Decision making in the pathway from genes to psychiatric and substance use disorders

Abstract

In influencing risk for psychiatric and substance use disorders, genes are typically conceptualized as working in silent physiological pathways in the bowels of our biology, far from the influences of human desires. I here argue that this model of gene action is too restricted. At the individual, family and societal level, humans can, through their decision-making capacity, intervene in causal pathways from genes to behavior. At the individual level, I present four paradigmatic cases involving alcohol dependence, major depression, general externalizing behaviors and animal phobia showing how human decisions can inhibit the expression of risk genes. I review the literatures demonstrating that parental behaviors can suppress or augment the heritability of traits in their children, and social attitudes can alter and even create causal pathways from genes to phenotypes. We evolved from organisms whose nervous systems were networks of reflexes that then developed simple cognitive systems and finally self-reflection. Just as our cognitions have gone ‘meta,’ we are now nearing a time when we can go ‘meta’ about our genetic risk. For many psychiatric disorders, our risk genes are not entirely cordoned off in our silent, purposeless biological substrate. Rather, we are able to make decisions that impact on the expression of our own genomes, those of our loved ones and those of our friends and neighbors. Our actions and our genes are often weaved together, integrated into the fabric of our lives.

‘Yes, we can imagine a process of self-creation that starts with a non-responsible agent and builds, gradually, to an agent responsible for its own character.’ (ref. 1 p. 170)

The pathways from genes to psychiatric disorders are complex and probabilistic. Such variegated pathways stand in contrast to the direct and deterministic ways in which disordered genes produce Mendelian disorders. I seek, in this essay, to add an additional layer of intricacy to this story. In influencing human behavior, ‘genes’ are typically conceptualized as working through silent physiological pathways in the bowels of our biology far from the influences of human thoughts, feelings or desires. They are ‘out of reach,’ beyond our ability to influence or alter save by the heroic and still futuristic methods of gene therapy.

I here argue that this model of gene action is too constricted. At the individual, family and societal level, humans can intervene in causal pathways from genes to behavior. My argument assumes the philosophical positions of non-reductive physicalism and ‘compatibilism.’ That is, I believe the kind of free will ‘worth having’ exists.¹ I view embodied humans as self-reflective and potentially self-directive and do not, therefore, accept the position of ‘hard determinism,’ that our strong internal sense of being able to direct our own behavior is inevitably and always mistaken.

Decisions and Gene Action

The person

A simplified causal pathway for a Mendelian disorder like Tay-Sachs disease looks like this:

(i) Genetic variant→(ii) disturbed physiological processes→ (iii) disease.

This pathway is uncontroversial and deterministic. All individuals with Tay-Sachs disease have critical mutations in both copies of their HEXA gene as a result of which they have inadequate function in their hexosaminidase A. The absence of this enzyme leads to an accumulation in cells of phospholipids that produces wide-spread brain dysfunction and early death. This diagram equally applies to disorders with prominent somatic manifestations and those that, like Tay-Sachs or Huntington's disease, substantially affect brain functioning and behavior.

Let us turn to the behavioral syndrome of alcohol dependence (AD). Although the evidence for the impact of genetic factors in aggregate is strong,^2–4 many genes are involved and the association between any one variant and outcome is probabilistic. We have some insight into the mechanism of action of these risk genes, including alcohol metabolism in the liver and neurotransmitter systems that may mediate some of the psychoactive effects of alcohol.^5,6

(i) Genetic variants→(ii) disturbed physiological processes→ (iii) elevated risk for alcohol dependence.

Nonetheless, the predominant model is that genetic risk for AD works silently on the biology of our liver and brain, far removed from the domain of human decision making. However, offspring of families with high rates of alcohol problems, who are at an elevated genetic risk for AD, also have an increased probability of being teetotalers.^7,8 This produces a different causal path:

(i) An individual with a strong family history of AD→(ii) This individual receives a range of high-risk genetic variants from parents→(iii) This individual perceives the harmfulness of a possible outcome of developing AD, leading to a decision to abstain from alcohol→(iv) zero risk for alcohol dependence.

