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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“But we always go there!”

And so begins another Friday night.  When it comes to choosing where to go to dinner, my husband likes to stick with the tried and true. I like trying out new places.

A new study suggests that the roots of this conflict could spring partly from our genes. It suggests that a DNA variation affecting the neurotransmitter dopamine influence a person’s willingness to explore new options instead of sticking with the status quo.

The finding comes from a study by Michael Frank and colleagues from Brown University and the University of Arizona. The researchers focused on how people learn from positive and negative feedback. Subjects were confronted with a clock face that counted down five seconds.  Before time was up they had to push a button to receive points.  In some trials, the experiment was set up so that the faster they pushed the button, the more points they got. In other trials, waiting longer got more points.

To the researchers’ surprise, people showed wide swings in response speed within each type of trial as they adjusted their timing in an attempt to maximize their scores. Computer models showed that a likely reason for these swings is that people change their strategy (pressing the button faster or slower) in proportion to how uncertain they are that a new strategy (speeding up or slowing down from what they’ve been doing) will yield better results.

It makes sense: If you think a new restaurant might be only marginally better than the one you usually go to (and could be worse), you’re probably not that likely to vary from the usual routine. Why risk it?

But if you really have no idea how good a place might be – who knows, it could blow your mind — you’d probably be more inclined to give it a whirl.

Further analysis of the data, which will appear in the August issue of Nature Neuroscience, showed that the extent to which a person tried out new strategies correlated with variations in the COMT gene. People who carried the “Met” version of the gene were more exploratory in the face of uncertainty about what strategy to try next than people with two copies of the “Val” version (“Met” and “Val” refer to particular amino acids encoded by different versions of the gene).

People with two copies of the Met version were the most adventurous, but even those with only one copy were statistically different in their exploration of new strategies from the people with two copies of the Val version.

(The different versions of the COMT gene are determined by rs4680, which is available to 23andMe customers in the Browse Raw Data feature.  A=Met, G =Val)

The protein encoded by the COMT gene is involved in dopamine signaling in the prefrontal cortex, an area of the brain involved in planning and decision-making.  The Met version of the gene leads to increased dopamine activity in this region and has been linked to more efficient information processing.

So does this explain my date-night drama?  Well, there’s undoubtedly more to it than genes alone, but I do have one copy of the more exploratory Met version of the COMT gene.  And my husband?  Two copies of the stuck-in-a-rut Val version.

Dopamine and Learning
In a region of the brain called the basal ganglia, dopamine helps us internalize positive and negative feedback in order to develop those “gut” feelings of what strategy will work and what won’t.

The effects of dopamine in the basal ganglia have been shown in experiments that use drugs to raise or lower levels of the neurotransmitter in the brain.  Higher dopamine levels help people learn to repeat rewarding behaviors, while lower dopamine leads to better learning from bad experiences.  In a game where “A” usually yields more points than “B,” people with boosted dopamine levels learn to choose A.  People with decreased dopamine levels learn to avoid B.

In non-medicated test subjects, genetic variations that influence dopamine signaling in the basal ganglia also impact so-called “Go” (choose A) and “NoGo” learning (avoid B). People with two copies of the A version of a variant in the DARPP-32 gene, which increases dopamine signaling, tend to be better at Go learning than their G-version-carrying friends.  Those with two copies of A at rs6277 in the DRD2 gene, which decreases dopamine signaling, tend to be better NoGo learners than people with one or two copies of the G version of this SNP.

The clock-and-button experiments Frank et al. conducted further tested the association of these two variants with Go and NoGo learning.  Trials that rewarded faster responses measured Go learning.  Trials that rewarded holding off on the action of button pushing measured NoGo learning. As expected, people with two As at the DARPP-32 variant tended to be better at Go learning than people with one or two Gs, and people with two As at rs6277 in the DRD2 gene were better at NoGo learning than people with AG or GG at this SNP.

(23andMe customers can see their data for rs6277 in the DRD2 gene using the Browse Raw Data feature.  Data for the DARPP-32 variant is not available at this time.)

Parkinson’s Disease Connection
Understanding the role of dopamine in learning from experience may have important implications for treating people with Parkinson’s disease, which is characterized by a loss of dopamine producing neurons in the brain.  Studies have shown that people with Parkinson’s have trouble with Go learning.  It’s thought that the lack of dopamine in their brains prevents the dopamine spikes needed to learn from positive feedback.

This fits with evidence that drugs that increase dopamine help people with Parkinson’s improve their performance on tasks that require Go learning.  But there is a downside:  because they flood the brain with dopamine, the normal dips in signaling that are needed to learn from negative feedback are blocked by these drugs.  This might explain why some people with Parkinson’s disease who take dopamine-increasing medications develop gambling problems – they’re overly attuned to winning, but incapable of learning from their losses.

