Not all alcoholics are created equal. People differ in why they drink, how they drink and what effects drinking will have on their health and relationships.

A key biological component of the variability in alcoholism may be in the control of signaling by serotonin, a brain chemical that carries messages between nerve cells and mediates the rewarding effects of alcohol.

Scientists at the University of Virginia have found that a variation in the serotonin transporter gene, which regulates serotonin levels, is associated with drinking intensity. The results, which will appear in the February 2009 issue of Alcoholism: Clinical and Experimental Research, were published online yesterday.

Senevirante et al tested six variations in the serotonin transporter gene for association with drinking intensity in 275 alcoholics seeking treatment — 165 were Caucasian and 110 were Hispanic. Women made up 21.5% of the sample.

In the Caucasian sample only, the researchers found that having one or two copies of a C at rs1042173 led to less intense drinking, defined as number of drinks per drinking day. There was no difference in number of drinks averaged over 90 days. People with the AA genotype drank an average of about 11 drinks per drinking day, while those with the AC or CC genotype drank about eight and a half.

(23andMe customers see their data for rs1042173 using the Browse Raw Data feature)

Previous research has linked a separate variation in the serotonin transporter (5-HTTLPR) with alcohol dependence, but results have been conflicting.

The study’s authors point out that in all cases, the number of drinks people had exceeds the threshold for what is considered heavy drinking (five or more standard drinks per day for men and four or more for women). They also note that their study looked only at alcoholics seeking treatment, who may not be representative of alcoholics in general.

In the future, the researchers say they hope to investigate whether rs1042173 can be used to provide more effective treatment for alcoholism by predicting whether medications that affect the serotonin system will work for an individual.

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Most people who have resolved to give up the bottle after a bout of New Year’s Eve overindulgence went cold turkey for a few weeks with no ill effects (even if by now they have gone back to their old habits). But for some people who are alcohol-dependent, quitting booze in the first place can result in severe symptoms, such as withdrawal seizures and delirium tremens. A French study in the January issue of Alcoholism: Clinical and Experimental Research found evidence that two SNPs in a single gene were linked with how likely alcohol-dependent people were to have withdrawal seizures. Because this finding is of modest statistical significance, and because it only affects a small fraction of people (about 3% of alcohol-dependent people), we do not currently include this report in the Gene Journal (now called Health and Traits).

However, 23andMe users can look at their genotypes in the Genome Explorer (now called Browse Raw Data). The two SNPs identified in the study are rs27072 and rs27048. The study found that alcohol-dependent people with the CC genotype at either SNP have just under twice the odds of having withdrawal seizures as those with CT or TT.

Caveats

1) Small study size. As with many studies of behavioral traits, small sample sizes can lead to evidence for a conclusion that are actually statistical flukes. 2) Multiple hypothesis testing. The authors performed at least three types of analyses on eight markers. There is reason to wonder if these results were due to a fluke—run enough tests and you’ll eventually get a hit. However, seeing statistical significance in more than one type of analysis, along with previous studies showing association between withdrawal symptoms and the DAT1 gene (though not with the SNPs reported here), lend support to the hypothesis that there is a real association, albeit possibly a small one.

(After the jump: detailed background and a dated cultural reference.)

Quitting the Sauce

Alcohol dependence is thought to be heritable because it clusters in families. Yet there have not been any conclusive links between the disease and genetic markers. Some of this lack of progress is because past studies have suffered from statistical biases and small sample size. For a rather extreme example of the problem with the latter, think about flipping a coin twice and coming up with heads twice. Would you be justified in concluding that the coin is double-headed? (The answer is no.)

Another issue is that alcohol dependence is a heterogeneous disorder whose definition is in flux. Most people have heard the term alcoholism, which the American Medical Association defines as “a primary, chronic disease characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking.”

But the psychiatrists’ bible, the DSM-IV, recently split its diagnoses into alcohol abuse and alcohol dependence. The former is defined as repeated drinking despite negative consequences (for example, on work or relationships), while the latter is defined as alcohol abuse in addition to tolerance and withdrawal: the classic signs of addiction. However, not all withdrawal symptoms—cravings, hallucinations, the shakes, seizures, and delirium tremens—need to occur to justify a diagnosis of alcohol dependence. Furthermore, the nature of addiction itself could be heterogeneous—physical, psychological, or both—meaning that the environmental and biochemical (and thus potentially genetic) events that lead to alcohol dependence can differ from person to person.

For example, take people who wear watches. Some do because they are obsessive about being on time, others do because they like stylish accessories, while a third group might do it to cover up the tan line on their wrist. Add to this heterogeneity an expansion of the category of “wearing a watch” to “knowing what time it is”—which could include carrying a pocketwatch, a cell phone, or standing next to Flavor Flav—and it becomes a nightmare to find a common factor.

Le Strat et al. (2008) try to reduce heterogeneity by looking for a genetic link to a specific symptom in alcohol-dependent patients recruited from French treatment clinics—in our example, whittling down the definition to just those people who wear digital watches. Withdrawal seizures are a potentially life-threatening side effect that occur when someone who is alcohol dependent quits drinking. Yet not all alcohol dependents have seizures. Withdrawal seizures are thus a sufficient, but not necessary, symptom of alcohol dependence.

The authors examined a single candidate gene, DAT1, based on previous (though inconclusive) evidence that different DAT1 variations are linked to alcohol dependence and withdrawal symptoms. DAT1 encodes a protein that plays a role in the signaling of the neurotransmitter dopamine. Dopamine receives a lot of attention in this field because of its well-accepted role in rewarding behavior. In particular, mice engineered to lack the DAT1 gene avoid alcohol, although it is not clear whether dopamine is playing a role in rewarding alcohol intake, the negative effects of withdrawal, or both.

Three different types of analyses were performed for each SNP (and six other markers), and the authors found that having two copies of the C version of the SNPs rs27072 and rs27048 increased one’s chance of having withdrawal seizures. The SNPs mentioned here reached statistical significance in two of the analyses performed, but only moderately.

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