What is happening here is simple but crucial to my argument. In step (iii), human volition is intervening between the genetic variants conveying a high risk to AD and the phenotypic outcome. Teetotalers with a strong family history of alcohol dependence are saying to their risk genes for AD, ‘I have seen what you can do to my father, uncle, brother…. I am not going to give you a chance to do that to me!’ This moves the causal cascade from risk genes to AD into the light of consciousness and decision making.

Here is a subtler story based on a real case from our population-based twin studies.⁹

Roseanne and her monozygotic twin sister, Mary, grew up in a devout Roman Catholic household dominated by marital conflict. Their parents had repeated separations leading to a permanent separation when the girls were 12 years. Their mother had several mild depressive episodes in response to the earlier conflicts but then had a severe, impairing episode of major depression (MD) when the father announced he was leaving. Roseanne described herself as sensitive and nervous as an adolescent. She began dating at age 16 years and found herself easily upset by the ups and downs of teenage romance. She became increasingly involved in her religion and after graduating from high school became a nun. Her twin sister, Mary, married her high-school sweetheart, but that marriage broke up after 4 years and 2 children. Mary had repeated depressive episodes over her adult life, all related to unsuccessful romances. When we interviewed Roseanne, she was 52-years old and denied any history of mood or anxiety disorders. When asked to reflect on the differences in her life course and that of her identical cotwin, she said, ‘I have often thought of this. Looking back, I think I realized I could not deal with men. I saw what was happening to my mother and saw the same future for myself. It was then that I decided it was better to fall in love with God. I have had a rich and wonderful life, and I feel so badly that Mary has had such an awful time of it.’

Like the future teetotaler, Roseanne saw what marital conflict had done to her mother, sensed her own vulnerabilities and chose a life path that would put her at low risk for MD. In this case, we have the ‘natural experiment’ of a monozygotic twin pair that can give us an inkling of what Roseanne's life might have been had she made different decisions. The causal pathway looks something like this:

(i) An individual with a family history of MD→(ii) This individual receives high-risk genetic variants from her mother→(iii) This individual notes environmental precipitants of MD in her mother deriving from romantic reversals and perceives her own vulnerability to these effects in early dating experiences→ (iv) These perceptions, along with her increasing religious devotion, leads her to become a nun and renounce romantic relationships with men→(iv) a life without evidence of MD.

A third story

James is a high-school junior and an athlete. Though smart and college-bound, he has also been an impulsive risk-taker since childhood. His father had repeated drug problems through adulthood, which often caused marital and family conflict. James started this school year hanging out with his old friends, college-bound kids who like himself, got good grades, played computer games and had fairly tame weekends listening to music, playing games and drinking a few beers. Lately, though, James felt he was ‘missing out,’ and these parties were getting boring. Last week at school, he was invited to a party on Saturday night, and decided it would be a lot more fun than playing video games again. When he showed up, there were people spilling out of the house and music blasting. It was a completely different scene than he was used to. Inside, joints were passed around, and the room was filled with clouds of bluish smoke. A group of girls and a couple of guys were in the bathroom with the door half open, laughing loudly and snorting bumps of cocaine. Kids were sitting on the counters in the kitchen making out. Although uncomfortable at first, James was having a good time and got an invitation to another party next weekend. But later in the night, while he was standing in line for the keg, an older guy James recognized from school came up to him. He held out a joint to James and with a funny look on his face, asked him if he wanted to ‘get wet.’ Though James did not want to look uncool, he shook his head and walked away from the keg line. He was not sure what the older guy meant but felt uncomfortable and pressured. He could not stop thinking about this over the next week and decided to talk to his older sister, with whom he had a close relationship. She told him that several kids in this crowd were flunking out of school and had drug problems, letting him know that ‘getting wet’ meant smoking PCP (1-(1-phenylcyclohexyl)piperidine), a dangerous drug that she said he should ‘stay away from.’ She was worried about him ‘hanging out with the wrong crowd and picking up the kind of bad habits that has plagued Dad most of his life.’ This advice hit home. James decided not to go to the second party. Even though they were ‘boring,’ he would stick with his best friends who supported him and encouraged his ‘better’ side.

