Smokers’ Genes: Evidence From a 4-Decade Study

How adolescent risk becomes adult addiction.

 Pediatricians have often remarked upon it: Give one adolescent his first cigarette, and he will cough and choke and swear never to try another one. Give a cigarette to a different young person, and she is off to the races, becoming a heavily dependent smoker, often for the rest of her life. We have strong evidence that this difference in reaction to nicotine is, at least in part, a genetic phenomenon.

But so what? Is there any practical use to which such knowledge can be put? As it turns out, the answer may be yes. People with the appropriate gene variations on chromosomes 15 and 19 move very quickly from the first cigarette to heavy use of 20 or more cigarettes per day, and have more difficulty quitting, according to a new report published in JAMA Psychiatry. From a public health point of view, these findings add a strong genetic rationale to early smoking prevention efforts— especially programs that attempt to “disrupt the developmental progression of smoking behavior” by means of higher prices and aggressive enforcement of age restrictions on smoking.

What the researchers found were small but identifiable differences that separated people with these genetic variations from other smokers. The gene clusters in question “provide information about smoking risks that cannot be ascertained from a family history, including information about risk for cessation failure,” according to authors Daniel W. Belsky, Avshalom Caspi, and colleagues at the University of North Carolina and Duke University.

The group looked at three prominent genome-wide association studies of adult smoking to see if the results could be applied to “the developmental progression of smoking behavior.” They used the data from the genome work to analyze the results of a 38-year prospective study of 1,037 New Zealanders, known as the Dunedin Study. A total of 405 cohort members in this study ended up as daily smokers, and only 20% of the daily smokers ever achieved cessation, defined as a year or more of continual abstinence.

The researchers came up with a multilocus genetic risk score (GRS) based on single-nucleotide polymorphisms associated with smoking behaviors. Previous meta-analyses had identified several suspects, specifically a region of chromosome 15 containing the CHRNA5-CHRNA3-CHRNB4 gene cluster, and a region of chromosome 19 containing the gene CYP2A6. These two clusters were already strong candidate genes for the development of smoking behaviors. For purpose of the study, the GRS was calculated by adding up the alleles associated with higher smoking quantity. The genetic risk score did not pertain to smoking initiation, but rather to the number of cigarette smoked per day.

When the researchers applied these genetic findings to the Dunedin population cohort, representing ages 11 to 38, they found that an unfortunate combination of gene types seemed to be pushing some smokers toward heavy smoking at an early age. Individuals with a high GRS score “progressed more rapidly to heavy smoking and nicotine dependence, were more likely to become persistent heavy smokers and persistently nicotine dependent, and had more difficulty quitting,” according to the study. However, these effects took hold only when young smokers “progressed rapidly from smoking initiation to heavy smoking during adolescence.” The variations found on chromosomes 15 and 19 influence adult smoking “through a pathway mediated by adolescent progression from smoking initiation to heavy smoking.”

Curiously, the group of people who had the lowest Genetic Risk Scores were not people who had never smoked, but rather people who smoked casually and occasionally—the legendary “chippers,” who can take or leave cigarettes, sometimes have one late at night, or a couple at parties, without ever falling victim to nicotine addiction. These “light but persistent smokers” were accounted for “with the theory that the genetic risks captured in our score influence response to nicotine, not the propensity to initiate smoking.”

Naturally, the study has limitations. Everyone in the Dunedin Study was of European descent, and the life histories ended at age 38. Nor did the study take smoking bans or different ages into account. The study cries out for replication, and hopefully that won’t be long in coming.

Could information of this sort be used to identify high-risk young people for targeted prevention programs? That is the implied promise of such research, but no, probably not. The gene associations are not so dramatic as to cause youngsters with the “bad” alleles to inevitably become chain smokers, nor do the right set of genes confer protection against smoking. It’s not that simple. However, the study is definitely one more reason to push aggressive smoking prevention efforts aimed at adolescents.


Belsky D.W.  Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine DependenceEvidence From a 4-Decade Longitudinal StudyDevelopmental Progression of Smoking Behavior, JAMA Psychiatry,   1. DOI: 10.1001/jamapsychiatry.2013.736

Graphics Credit: http://cigarettezoom.com/

Chasing the Genes for Cocaine Addiction

Brain protein MeCP2 in the spotlight.

Dr. Edward Sellers, former director of the psychopharmacological research program at the University of Toronto’s Addiction Research Foundation once said to me: “Every cell, every hormone, every membrane in the body has got genetic underpinnings, and while many of the genetic underpinnings are similar in people, in fact there are also huge differences. So on one level, the fact that there is a genetic component to addiction is not very surprising. What is surprising is that you could ever have it show up in a dominant enough way to be something that might be useful in anticipating risk.”

