing on the sex chromosomes because ADHD disproportionately affects boys. "The first step is to uncover the genes and polymorphisms, figure out what they do, and then work with the environment," she says.

"We're really betting on the genome scans," says McCracken. "We hope they will lead us to spots in the genome where we'll find new—and likely surprising—risk genes for ADHD." Finding candidate regions with genome scans depends partly on the density of the genetic map. The UCLA map has 450 genetic markers, and new ones will be added over the next few years, says Smalley.

When contacted for this article, Kidd was unaware that the UCLA group had completed a study of the 120/240 polymorphism discovered that night by Michael Jensen-Seaman. In a matter of minutes, however, he had read an electronic copy of the paper in Molecular Psychiatry sent via email. "What a pleasant surprise to learn that someone's paying attention to something other than the 48-base pair variant," he says.

Jensen-Seaman, who is now at the University of Chicago, reported that chimpanzees, gorillas, and orangutans lack the 120/240 polymorphism, but the repeat is present in great apes. Because the duplication is perfect, he suspects that it occurred during relatively recent evolutionary history, perhaps in the last million years. "Mutations will occur following any duplication," he says, "and over the course of time the two copies will slowly diverge in sequence."

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McCracken, J.T. et al. Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD). Mol Psychiatry 5, 531-536 (September 2000).
Seaman, M.I. et al. Tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4). Am J Med Genet 88, 705-709 (December 1999).
Seaman, MI et al. Evolution of exon 1 of the dopamine D4 receptor gene (DRD4) in primates. J Exp Zool 288, 32-38 (April 2000).

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