Genetic factors can impact on the risk for externalizing disorders through encouraging or discouraging selection of deviant peers, a process I have previously called genetic control of exposure to the environment.^10–13 James was given the opportunity to switch peer groups in his junior year in high school. Realizing its potential seriousness, he took time to think and consult a trusted sibling. The causal pathway looks something like this:

(i) Individual with a family history of substance abuse→(ii) This individual receives high-risk genetic variants from his father resulting in risk-taking personality traits→(iii) Attracted to peers with similar characteristics and experiments attending a party→(iv) Although liking the ‘exciting’ environment, he is concerned enough about the implications to seek advice, on the basis of which he returns to his much less deviant original peer group→(v) considerably reduced risk for drug and alcohol problems in high school.

By shifting back to a low-risk environment for drug and alcohol problems, he has substantially reduced—at least during high school—the ‘penetrance’ of his risk genotype. He was consciously thwarting the desire of his genetically influenced impulsive personality traits to control his selection of a deviant peer group.

The family

Parents can impact on the expression of genetic influences in their children. In an elegant study, 348 9-month-old adopted infants were put into a frustrating situation in which they could see an attractive toy that they could not touch.¹⁴ In the entire sample, the infant's ability to deal effectively with this situation by shifting attention away from the desired toy (and thereby distracting themselves from the rising frustration) was negatively correlated with externalizing traits in their biological mothers. That is, offspring of mothers high in externalizing traits were more likely to keep trying to get to the toy, thereby becoming frustrated and irritable. The research team then divided the sample of adoptees into two groups based on the levels of negative affect in the adoptive mother. In the infants raised by a mother with high-negative affect, the correlation between externalizing traits in the biological mother and irritability in the infant was quite substantial. If the adoptive mother had low levels of negative affect, this correlation disappeared.

Adoptive mothers were able to exacerbate or attenuate a genetic predisposition to irritability. The causal pathway in families with the adoptive mother with good mental health would look something like this:

(i) Genetic variants for high externalizing/irritable traits→(ii) high quality parenting by a calm reassuring mother→(iii) low levels of irritable traits in infancy.

Although parenting is a complex behavior influenced by many factors,¹⁵ parents can influence, at least in part, how they raise their children. So, again, step (ii) shows that volitional behavior, now of a parent, can sit in the causal pathway from genes to behavior.

Of the numerous other examples of this kind of process in the literature, I provide two. In 14-year-old Finnish twins,¹⁶ the heritability of smoking behavior was quite high (∼60%) in the presence of low levels of parental monitoring, and quite low (∼10%) when the parents consistently kept tabs on their children's behavior and whereabouts. In a high-risk youth whose parents were high on monitoring, the causal path would look like this:

(i) Genetic variants for smoking behavior→(ii) high-parental monitoring→(iii) reduced exposure to smoking→(iv) reduced opportunity for expression for risk genes for smoking.

In Dutch male adolescent twins, genetic influences accounted for 49% of the variance in the personality trait of disinhibition if they were raised in nonreligious families, and had no impact if raised in a religious household.¹⁷ Here the pathway for a boy with risk genes for impulsivity raised in a religious home would look like this:

(i) Genetic variants for disinhibitory trait→(ii) religious house-hold with high levels of parental control→(iii) impulsive traits much reduced by parenting style→(iv) no genetic impact on levels of disinhibition.

For genetic variants that predispose to many human behavioral traits, parents have the capacity to augment or diminish their effect. The volitional behavior of parents can sit in the causal pathway from genes to behavior.

The culture

Cultural values can profoundly impact on pathways from genes to phenotypes, literally creating new paths and modifying others. I give examples of each.