If there existed a set of genes that predisposed people to alcoholism, and possibly other addictions, then these genes had to control the expression of something specific. That’s what genes did.  However, back in the 1990s, addiction researchers could not even agree on the matter of where they should be looking for such physical evidence of genetic difference. In the brain? Among the digestive enzymes? Blood platelets? A gene, or a set of genes, coding for…what? What was it they were supposed to be looking for?

What set of genes coded for addiction?

Something about modern genetic research breeds a strong jolt of excitement. There is the promise of sudden discoveries, headlines, and great leaps forward toward cures for stubborn diseases. Even the most sober scientists seem to get enthused about gene hunting. The idea of curing a disease by locating a defective gene and repairing it is one of the brightest and fondest hopes in medicine. At least 3,000 medical disorders, including diabetes, cystic fibrosis, and some forms of Alzheimer’s are inherited diseases caused by defective genes passed on from generation to generation. But the premature announcements and retractions involving genes for everything from drinking to shyness has brought a hard-won maturity to the field.

These days, the hunt for evidence of genes influencing addiction is drilling very deeply into the molecular underpinnings of neural activity, in a wide-ranging effort to sort out the variety ofgene interactions involved in the genetic propensity for alcoholism and other addictions. 

Work done at the Scripps Research Institute in Florida, funded by the National Institute on Drug Abuse (NIDA) and published in Nature Neuroscience, recently shone a spotlight on a gene responsible for making a particular protein—MeCP2—needed for normal development of nerve cells in the brain. This gene for methyl CpG binding protein 2 is best known as the gene responsible for a rare genetic brain disorder called Rett syndrome.  

Researchers at Scripps discovered that cocaine increased levels of this regulatory protein in the brains of rats. So did fluoxetine , better known as Prozac, suggesting that the serotonergic system may be involved. “At that point,” according to lead author Paul Kenny, “we wanted to know if this increase was behaviorally significant—did it influence the motivation to take the drug?” Evidently it did. The higher the levels of MeCP2 in the brain, the higher the rats’ motivation to consume cocaine. When the researchers disrupted the expression of MeCP2 with a virus, the rats showed less interest in cocaine.

This is the first evidence that MeCP2 plays some as yet unexplained role in regulating vulnerability to cocaine addiction. Earlier this summer, investigators reported in Nature that another regulatory molecule known as MiRNA-212—a type of RNA involved in gene regulation--had the opposite effect, lessening the test animals’ interest in cocaine. The balancing act between MeCP2 and MiRNA-212 may help explain “the molecular mechanisms that control the transition from controlled to compulsive cocaine intake,” according to the paper, although the mechanisms that regulate this balance are not known.

One strong piece of evidence for this regulatory feedback loop was the finding that, while MeCP2 blocked miR-212 expression, the opposite was also true. “We still don’t know what exactly influences the activity levels of MeCP2 on miR-212 expression,” according to Kenny. “Now we plan to explore what drives it—whether it’s environmentally driven, and if genetic and epigenetic influences are important.” (For more on MeCP2, check this Lab Spaces post.)

NIDA director Nora Volkow said in an NIH press release that the work on MeCP2 “exposed an important effect of cocaine at the molecular level that could prove key to understanding compulsive drug taking.”

Graphics Credit: http://www.labspaces.net/

Im, H., Hollander, J., Bali, P., & Kenny, P. (2010). MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212 Nature Neuroscience DOI: 10.1038/nn.2615

Friday File

Book and blog recommendations for the weekend.

Books

I just finished reading a splendid book, Barbara Oakley’s Evil Genes: Why Rome Fell, Hitler Rose, Enron Failed, and My Sister Stole My Mother’s Boyfriend. Oakley, a systems engineer at Oakland University in Michigan, has done a great service for interested non-scientists by picking apart the intricate genetics of psychopathy and antisocial behavior.

Primarily a history of borderline personality disorder and the “great men” who suffered from it, Oakley takes the “nature-nurture” debate to the next level, asserting that bad behavior is a genetic propensity triggered by environmental influences—precisely the argument I make about addiction in my book, The Chemical Carousel: What Science Tells Us About Beating Addiction.

Oakley deftly beats back the usual panoply of objections to genomic research—that it is a slippery slope leading to eugenics, or that it is an excuse for bad behavior. Even worse, for many people, Evil Genes suggests that individual ethics are largely biochemically determined. The “successfully sinister,” as she calls them, have a baffling ability to charm their way to the top, and the author suggests some evolutionary reasons why this might be so.

