August 25, 2003
Serotonin Transporter Gene Linked To Depression, Binge Drinking

People with short versions of the serotonin transporter gene are more prone to binge drinking and anxiety. (bold emphasis added)

NIAAA clinical investigators Paolo B. DePetrillo, M.D., and Research Fellow Aryeh I. Herman B.A., along with researchers from George Washington University in Washington, D.C., conducted the study of 262 male and female college students and analyzed data from the largest homogenous group: 204 male and female Caucasian college students aged 17 to 23 years. To assess the frequency and patterns of alcohol consumption, the scientists asked all the students a set of questions, for example, how many times in the past two weeks they had engaged in binge drinking (five or more drinks for men and four or more drinks for women on one occasion).

The research team also analyzed each student's genotype with a focus on the 5-HTT gene, which is involved in recycling the chemical serotonin after it is secreted into the synapse of a cell. The researchers determined which students had long or short versions of this so-called serotonin transporter gene.

Everyone inherits two copies of each gene, one from each parent. There are two normal variations, or polymorphisms, of the serotonin transporter gene, labeled the long and the short variants. Most people are heterozygous, that is, they have one copy of each variant, but about 30 percent of the Caucasian population are homozygous (carry duplicate copies) of either the long or the short version. This percentage varies depending on the ethnic background of the individual.

The researchers found that the students who carried two copies of the short version of 5-HTT were more likely to report troublesome drinking patterns. Dr. DePetrillo says, "Our findings reveal a significant association of the serotonin transporter promoter polymorphism with increased alcohol consumption behavior in the students that we studied. Taken together with other research, this finding suggests that genetically mediated differences in serotonergic response play an important role in mediating patterns of alcohol intake." The students with two copies of the short form of the gene engaged more frequently in binge drinking, drank more often to get drunk, and consumed more alcoholic drinks per occasion than did students with the other genotypes.

Another difference the researchers observed was that students with at least one copy of the long variant of the 5-HTT gene tended to consume a smaller number of drinks at a sitting, even though they went out to drink as often as the other students.

Why should the presence of the shorter gene variant make such a difference? The authors speculate that, because individuals who are homozygous for the short version are known to be at risk for higher levels of anxiety, they may use alcohol to reduce tension. Further studies are needed to understand the influence of the serotonin transporter gene on drinking behavior, with special attention given to replication in other ethnic groups.

Does anyone happen to know what the distribution of 5-HTT variations is in various ethnicities and races? There are probably regional differences in distribution well below the level of the major races.

The short version of the serotonin transporter gene also predisposes a person to depression in response to stressful life events.

Among people who suffered multiple stressful life events over 5 years, 43 percent with one version of a gene developed depression, compared to only 17 percent with another version of the gene, say researchers funded, in part, by the National Institute of Mental Health (NIMH). Those with the "short," or stress-sensitive version of the serotonin transporter gene were also at higher risk for depression if they had been abused as children. Yet no matter how many stressful life events they endured, people with the "long" or protective version experienced no more depression than people who were totally spared from stressful life events. The short variant appears to confer vulnerability to stresses, such as loss of a job, breaking up with a partner, death of a loved one, or a prolonged illness, report Drs. Avshalom Caspi and Terrie Moffitt, University of Wisconsin and King's College London, and colleagues, in the July 18, 2003 Science.

The serotonin transporter gene codes for the protein in neurons, brain cells, that recycles the chemical messenger after it's been secreted into the synapse, the gulf between cells. Since the most widely prescribed class of antidepressants act by blocking this transporter protein, the gene has been a prime suspect in mood and anxiety disorders. Yet, its link to depression eluded detection in eight previous studies.

"We found the connection only because we looked at the study members' stress history," noted Moffitt. She suggested that measuring such pivotal environmental events which can include infections and toxins as well as psychosocial traumas might be the key to unlocking the secrets of psychiatric genetics.

Although the short gene variant appears to predict who will become depressed following life stress about as well as a test for bone mineral density predicts who will get a fractured hip after a fall, it's not yet ready for use as a diagnostic test, Moffitt cautioned. If confirmed, it may eventually be used in conjunction with other, yet-to-be-discovered genes that predispose for depression in a "gene array" test that could help to identify candidates for preventive interventions. Discovering how the "long" variant exerts its apparent protective effect may also lead to new treatments, added Moffitt.

Everyone inherits two copies of the serotonin transporter gene, one from each parent. The two versions are created by a slight variation in the sequence of DNA in a region of the gene that acts like a dimmer switch, controlling the level of the gene's turning on and off. This normal genetic variation, or polymorphism, leads to transporters that function somewhat differently. The short variant makes less protein, resulting in increased levels of serotonin in the synapse and prolonged binding of the neurotransmitter to receptors on connecting neurons. Its transporter protein may thus be less efficient at stopping unwanted messages, Moffitt suggests.

There is one odd thing about their dataset: half of them had one of each variant. But far more had two long versions than had two short versions.

Moffitt and colleagues followed 847 Caucasian New Zealanders, born in the early l970s, from birth into adulthood. Reflecting the approximate mix of the two gene variants in Caucasian populations, 17 percent carried two copies of the stress-sensitive short version, 31 percent two copies of the protective long version, and 51 percent one copy of each version.