Beauty and height are highly heritable.^18–20 In our culture, beautiful and tall people are viewed more positively, and make more money than ugly and short people.^21–23 This attitude creates the following pathway:

(i) Genetic variants for beauty and height→(ii) Negative social biases toward ugly and short people→(iii) Beautiful and tall people preferentially hired into high paying jobs→(iv) increased income associated with genetic factors for height and beauty.

Because of the presence of these attitudes, genes for beauty and height contribute to genetic variation in income. If these attitudes disappeared, so would this causal pathway. (A similar and more morally repugnant story could be told about genetic influences on skin color producing prejudice in educational and employment opportunities leading to changes in income.)

Social attitudes toward smoking in women changed dramatically during the 20th century. One study of twins reared together and apart²⁴ showed that for women born in Sweden from 1910–1924, smoking rates were low and genetic risk factors had no impact on smoking behavior. For women born from 1940–1958, smoking rates had risen more than three-fold and heritability was now estimated at 64%. This study would suggest the following casual path for those born in 1910–1924:

(i) High genetic risk for smoking→(ii) Strong social stigma to smoking behavior→(iii) Low risk for smoking and progression to nicotine dependence.

And those born in 1940–1958:

(i) High genetic risk for smoking→(ii) Low social stigma to smoking behavior→(iii) High probability of smoking and progression to nicotine dependence.

Moral luck

The offspring of a family with a high rate of alcoholism knows something about his risk for alcohol dependence before he starts to drink. But what about people who try alcohol or other drugs like cannabis, cocaine or heroin knowing nothing about their genetic risk for successful recreational use versus abuse or dependence? This brings us to the concept of moral luck, as described initially by Bernard Williams.²⁵ It refers to circumstances in which a moral agent is assigned blame or praise for the results of an action when the agent had control over the action but no control over the consequences of the action. An example of moral good luck would be:

In a fit of rage you grab the loaded gun out of your desk drawer to kill your good friend who just insulted you. You point the gun at your friend and pull the trigger. It misfires. You realize your mistake and are immediately filled with regret about your actions, and gratitude at your gun's malfunction.

Your intent was to murder. In a court of law, as a result of good luck, you would be guilty of attempted murder and not murder. An example of moral bad luck would be:

You are a careful driver. A song comes on the radio that you particularly like. You reach down to turn up the volume just as a dog chasing a ball runs in front of the car. You stomp on the breaks but it is too late. You hit and kill the dog. The little boy who threw the ball runs toward you, weeping and trying to hug his bloodied dog.

You had changed the volume knob on your radio hundreds of times without consequence. Had you anticipated these events, you surely would have kept your eyes firmly on the road. But you did not. You had bad moral luck.

Now, imagine an individual—John—a college student with a low genetic risk for cocaine dependence who is given his first chance to try cocaine at a party in college. As far as he knew, no one in John's family had ever tried cocaine, and he never thought about his own level of genetic risk for cocaine dependence. John decides to try and has a good time. He has few after-effects and uses the drug recreationally a few more times with no problems and then stops. John had good moral luck.

Now imagine Bill, also a college student. Unbeknownst to him, he has a range of common genetic variants, which make him at high risk for cocaine dependence. At a similar party, he gets a similar invitation and, like John, tries the cocaine. However, unlike John, Bill is extremely attracted to the cocaine high. That first night, he uses all the available cocaine that his friend is willing to give him. He asks his friend where to get more. Fast forward to a few months later and Bill has stopped going to class, is using crack cocaine daily and stealing to support his habit. In trying cocaine, Bill had bad moral luck.

Each of us has a latent causal pathway from our genotype to outcomes ranging from benign experimentation to severe dependence for each of the rather large class of psychoactive drugs of abuse. However, we are not all born with an equal genetic risk for drug dependence.^26–28 Few of us, however, know our risk level. Whenever we try a psychoactive substance with abuse potential, we are creating a possible causal path from our genes to drug abuse. That is, our decisions to try and use these substances ‘turn on’ these latent pathways. We are gambling that our moral luck will be good and our abuse potential low. The lifetime teetotaler with the strong family history of alcoholism is just someone who has decided that the gamble is not worth it. The odds are too high that he will have moral bad luck.

