Addiction to alcohol is associated with the brain’s reward system, which reinforces behaviors that feel good — like drinking — by releasing neurotransmitters such as dopamine and endorphins. With prolonged alcohol consumption, a person’s brain can gradually adapt to the point that excessive amounts of drinking are required in order to produce the same pleasure response, and alcoholism results.

That means genetic factors that influence the biochemistry of the reward pathway, as well as environmental factors that encourage alcohol consumption (such as peer pressure and stress) can increase a person’s alcoholism risk.

Researchers have long suspected that a combination of genetic and environmental causes can act together, increasing alcoholism risk more than either acting alone. But so far little evidence has been found for such an effect.

A new paper to be published in the December issue of Alcoholism: Clinical and Experimental Research has found evidence for a synergistic effect between a genetic variation and level of education in a study of 700 Mexican-Americans. The prevalence of alcoholism among Mexican-Americans is relatively high; Mexican-American men report past heavy drinking at three times the rate of men belonging to other ethnicities.

The researchers, Yanlei Du and Yu-Jui Yvonne Wan of the University of Kansas Medical Center, measured three genetic variants associated with the function of chemicals involved in the brain’s reward system. They also looked at marital status and education level in the study participants.

The study found that of the three genetic variants, two were associated with severe alcoholism (defined by consuming more than 35 drinks per day).

o Having two copies of the A version at the SNP rs1799971, which is located on the opioid receptor gene OPRM1, increased the odds of severe alcoholism 2.16 times.
o Having two copies of a variant in the DRD2 gene, which affects the structure of a receptor for the neurotransmitter dopamine, increased the risk of severe alcoholism 1.85 times.

(23andMe customers can see their data for rs1799971 and rs1799732, which is diagnostic of the DRD2 variant, using the Browse Raw Data feature. For rs1799732, a result of II indicates the riskier variant. SNP rs1799971 has previously been associated with the need for morphine as pain relief after surgery as well as sensitivity to social rejection.)

Of the two environmental factors, only education level had an effect. Those with less than 12 years of education had 1.97 times the odds of severe alcoholism. (Having less than 12 years of education also increased a person’s odds of less-severe alcoholism by about the same amount.)

But when the researchers considered combinations of the three associations, they found that having two A copies of the OPRM1 SNP rs1799971, combined with less than 12 years of education, increased a person’s odds of severe alcoholism 3.3 times.

The researchers suggest that a low education level may magnify the effects of the OPRM1 variant, or that higher education may mask its effects by improving brain function.

However, other factors might be responsible for the effect. For example, it is possible that those who attain an education past high school have other characteristics that make them less likely to become addicted to a substance.

There is no way yet to measure an individual’s vulnerability to alcohol addiction, and the complex interaction between genetics, education and other environmental factors must be further studied to clarify the causes of alcoholism in this and other ethnicities.

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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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