824201594256 DRUGS & ADDICTION - Part 3.


March 21, 2016

Genetic basis of addiction

"What is it that makes a person become addicted?"


In the 1940s and '50s researchers asked themselves this and to get an answer to this question they set up large twin and family studies. It was already known that if a family had an addicted parent or relatives that the children of the addicts were eight times more likely to develop addiction. Well, that could be just the environment. If you grow up in a really lousy, very dysfunctional environment, then you might end up becoming addicted.


Was there more to this question?

In the '50s, there were two main groups of studies, one in Virginia and the other on the West Coast. 


If we use identical twins and non-identical twins, perhaps we could tease out: "Were the genes playing a role, or was it the environment, or was it a mixture of the two?"

In the Virginia twin sample study of 861 pairs of identical twins and 653 non-identical or fraternal twins. The idea is that the identical twins must share almost all their genes. So if you saw an effect that was stronger in the identical twins, then that suggested that genetic factors were playing a big role. But if you saw the same effect in non-identical twins, then really the environment must be playing a role.

In this particular study, they found that almost 50 - 60% of the risk of becoming alcoholic was really due to genetic factors.

Yes, the environment was playing a role, but not such a big role as the genetics were, the addiction being heritable. 


The same group then went on to look at how genes' environment alter over time.


They looked at four different substances; caffeine, cigarettes smoked, consumed alcohol and cannabis.

They measured the rates of the genetic factors and environmental factors and not the family environment, but also their personal environment: things like what mates do they have? Do they have school friends? Does their neighbours actually affecting them?

..and they found something really surprising - in fact the family environment stayed stable over ages. In one case in cannabis, there was a dip in consumption over about the age of about 20 to 30, because obviously the people kind of settled down, then they cut back and then it went up again.


Their personal environment didn't change over time, but the genetic aspect did.


Up to the teenage period, it's the environment that makes a difference. Your peer group is really important. For an adult the family environment doesn't play a role. But the genetic aspect actually causes some individuals to become dependent and consume more than they should, which in clinical terms is known as risky consumption.


We've seen that genetic factors are important, so our next key questions today is:

What are these genes? How do they affect addiction?

Are there certain factors that make certain genes more relevant? Well, certainly the way the drug is going to be metabolised is going to be important. In some individuals, this may be the rate - it might actually affect whether they consume the drug more, or the way the drug makes them feel. If the drug makes a person feel good, you want to feel that way more often, maybe always. 


I mentioned earlier (see PART 1), that dopamine is raised by most drugs. Dopamine is that chemical in the brain that makes us feel good. For some of us, we don't need to consume drugs to feel good. Maybe a shopping expedition is all we need (which can be part of an addiction, or a stimuli for an upliftnig experience). But for some individuals, they need to take more and more drugs in order to feel good.


In an interesting study on 30,000 smokers was done where they looked at the genes that code the two enzymes that actually break down nicotine, cytochrome (iron) A6 and B6. Could one see a change in the sequence of these enzymes, would that make a difference to smoking? For one of the genes, cytochrome 6, there's a variant, a change in that gene which has a reduced function of the enzyme. And guess what? Those people actually smoked less. This in a way is interesting, because perhaps we could design drugs that actually would help people reduce smoking! 


Lots of work has been done on the metabolism in alcohol, partly because alcohol is a very common drug. In most societies on Earth, alcohol is a socially acceptable drug. But it's the THIRD leading cause of death, so we need to understand what is it that makes people want to drink so much?


Two enzymes that break down alcohol is alcohol dehydrogenase and acetaldehyde dehydrogenase. Would the genes that code these enzymes make a difference to drinking behaviour? Indeed, it does! But what is interesting is that some of the variants are protective factors, one in particular called ADH1B.  It occurs at a higher frequency in East Asians. What happens is that this particular variant produces alcohol to a greater extent. It makes people feeling sick, and therefore they actually don't want to drink. But that doesn't explain why people become dependent so there must be other factors and other genes.


More recently there's been a study that was done in an ageing population.

They found that the gene ADH1A actually leads to increased drinking, but it isn't associated with alcohol dependence, but number of drinks. It's actually somehow leading to people drinking more. There was another study done in Australia that found a similar result where this gene was associated with increased drinking. Now we have genetic factors that actually lead to either more drinking or some sort of behaviour.


Genetics research in addiction has only really beed questioned the last 10 or 20 years. Just identifying a few genes doesn't tell us really why people become addicted. But if we can understand the mechanism, then what we can do is actually understand the kind of person who is likely to become addicted. If we can identify addiction early, personality traits, then we can help these individuals at an earlier age and then we can actually prevent them from getting into the cycle of addiction. I think that's where we want to go, where we can actually offer these individuals a better quality of life at a much earlier age. It's no point bringing in policies when the person is 20 or 30 years old dependent on heroin and really they cannot get out of that cycle. The key thing is helping them at a much earlier age when they can manage the disease, this is what we want to aim for with genetics research.





SUMMERY - genetic and environmental factors may be correlated or may interact in a number of different ways. Individuals exposed to high genetic risks for a particular outcome may also experience more adverse environments, while environmental factors may also influence the importance of genetic influences and vice versa.

Years back there were debates about whether nature or nurture was most important in the development of addiction or other behaviours. Now I think it is well accepted that both nature and nurture are important, and increasingly interest is focused on the interplay between these factors in the development of addiction.

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