The future

Our ability to intervene in pathways from genes to phenotypes is increasing. The future for psychiatry may be glimpsed through advances in other areas of medicine. Mutations in the BRCA1 gene lead to marked elevations in risk for breast cancer.²⁹ In addition to heighted screening, women carrying such mutations can substantially reduce their risk of illness with salpingo-oophorectomy, treatment with the anti-estrogen tamoxifen or most definitively, prophylactic mastectomy.³⁰ The causal paths would look like this:

(i) pathogenic genetic variant in BRCA1 gene→(ii) positive genetic test→(iii) decision to take medical or surgical intervention→(iv) marked reduction in risk of illness.

It is difficult to see clearly the nature of gene-based interventions that might arise in psychiatry. We are unlikely to discover single gene variants with large impacts on rates of illness. Risk scores from many genes of small effect are more realistic. Questions about the efficacy and ethics of preventive treatments for psychiatric illness are substantial.³⁰ However, the future will undoubtedly provide us further ways for human decision impacting on causal pathways from genes to psychiatric illness.

Discussion

I sought, in this essay, to further complicate the causal pathways from genes to behavioral, psychiatric and substance misuse phenotypes and show that human decision making can interpose itself at various points along these pathways. Causal effects are not restricted to silent, biological processes occurring outside of human awareness.

Let us first focus on decisions individuals make that influence their own genetic risk. We evolved from organisms whose nervous systems were little more than complex networks of reflexes. At some point, simple cognitive systems emerged from these networks and then, critically, self-reflective processes arose. Our cognitions went ‘meta’ as we developed the self-representations that had an important role in the emergence of consciousness.³¹

But throughout this evolutionary time period, our genetic system ran without notice in the background, below the level of conscious detection. But this has changed in the last 150 years with the discoveries of Mendel and Watson and Crick. We are approaching a period of history in which we will be in a position for us to go ‘meta’ about our genetic risk. As we realize its presence and potential importance, we can consider, intervening in the involved causal paths. The great British philosopher John Locke³² proposed one definition of human freedom:

‘For, the mind having in most cases, as is evident in experience, a power to suspend the execution and satisfaction of any of its desires; and so all, one after another, is at liberty to consider the objects of them, examine them on all sides, and weigh them with others. In this lies the liberty man has. ’Essay II, XXI, 48.

Increasingly, through our self-reflective abilities, we can treat our genetic propensities the way Locke believed we should treat our desires. We can weigh them to see if we should try to seek or deny their satisfaction. Richard Dawkins concludes his influential book, The Selfish Gene, wherein he describes genes as ‘selfish replicators’ by making a similar point (here referring to our ability to develop altruism): ‘We, alone, on earth, can rebel against the tyranny of our selfish replicators.’ (ref. 33 p. 215)

A good deliberator focuses on the range of the possible. We cannot consider all outcomes so our efforts are best spent with the plausible rather than the highly unlikely. That is, any finite control system—including the human mind/brain—has to deal probabilistically with available inputs and reach decisions in real time. This is an error-prone process often because key information is lacking or over-looked.

You are offered drug Z at a party. How do you decide whether to indulge? How do you balance the short-term rewards of feeling part of the group and the possible pleasures of the intoxicated state with the longer-term risks? Here, your genes have a role in your chances for good or poor moral luck. But notice that the moral luck now arises in part from ignorance and not solely from random events in the world, which are inherently unknowable (like the chances your gun would jam).

Furthermore, it is not just your response to the first exposure that counts. Any control system needs the capacity to modify itself—to learn. Can you take account of the corrective feedback loops? Although a sure way to silence your risk genes for addiction is to never try the substance; if you want to partake, there is still room for maneuvering before addiction develops. When it is offered again, it is possible to say ‘Sorry. I liked it too much the first time and fear that I will lose control if I try it again.’ Furthermore, as illustrated by the story of James, it is possible to avoid the social milieu that provides access to the drugs and encourages their use. Or, as illustrated by the story of Roseanne, it is possible to escape from the social requirements (dating and romance) that are likely to be depressogenic. ‘Outside the skin’ pathways for gene action in psychiatric illness³⁴—a mechanism for which there is now substantial empirical support³⁵—may be particularly susceptible to the impact of human decisions.

