SNPwatch: Next Year It’s Martinelli’s…

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason, it is important to remember that the studies we describe in SNPwatch are for informational and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

bottles2.jpgMost 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).

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.


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 and increased one’s chance of having withdrawal seizures. The SNPs mentioned here reached statistical significance in two of the analyses performed, but only moderately.