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There are two simple ways to train animals to perform a new behavior: the carrot and the stick. The carrot rewards desired, “correct” behaviors, while the stick punishes “errors.” Over time, this scheme results in preference for positively reinforced behaviors, and avoidance of negatively reinforced ones. In the December 7 issue of Science, German scientists reported that the SNP rs1800497 is associated with how well subjects learn to avoid errors in a simple reward/punishment scheme. (What the paper calls the “A1-allele” of the “DRD2-TAQ-IA polymorphism” is actually what we store as the A version of the rs1800497 SNP, according to OMIM and and MutDB.)

Though we do not yet consider this finding solid enough to include in the Gene Journal (now called Health and Traits), 23andMe users can still examine their genotype at the rs1800497 using the Genome Explorer (now called Browse Raw Data). In the study, people with the GG genotype appeared to avoid choices for which they had received negative feedback, while those with the AG or AA genotypes did not seem to avoid those choices.

(There are currently no genetic associations for whether people prefer to be rewarded with actual carrots, although someone is clearly thinking about this question.)

Caveats

1) Study size. The authors only tested 12 subjects with the GG or AG genotype and 14 subjects with the AA genotype. This makes it more likely that the result could be a fluke (though the authors also present functional data to support their conclusions). At the very least, the training/testing portion of the study should be repeated in a much larger group. The same goes for other DRD2 association studies. 2) Real-world relevance. The test was highly abstract and the reinforcement simplistic and binary—this type of learning may not be relevant to real-world situations. 3) Multiple hypothesis testing. Other researchers have looked at whether this SNP is associated with behavioral traits from alcohol dependence to creativity, usually in undersized studies. If you run enough tests, something will eventually look like a positive hit just by chance.

(After the jump: detailed methods and smiley/scary faces.)

You Have Chosen…Poorly

How do you find out how well people learn? Give them a test where they have no idea what the correct answers are—and then reward or punish their choices!

During the training phase of this experiment, subjects took a series of trials. In each trial, they were presented with a pair of abstract symbols and asked to choose one. The subjects received immediate feedback about their choices: either a smiling face as a positive reinforcement (reward), or a frowning face as negative reinforcement (punishment).

The trials were repeated many times, using three different training pairs comprising six symbols—AB, CD, and EF. Of the possible choices, the most-rewarded choice was “A”, which received a happy face 80% of the time and a frowning face 20% of the time. The least-rewarded choice (and thus most punished) was “B”, which received a happy face only 20% of the time, and a frowning face 80% of the time. The reward schedule and the actual symbols used are in the figure to the right.

In the second phase, subjects were again asked to choose between two symbols. Although the same six symbols were used, in this phase the pairs did not include the three from the training set (i.e. BE and FD were shown, but not AB). The researchers measured preference for reward by recording the number of times the subjects chose “A” when it was offered. They measured avoidance of punishment by recording the number of times the subjects chose the non-”B” symbol when “B” was offered.

Those with the GG genotype at this SNP—avoiders—chose the non-”B” symbol 70% of the time. But those with the AA or AG genotypes—non-avoiders—chose the non-”B” symbol only 50% of the time, which is no different from choosing at random. The difference between avoiders and non-avoiders was of moderate statistical significance.Interestingly, there was no statistically significant difference between the two groups on preference for “A”—only for avoiding “B”.

Mechanism

The SNP occurs inside a gene called ANKK1, but scientists believe that the SNP acts on a neighboring gene, DRD2. The DRD2 gene encodes a receptor in the brain that responds to the neurotransmitter dopamine. At least two previous studies have shown that people with the AG and AA genotypes have lower levels of the dopamine D2 receptor in their brains. It’s possible that variation at the SNP affects how DRD2 is turned on and off, or that it is tightly linked to another SNP that does.

Klein et al. (2007) also used fMRI images of the brain to show that avoiders and non-avoiders had different activity levels in a zone of the brain thought to be involved in learning from errors. They suggest that “reduced dopamine D2 receptor density is associated with reduced capacity to learn negative characteristics of a stimulus from negative feedback.” In other words, if it’s true that people with the AG or AA genotypes make less of the dopamine D2 receptor, this might explain the reduction in activity they observed.

The authors also cite studies showing that lower dopamine D2 receptor density is linked to addiction, obesity, and novelty-seeking behaviors such as compulsive gambling, which suggests that avoiders in this study might also be prone to these behaviors. Interestingly, another study suggests that people with the same rs1800497 genotype as the non-avoiders (AA or AG) have higher verbal creativity.

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