Most of us are aware of how our genetic heritage influences our physical characteristics and capacities. It will, for example, have occurred to many male readers, that, regardless of the amount of dedicated practice, they do not have the endowment to be a professional basketball player. We seem less inclined to adapt our deliberations to how our risks for psychiatric and substance abuse disorders might be altered by our genotypes.

Turning to families, for eons human parents have unconsciously tried to modulate the impact of the genetic propensities of their children. In teaching self-restraint to the impulsive or self-confidence to the socially anxious, parents try to redirect or suppress what they see to be negative genetic vulnerabilities in their offspring. In paying for music lessons for the young musician or basketball camp for the young athlete, they try to actualize the genetic propensities they see as positive. They can be more effective parents if they know more about the predispositions and vulnerabilities of their offspring.

Our behaviors and attitudes can also act on the broader stage of human society and culture. We can create, consciously or unconsciously, environments that can augment or suppress genetic effects on behavioral traits.^35,36 More frighteningly, we can create new pathways from genes to human traits.

In one way, the message of this essay is far from new. We have long known that the heritability of many human traits is context dependent. Change the environment and you can change the magnitude of genetic influence.³⁷ Some of these environments are governed solely by natural forces or the effects of chance. However, it was not fully realized that humans often create the environments, which in turn alter the heritability of their traits.

Having good information about our risks can help us make decisions that influence the expression of our genes and those of our children. The child in a family dense with alcoholism does not need sophisticated genome sequencing or genetic counseling to reach the conclusion that abstaining from alcohol might be the safest course of action. Will increased knowledge of our genetic risks for psychiatric and substance use disorders eventually result in allowing us to be better deliberators—to have a more prominent and salutary part in the causal pathways from genes to disorders? This is an outcome to be wished for.

The major points made in this essay are not unique to behavioral or psychiatric disorders. An individual with a strong family history of heart disease who sees his father die from a myocardial infarction in his early 50s, who then starts to exercise, monitor his cholesterol level and reduce his saturated fat intake, is very much like the lifetime teetotaler from the high-density alcoholism family. Although not as effectively as the lifetime abstainer, he is trying to tell his high-risk genes for coronary artery disease to ‘take a hike.’

I emphasized drug abuse in this essay because it is in this group of disorders that the impact of human decision making can be most clearly seen. Other psychiatric syndromes, such as bulimia or pathological gambling, where the focus of concern is disordered behavior, could also have been highlighted. The decision to go to a casino and gamble for the first time, or try that first binge on a dozen doughnuts and then vomit into the toilet, may not differ so much from the moral-luck examples outlined above. That is, they might be roughly equivalent to taking cannabis or cocaine for the first time. You are at risk for liking it too much.

For other disorders, the role of decision making may be much more subtle. Consider the following case:

An 11-year-old girl, Rachel, was quite traumatized when the neighbor's German Shepard became aggressive and bit her leg, requiring stitches. Over the next few weeks, Rachel became quite frightened of this dog—nearly to tears. She also began avoiding the other dogs in the neighborhood and became upset if they barked at her when walking home from school. Then, she went to visit her grandparents who have a gentle Cocker spaniel (Mammy) that she had known all her life. On the drive over, Rachel thought of seeing Mammy and felt the fear rising in her. Being a determined sort, she said to herself, ‘That is silly. Mammy would never hurt a flea!’ On seeing Mammy, despite her anxiety, Rachel played with her actively all day by the end of which her anxiety in being around Mammy had disappeared. Her parents noted that Rachel's fears of the neighborhood dogs declined and then disappeared over the ensuing months, although she still kept a respectful distance from the neighbor's German Shepard.

