“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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Although obesity was seen as a sign of social status during the Renaissance, it’s been known since long before then that being overweight is actually unhealthy. We all know that carrying around extra pounds increases the risk for high blood pressure, diabetes and cardiovascular disease, yet one out of three Americans is obese.

New research, published online today in Science, suggests that for some obese people, genetic variations may desensitize the brain’s reward centers, making food less satisfying and leading to the consumption of more calories followed by the predictable result — weight gain.

When we eat, feelings of pleasure are produced by the release of a chemical called dopamine into the brain. Recent research has shown that the brains of obese people have fewer dopamine-responsive receptors; this deficit may decrease the pleasure obese people get from food and prompt them to overeat in order to compensate.

“Individual differences in how the brain processes food reward have been postulated to play a role in explaining why some, but not all, people are gaining weight in an environment where calories are plentiful. Our finding is exciting because it supports this possibility by demonstrating an association between an abnormal response to food and future weight gain – and it shows that this relationship depends on your genetic make-up,” said study author Dana Small in statement.

Small and her colleagues examined 43 college women and 33 adolescent girls using functional magnetic resonance imaging scans, which analyze brain activation by measuring blood flow in the brain, while the study subjects tasted either a chocolate milkshake or a flavorless solution.

In both study groups, women with higher body mass indices (BMI) had lower levels of activation in dopamine-responsive areas of their brains as they tasted the milkshake. This relationship was significantly stronger in women with one or two copies of a variation in the dopamine receptor gene DRD2 that scientists call the “Taq1A A1 allele”.

The A1 allele has been associated with fewer dopamine receptors in the brain. Previous research has shown that people with one or two copies of the A1 allele are more likely to be obese. Other traits — such as alcoholism, obsessive-compulsive disorder, and error avoidance – have also been linked to the A1 allele and thus the brain’s reward pathways.

After one year, the researchers found, women with one or two copies of the A1 allele who had also shown lower brain activation in response to food gained more weight, possibly because of their diminished pleasure response.

“Identifying changes in behavior or pharmacological options could correct this reward deficit to prevent and treat obesity,” said the study’s lead author Eric Stice.

(23andMe customers can find out if they have the DRD2 A1 allele by checking their data at rs1800497 with the Browse Raw Data feature. “ A” corresponds to the A1 allele. A “G” at this SNP is called the A2 allele. Customers can also click on the links above to view Research Reports for other traits linked to this variation.)

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In the movie Batman Begins, young Bruce Wayne attends the opera with his parents and becomes increasingly uncomfortable at the costumes that remind him of the bats he had encountered earlier that day.

German and American scientists have now found that the gene variant rs4680 is associated with regulating such anxious reactions to emotional images.

With more research, study co-author Christian Montag noted in a statement, “it might be possible to prescribe the right dose of the right drug, relative to genetic makeup, to treat anxiety disorders.”

For the study, which appears online August 10 in the journal Behavioral Neuroscience, researchers measured the startle responses — blinking in reaction to unexpected loud noise — of 96 German women as they viewed various images. Each woman was shown happy images such as those of animals or family; threatening or fear-inducing images such as those of injured people or weapons; and emotionally neutral images like a hair dryer or power outlet. A few seconds after each image appeared, researchers randomly startled the women with short, loud blasts of white noise and recorded the their startle responses.

The researchers found when viewing unpleasant pictures, the startle response of women with an A at both copies of rs4680 was about six times stronger compared to those with only one A or none at all.

“This single gene variation is potentially only one of many factors influencing such a complex trait as anxiety,” said Montag in a statement. “Still, to identify the first candidates for genes associated with an anxiety-prone personality is a step in the right direction.”

The SNP is in the COMT gene, which is involved in regulating the “feel-good” hormone dopamine. It has also been linked with breast cancer risk — Asian-American women who have an A at one or both copies of rs4680 and also drink black or green tea appear to have a decreased chance of developing the disease. People with an A in both copies of rs4680 have been shown to break down dopamine less efficiently. Studies have also correlated the variant with behaviors such as obsessive-compulsive disorder.

The researchers think the stronger reaction to unpleasant images by people with two copies of the A version of rs4680 might be due to increased dopamine levels in some parts of the brain.

“Elevated dopamine in the prefrontal cortex could result in an inflexible attentional focus on aversive stimuli,” Montag and his colleagues wrote.

That’s a fancy way of saying that people with elevated dopamine in that part of the brain are more prone to respond like a deer in the headlights when faced with a potential threat. In their paper, the research suggest that evolution has created a trade-off. The A version of rs4680 appears to boost working memory and cognitive function compared to G — but it also hampers emotional control. Plus, being unable to take one’s eyes away from something unpleasant could be dangerous, especially if people stop paying attention to their surroundings.

Maybe that’s why Bruce Wayne chose to become a bat; having criminals momentarily distracted at the sight of something scary and terrifying might give him a valuable edge.

Image from: Don Pfitzer, US Fish and Wildlife Service

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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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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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