Is this dataset representative of the larger population of New Zealanders? If so, then something interesting is going on. If the carriers of the short and long gene versions were equally likely to reproduce and equally likely to mate with others regardless of whether the others are the same or different for this gene and if half the population was heterozygous for this gene then we'd expect to see equal numbers homozygous for the short and long versions. But in this study group the homozygous short versions were less common than homozygous long versions even though half the study participants were heterozygous short-long.

Is there some kind of preferential mating going on where those who pair up with opposite homozygous types have more children than matings between pairs who are homozygous for the short version? Or are heterozygous people more fecund than the homozygous for this gene? Or are homozygous shorts less likely to mate with their own kind but more likely to have more children when they pair up with a member of the other groups? There are a lot of possibilities and those are just a few of them.

The reseachers ought to survey these people for how many children they've had and at what age. Also, they should test the serotonin transporter genes of their children and the other parents of their children to see if there are any obvious patterns at work.

Update: The same research team has done previous work on the New Zealand longitudinal Dunedin Multidisciplinary Health and Development Study.

"We now understand the biological basis of some people's ability to bounce back successfully from adverse life events," said Science's deputy editor, life sciences, Katrina Kelner. "This is tremendously exciting. The research adds to the findings published in Science by the same team last year which showed why certain maltreated children grow up to be healthy adults and certain ones develop antisocial behaviors."

So this is the same research team that published a report showing that a particular variation in the gene for monoamine oxidase-A caused mistreated children to become violent and anti-social.

Here is an excerpt from the press release on the previous work by Moffitt and associates on MAOA and violence using the same New Zealand longitudinal study.

By age 11, 36 percent of the subjects had been maltreated (8 percent severely), as defined by frequent changes in primary caregiver, rejection by the mother and physical or sexual abuse. Although only 12 percent of the maltreated children had low activity levels of the MAO A, they accounted for 44 percent of their generation's total convictions for assault and other violent crimes.

"As adults, 85 percent of the severely maltreated children who also had the gene for low MAO A activity developed antisocial outcomes, such as violent criminal behavior," says Moffitt. "The combination of maltreatment and the genetic variation magnified the odds by nine times."

On the other hand, the group found that children who had been maltreated but who had higher levels of MAO A were unlikely to develop behavior problems, suggesting that the gene regulating the enzyme does serve a protective function. "The genotype of high MAO A activity," explains Moffitt, "may promote 'trauma resistance.'"

Based on these initial findings, Moffitt says, "The combination of the low-activity MAO A genotype and maltreatment predicts antisocial behaviors about as well as high cholesterol predicts heart disease."

Low levels of the MAO A enzyme may help explain why some abused children are more likely to develop aggressive or criminal behavior, but Moffitt stresses that it does not explain why people are violent: "Low levels of the enzyme did not predict antisocial outcomes in the whole population. It's relation to aggression only emerged when we considered whether the children had been maltreated."

However, the UW-Madison researchers suspect that the MAO A genetic variation may play a similar role in protecting people who have experienced other stressful events, such as car accidents or wars.

Share |      Randall Parker, 2003 August 25 01:25 PM  Brain Genetics


Comments
curious said at August 29, 2003 10:00 AM:

"Most people are heterozygous, that is, they have one copy of each variant, but about 30 percent of the Caucasian population are homozygous (carry duplicate copies) of either the long or the short version. This percentage varies depending on the ethnic background of the individual."

Does anyone have the figures for different ethnic groups?

lesile dull said at May 15, 2005 4:08 PM:

i really need some help. i would love for someone to message me that knows a little bit more about this. PLEASE HELP

Ian said at July 7, 2005 6:05 PM:

These two articles are really dumb and counterintuitive.

For starters, it suggests that the individuals with low MAO activity were more likely to be affected by traumatic event. But don't we routinely use MAO-A inhibitors to treat these sorts of problems.

The second problem is this. The article suggests that the short-short varient of the serotonin transporter gene is more likely to suffer depression. The problem is this: The short-short viarient actually codes for a lower reputake of serotonin than does the other versions. So we are giving these depressed indivudials SSRI's, which will serve to slow the reputake even further.

In all, I would say that the two articles suggest that high serotonin is related to these types of problems, and not low serotonin.

Linkadge

Cedders said at November 17, 2005 12:43 AM:

"If the carriers of the short and long gene versions were equally likely to reproduce and equally likely to mate with others regardless of whether the others are the same or different for this gene and if half the population was heterozygous for this gene then we'd expect to see equal numbers homozygous for the short and long versions."

Not really. Given the statistics in that sample (17-51-31), the overall prevalence of the short allele is 42.9%. Working back from that, you would expect 18% (0.425*0.425) short-short homozygous, and 33% long-long. If this represented any significant difference from observation (and given the small sample size, and without doing the maths, it doesn't), it would be a very slight tendency to xenogamy (mating with complements).

Agree with comments from Ian about treatment, FWIW. There is little or no basis for the 'monoamine hypothesis' of mental disorders, anyway. [http://medicine.plosjournals.org/archive/1549-1676/2/12/pdf/10.1371_journal.pmed.0020392-p-L.pdf] You tend to find results from these genetic studies cannot be replicated once they are controlled for other familial/social factors.

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