Rachel was on her way to developing a dog phobia for which she likely had a modest genetic predisposition. Her avoidance, which was maintaining her conditioned fear response, was ‘settling in.’ Although the original conditioning may have resulted entirely from unconscious brain pathways, she was confronted with a decision about whether to play with Mammy, as she had always done, or avoid her as well. Once the decision was made, the extinction process was able to get started. The fear declined, the dog phobia was avoided and the pathway from her genetic risk to the disorder was broken. As we saw with Roseanne's choice to become a nun, the relationship between decision making and genetic risk for internalizing disorders is less direct than might be seen with drug abuse. But it nonetheless can have an important role. This may not be the case for other psychiatric disorders, such as schizophrenia or autism, where there may be little or no opportunity for human decisions to impact on the pathway from risk genes to disease.

The human decision making referred to in this essay occurs within the human mind/brain system. As noted above, I assume the philosophical positions of non-reductive physicalism and ‘compatibilism’.¹ We humans are self-reflective and can be self-directive. I say potentially because we have a range of psychobiological forces at work on our decision making (hunger, sexual drives, addiction) that can sometimes render decisions extremely difficult to enact.^38,39 I do not seek to underplay the potential power of these deeper urges, which through their strength and persistence can be overwhelming.^38,40 Wallace,⁴⁰ who termed the subjective urge of the addicted individual to use drugs as ‘A-impulses,’ summarizes this position well ‘The specific kinds of defects… [in] addiction are best understood as impairing our powers of reflective self-control, without depriving us of those powers all together.’ (p. 652). Although not central to my argument, it is also noteworthy that the belief in free will is empowering for patients and its denial has been empirically shown to encourage antisocial and irresponsible behavior.⁴¹

The philosophical position of hard determinism argues that human volition is an illusion⁴² and all we are is cold biology with no emergent ability to influence our course through life. Thus, the decision by the teetotaler to abstain from alcohol or the mother to carefully monitor her impulsive son is fully predetermined by their genes and previous environmental exposures. If true, this position would undermine all the key arguments presented here.

I have not here attempted to deal with the subtleties of how individuals respond to the availability of information about their genetic risk for illness. As indicated by the modest proportion of subjects at risk for Huntington's disease who request genetic testing,⁴³ in at least some circumstances, people do not always want to know. As sensitively reviewed by Klitzman,⁴⁴ many factors, including the plausibility of prevention or treatment and the implications of test results on risk to offspring, impact on individual decisions of whether to get genetic testing. We now have only a modest research base of information about attitudes towards genetic testing in psychiatric illness (for example, Trippitelli et al.⁴⁵ and Wilde et al.⁴⁶). We can expect a range of factors to impact on how much people will seek out information on their risk for psychiatric and drug abuse disorders, and how they deal with the information once received.

I do not advocate any kind of dualism between genes and the environment. Environmental experiences—brain trauma, sexual abuse—can be as deeply physically instantiated in the mind/brain system as effects of genetic variants. However, genetic determinism is currently a far greater concern than environmental determinism and hence is the focus of this essay. I could have written about how human decision might sit in the causal pathway from child abuse to psychiatric illness.

Finally, this essay argues against viewing addiction solely as a ‘brain disease’.⁴⁷ Drug addiction was once seen entirely in moralistic terms as the result of bad choices. Although more benign, it is also overly simplistic to assert that human volition has no important role in the development of addiction.^41,48 As elsewhere, our science and clinical work would do best to adopt a pluralistic perspective recognizing that addiction arises from a complex mixture of social, psychological and biological factors along with an important role for human volition.⁴⁹

Conclusions

Our genes are not entirely cordoned off in our silent, purposeless biological substrate, distinct from our existence. We are able to make decisions that impact on the expression of our own genomes, those of our loved ones and those of our friends and neighbors. These decisions can impact on the degree to which these risk genes are expressed. Our actions and our genes are often weaved together, integrated into the fabric of our lives.