Genetic causality and addiction

Martin Nicolaus caught my attention a month ago when he made some bold statements about the genetics of addiction:

Modern genetic research has wiped away any basis for the idea that alcoholism is a genetically transmitted disease. The most that can be said is that some people appear to inherit a lower responsiveness to alcohol, so that if they drink, they must drink more to get the same high.
...
Much of the myth of genetic causality rests on twin studies.[emphasis mine]

A recent commentary in Addiction wrestles with the elusiveness of easy genetic causality but doesn't throw the baby out with the bath water, explaining the difficulty in identifying genetic markers for diseases:

...there are two main reasons why association studies may not identify genes for addiction.

First, as stated above, there is the absolute requirement of adequate exposure to the drug in question for addiction to occur. For most illegal drugs the majority of the population, from which the control group is drawn, have not been exposed to the drugs and they are, therefore, unscreened controls. (The effect this may have on statistical analysis of association studies is described below.)

Secondly, the required exposure to illegal drugs is not likely to be random, but due rather to genetic and environmental characteristics of the individuals who choose to seek out these drugs, or if offered to them, choose to experiment.

The problem is that many, perhaps most, linkage or association studies will result in finding genes which predispose people to start taking illegal drugs in the first place rather than genes involved in the addiction process. The genes they find may be involved in risk taking, sensation seeking, impulsivity, etc. It seems likely that these genes/variants may also predispose individuals to mountain climbing, race-car driving, extreme sports, etc. and are therefore not related to the biological processes involved in the development of addiction. This does not necessarily mean that identification of such genes are not helpful, but they are not likely to be related to the addiction process of any specific drug, nor of its treatment, which usually does not have alteration of personality as its goal.

Further, it explains that genetic effects can be divided into two categories:

...those which directly affect the process which is perturbed during drug addiction and those which modify the known environmental effect, i.e. the liability to take drugs in the first place.

The author goes on to explain the difficulty in defining and obtaining controls for genetic studies:

While the definition of the phenotype is a major problem for any genetic study of addiction, the definition of an unaffected control is at least as problematic. For most diseases a control subject is someone who has been exposed to the known specific environmental risk factors, such as passing a certain age in studies of Alzheimer's, but who is disease free. For addiction to drugs to occur, as stated above, at a minimum there is a requirement that the individual has taken the drug in question for a sufficient length of time and in sufficient quantities as to have become addicted should they have the propensity to become so, and has continued access to the drug. Buckland suggested previously that students, at least in the United Kingdom, would make good controls for alcohol addiction [36]. However, there is no evidence that students drink more than their peers, and in addition students are relatively young to manifest alcohol addiction. Given this, it is even less easy to find a sample who have been exposed sufficiently to other drugs and are clearly not addicted; for most purposes control groups must be considered to be unscreened. The power to detect an effect is lowered by the use of unscreened controls, the extent of this depending upon the population frequency of the underlying trait, but this can be compensated for by increasing the number used by twofold or more. A statistical study [44] shows two things of importance to this concept: first, to achieve the same power, if the population frequency of the trait is less than 10% then in general simply doubling the number of controls will be enough. However, above this population frequency, the required number of controls increases exponentially. Secondly, in general, the number of unscreened controls required to give equivalent power to one screened control increases as the odds ratio of the associated allele decreases, and therefore screening controls appears to be more important when studying small genetic effects with a high prevalence of the trait [44].

He sums up the challenges in his conclusion:

There are numerous reasons why it has proved far more difficult to find genes associated with complex illnesses than what was predicted in the early years of these studies. Only now are serious advances being made by using very large sample sizes; however, the genes for addiction may still be out of sight. There are two principal specific impediments to the identification of susceptibility variants for drug addiction.

First, it is likely that a greater portion of the genetic variance in drug abuse originates from effects which are non-specific to any one drug, or to drug abuse in general, than from genetic variance which underlies the specific addiction process.

Secondly, when compared to other complex phenotypes, addiction to drugs is far less well defined, the structure of the phenotype is not fully understood, controls are effectively unscreened and heritability is relatively low.

Both of the above suggest that far larger cohorts of probands are required for genetic studies in addiction compared to other complex illnesses. Unfortunately, the largest study to date of any drug of abuse has used numbers of samples an order of magnitude fewer than are being used currently in comparative studies.

What does all this mean? Clearly, establishing the extent and specifics of genetic causality is proving far more difficult that most of us anticipated and it is pretty clear that no single gene will exert a very strong influence and that it will be certain combinations of genes that predict addiction.

I've always thought that there is a lot for us to learn about typologies of addiction. Maybe learning more about the genetic combinations that contribute to addiction will help us understand who is more or less susceptible to multi-drug addictions. We may also learn more about shared genetic traits with some process addictions. We'll know more in a decade.

Farm staff who want a copy, let me know.