Bioinformatics Research Laboratory, IBI Biosolutions Pvt. Ltd. India

The DRD4 Gene

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.

Gene: DRD4

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.

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Facts Related To DRD4 Gene

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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Am I genetically predisposed to being a smoker?

Genes can definitely influence whether someone will become a smoker. They aren’t the whole story, but they can make someone more likely to start and keep smoking.

How? To get at this question, let’s split up becoming a smoker into two parts—taking a risk and becoming addicted. This obviously isn’t the whole story but it will give some idea about how genes can impact a behavior like smoking.

As almost everyone knows, smoking is a huge health risk. If you decide to smoke anyway, you are definitely a risk taker.

Being a risk taker has been linked to a certain DNA change in the DRD4 (Dopamine Receptor D4) gene. The idea is that if you have this mutation, you will do riskier things. Like maybe taking up smoking.

How did scientists stumble across this risk taking gene? The first hint was some earlier studies that linked risk taking to a brain chemical called dopamine. As its name implies, the DRD4 gene is involved with dopamine.

The other hint came from the fact that the DRD4 gene comes in so many different versions. The idea was that each version corresponded to a certain level of risk taking. Enough different versions and you can end up with accountants and stuntmen, people with 30 year fixed and ARM mortgages, hang gliders and chess players.

The researchers studied two common versions of DRD4—one that has a 4 repeat and one that has a 7 repeat*. What they found was that people with 7 repeats scored higher on the standard test for risk taking, the TPQ Novelty Seeking scale, than did those with 4 repeats. So, maybe if you have 7 repeats in your DRD4 gene you’ll be more likely to take the risk of becoming a smoker. Before running out and trying to get tested, it should be noted that this finding has been a tough one to prove.

Lots of other groups have tried to replicate the results with limited success. Some have been able to show the same thing, others haven’t. As you can imagine, something like risk taking can be hard to pin down. Most likely there are many genes involved in establishing someone’s level of risk taking. Not to mention other influences like where you grew up, what your family did on the weekends, etc. But still, genes are probably involved in risk taking. While the involvement of genes in risk taking is murky, their role in addiction is not. How quickly you become addicted to smoking can obviously influence whether or not you keep smoking.

Once you’ve taken the risk and picked up a cigarette, how hard is it for you to not pick up a second. Or a third. Or… When people are addicted to smoking, we usually think of them as being addicted to nicotine. And nicotine works by causing dopamine, that same brain chemical we talked about earlier, to be released in the brain.

Dopamine is involved in feelings of pleasure. Whenever someone takes a puff of a cigarette, the nicotine stimulates the brain to make dopamine. And it feels good. The feelings of pleasure quickly wear off though. So, the smoker needs to take another puff. And another. And another.

One of the reasons the effects of nicotine wear off so quickly is because of a gene called CYP2A6. The CYP2A6 gene is involved in ridding our body of nicotine. There are some versions of the CYP2A6 gene that don’t work, though. People with these defective copies of CYP2A6 break down nicotine more slowly than people with working copies. And these people are less likely to become addicted to nicotine. Why getting more bang for the buck would make someone less likely to become addicted isn’t obvious, though. Maybe the dizziness and nausea that happen when you smoke your first cigarette lasts longer for these people. And because of this, they don’t stick with it long enough to become addicted. These folks also suffer less from the harmful side effects of nicotine because they need fewer puffs to keep their dopamine high. Fewer cigarettes mean a lower risk for cancer.

OK, so are you genetically predisposed to becoming a smoker? Maybe, if you have two working copies of the CYP2A6 gene and 7 repeats in your DRD4 gene. As long as the science is right, that is. There are most likely other as yet undiscovered genes involved in becoming a smoker. And we’ve totally ignored nurture in our discussion of nature. Peer pressure, family, tobacco advertising, how cool Humphrey Bogart looked in Casablanca are all important as well.

But wait a minute…how much of peer pressure is genetic? We’ll save that for another answer.

*A repeat is a DNA sequence that, well, repeats itself. Something like the CAG in CAGCAGCAG. These kinds of repeating sequences are a common place to develop DNA changes that increase or decrease the number of repeats. Diseases like Huntington’s and Kennedy syndrome are examples of diseases caused by these mutations.

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The dopamine receptor DRD4 gene: are duplications distracting?

The dopamine D4 receptor DRD4 gene has been implicated in psychotic, mood, addictive, personality, movement and behavioral disorders [e.g. attention deficit hyperactivity disorder (ADHD)]. Now, there is convincing evidence to support the genetic association of DRD4 polymorphisms with ADHD. The particular polymorphism, a 5' 120-bp duplication, might be functionally active. These findings suggest that manipulation of the DRD4 gene pathway could offer more selective pharmacological approaches to the treatment of ADHD.

Functional effects of a tandem duplication polymorphism in the 5'flanking region of the DRD4 gene Several polymorphisms have been identified in the 5'flanking region of the human dopamine D4 receptor gene (DRD4), including a tandem duplication polymorphism. This comprises a 120-base-pair repeat sequence that is known to have different allele frequencies in various populations around the world. Furthermore, various studies have revealed evidence of linkage to attention-deficit/hyperactivity disorder and association with schizophrenia and methamphetamine abuse. The location of the polymorphism in the 5'regulatory region of the DRD4 gene and the fact that it consists of potential transcription factor binding sites suggest that it might confer differential transcriptional activity of the alleles.

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