The Changing Understanding of the Genetic and Environmental Causes of Mental Illness

Abstract

Abbreviations5-HTT serotonin transporterMAOA monoamine oxidase APTSD posttraumatic stress disorderPsychiatrists have always been trying to understand the reasons why some people become mentally ill while others remain well. In the 20th century, the thinking about the causes of mental health and illness crystallized into the nature versus nurture debate, with the genetic causes (nature) seen as independent and separate from the psychosocial causes (nurture). This divided thinking led to damaging excesses on both sides. The demonstration of genetic contribution to mental illness was interpreted as deterministic causation that was stigmatizing and left little room for preventive or curative interventions short of extreme measures, such as birth control. Conversely, strictly psychosocial interpretations of mental illness led to parent blaming and obscure therapies leading patients to search for nonexistent traumata. In the last decades of the 20th century, findings of quantitative genetics converged to the understanding that genetic and environmental effects are unlikely to be independent of each other. However, it was not until the first decade of the 21st century that the reports of interactions between specific genetic variants and environmental exposures had significant impact on the professional and public understanding of mental illness.The reports that functional polymorphisms in several neuromediator-related genes do not directly cause mental illness but rather sensitize their carriers to the pathogenic effects of environmental exposures brought a new way of thinking about mental illness. A variant in the MAOA gene was found to make its carriers vulnerable to the long-term effects of childhood maltreatment on developing conduct problems and antisocial behaviours.' A variant in the 5-HTT gene sensitizes its carriers to the opposing effects of adverse and supportive environments in the development of depression.2 Variants in several glucocorticoid-related genes may make people sensitive to developing PTSD and other problems after a traumatic event.3 These findings suggest an intuitively plausible mechanism where biology interplays with the surroundings to mould the person's mental processes into healthy or disordered states. It agrees with the observations that some people are resilient to adversity and others are sensitive. Psychiatrists across the world have found this helpful in communicating with patients: nature is no longer deterministic but simply means that different people may need different approaches and each one may have a potential to thrive in his or her niche. Nevertheless, the numerous reports on gene-environment interactions have also proven puzzling. The existence of specific gene-environment interactions has been contested and subjected to complex arguments on issues, such as the statistical nature of interaction, which most psychiatrists find hard to understand.The 2 In Reviews in this issue4,5 provide fresh updates on findings in gene-environment interactions in anxiety and mood disorders. They also exemplify the current debate surrounding the issue of gene-environment interactions. While Dr Marco Battaglia4 probes and questions the nature of causal interactions, Dr Torsten Klengel and Dr Elisabeth B Binder5 assume an affirmative answer to the existence of gene-environment interactions and expound on their meaning and mechanisms. What comes across in both reviews is that the value of gene-environment interactions comes down to whether they are reliably present across populations, that is, whether they replicate.Regarding replication, the various interactions fared differently. The very first reported interaction between MAOA gene and childhood maltreatment in the development of antisocial behaviour was followed by numerous replications, and its validity can hardly be disputed.6,7 Interactions between variants in the glucocorticoid-related FK506 binding protein 5 and corticotropin-releasing hormone receptor 1 genes and environmental adversity also appear promising with initial replications. …