Overall, Oakley makes a strong, eye-opening case for the importance of modern neuroscience in the quest to understand human behavior. This book should come as a serious shock to a generation of lawyers, judges and forensic psychologists who have spent a lifetime adhering to the “blank slate” view of human nature, when the “bad seed” analogy appears to be closer to the truth.

Blogs

Check out Brain Blogger for a look at “Topics from Multidimensional BioPsychoSocial Perspectives,” as the site is subtitled. Recent posts include articles about antibiotic overuse, gender reassignment, autism, torture, proprioception, neural plasticity, and my own article on marijuana withdrawal, which has drawn a panoply of heated responses.

A fascinating site with a multidisciplinary perspective.

addiction drugs

The Dapsone Analogy

Another way of looking at addiction.

Medical science tells us that there are diseases called “pharmacogenetic disorders.” A common one is known as glucose-6-phosphate dehydrogenase deficiency. This disorder is a human enzyme deficiency that reduces the ability of red blood cells to carry oxygen, resulting in severe anemia. Its origin is genetic, and it is found predominantly in Jews and African-Americans. People who have this disease don’t necessarily know it. They don’t get into trouble until they are exposed to a very particular kind of environmental insult: an oxidative agent. Like eating fava beans, for example. If a person suffering this disorder eats fava beans, as one addiction expert told me, sparing the technical details, “their red blood cells go to hell.”

Okay. But how can something be a disease if the people who supposedly have it are perfectly normal until they start messing with fava beans—or alcohol or heroin? To some people, that just does not sound like a disease. And there are, in addition, obvious environmental influences on the course of addiction. However, there are also strong environmental causes and impacts related to diabetes, hypertension, and a host of other common diseases.

As it happened, African Americans who served in Viet Nam who suffered from glucose-6-phosphate dehydrogenase deficiency found out about it fast, whenever they took an anti-malarial medication called Dapsone, a drug now used to treat certain skin diseases similar to leprosy.

Blacks with glucose-6-phosphate dehydrogenase deficiency would take Dapsone, which pulled the environmental trigger on their disease, and they would suffer acute hemolysis—the complete breakdown of their red blood cells. If they didn’t take Dapsone, or eat fava beans, they were fine—you couldn’t tell them from anyone else. (The same thing happened in Korea when service personnel suffering this deficiency encountered a different environmental trigger—the antimalarial drug primaquine.)

Now try this: What if eating fava beans for the very first time didn’t make certain people sick—it made them feel incredibly good; better than they had ever felt in their life? Better than they ever thought possible. What if that first experience felt like a life truly worth living; a surcease from years of sadness, a miracle drug, the healing hand of God? What if certain people, for reasons of abnormal biochemistry, had never experienced the typical feelings of happiness and contentment most people take for granted—until they ate fava beans. And then, for the first time in their lives, they felt better than okay.

If fava beans were a rewarding stimuli instead of aversive, the disease would still be a pharmacogenetic disorder, hidden from view in the absence of the environmental trigger. Once having tasted the bean, however, a stubborn minority of people would be drawn to eat it repeatedly. And the more they ate the beans, the more their bodies would become dependent upon the artificial reward the beans provided—until they reached a point where they simply could not function unless they had their beans.

Photo Credit: Astragen LLC

addiction drugs

If the Genes Fit....

U.K psychiatrists agree addiction is "genetically determined."

Although the verdict is very little in doubt these days, the heritability of addictions was reaffirmed by the U.K.'s Royal College of Psychiatrists in London on July 4th.

In a presentation at the group's annual meeting, held at Imperial College, Professor Wim van den Brink of the University of Amsterdam's Academic Medical Center pinned the blame for addiction squarely on the absence of a sufficient number of dopamine receptors in the brain. "Addicts find it difficult to receive pleasure," he said. "They are not likely to enjoy most of the ordinary things most of us enjoy... they are looking for more stimulus."

Professor van den Brink also made clear the importance of environmental interactions for gene expression: "You might start off smoking or taking cocaine, and that first introduction is very much determined by your environment. But to stick with it and become dependent on it is genetically determined."

The self-defeating nature of addiction is graphically illustrated by the overall decrease in the number of pleasure receptors for dopamine and serotonin over time, as drug use escalates. Moreover, addicts show a striking deficiency in the ability to engage in long-term thinking. This behavioral link, the Royal College maintained, is the reason addicts fail to realistically differentiate between short-term pleasure and long-term negative effects.

This inability of drug addicts to engage in effective long-term thinking is well summarized in the old Reverend Gary Davis song: "Cocaine's for horses and it's not for men/Doctor said it kill you, but he didn’t say when."

Photo Credit: National Institute on Drug Abuse

dopamine addiction drugs