Article summary with Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits by Caspi a.o. - 2010

The concept of serotonin transport genes and the consequences for research into complex illnesses and traits

Despite the same exposure to equal risk factors in environments, the effects of stressors varies greatly between individuals. This finding can be explained by individual differences in genetic vulnerability. In this article, the variation in serotonin (also called 5-HT) systems is examined and the contribution of these systems to stress sensitivity is evaluated. Specific attention is paid to the serotonin receptor (also known as the 5HTT receptor). This receptor ensures the reuptake of serotonin that is released into the synaptic cleft.

Preface

Studies show that the reuptake of serotonin by the 5HTT receptor is an important predictor for the amount of depressive symptoms that someone experiences. SSRIs (selective serotonin reuptake inhibitor), antidepressants, work by reducing the effect of the 5-HTT receptor. When the effect of this receptor is inhibited, this leads to more serotonin in the synaptic cleft, which leads to a reduction in depressive symptoms. 

In the promoter region of the 5-HTT gene there is a polymorphism which is also called 5-HTTLPR (serotonin transporter promoter polymorphism). A polymorphism is a variation in the same gene. This means that individuals differ in which variation of the gene they possess. This polymorphism concerns the length of the 5-HTT gene. Studies have shown that the short variant of the 5-HTTLPR gene leads to that individuals more susceptible to anxiety and depression in response to stress compared to people who possess the longer gene. This creates a relationship between the short variant of the 5-HTTLPR gene and the development of neuroticism. An increased anxiety response to stress is due to increased amygdala reactivity. Increased amygdala activity occurs in people with this short gene. The amygdala regulates physiological and behavioral responses so that an individual can effectively respond to the environment during social challenges. The extent to which the amygdala is sensitive to environmental threats predicts individual differences in sensitivity to environmental stressors.

Evidence for the 5-HT stress sensitivity hypothesis

Studies show that variation in length of the 5-HTTLPR gene alters the stress response of an organism. The authors of this article made use of observational research to study depressive outcomes.

Observational research in humans

Most observational research with humans into the variation in length of the 5-HTTLPR gene and the interaction of this gene with the environment focused on depression. These studies showed that people with a short variant of this gene who had experienced child abuse or other stressors were more anxious and had more negative thoughts compared to people who possess the long variant of the gene. Children with a short variant of the 5-HTTLPR gene who had a non-supporting mother had lower self-regulation skills. Lower self-regulation skills predict having a psychiatric disorder in adulthood. The underlying mechanism for this is that 5-HT is a genetic basis for personality traits such as negative affect and neuroticism. Negative affect in turn is a predictor for the development of psychopathology in adulthood.

Human primate studies

Rhesus monkeys have a similar variant of the 5-HTTLPR compared to humans, which means that results from studies on gene-environment interactions with these animals are generalizable to humans. Studies looked at the short version of the 5-HTTLPR and its influences on the experience of stress in early life. The monkeys were separated from their mother at a young age and showed increased fear responses and also increased responses from the HPA axis. These responses persist throughout life in the form of higher ACTH responses to stressors released upon activation of the HPA axis. These consequences are associated with depression in humans.

Recommendations for research into gene-environment interaction

Research into gene-environment interaction is a useful tool for discovering genes

It is suspected that genes can reduce the effects of the environment on an organism. Genes that may play a role in this are genes that are involved in physiological responses to psychological stress (regulated by the HPA axis). A gene that has potential involvement in a trait or a disease is called a candidate gene. One can discover new genetic traits through studies into risk factors in the environment. By looking at effects of genotype on gene expression, polymorphisms in positively responsive genes on the environment can be studied to explain why some people develop an illness and others don't.

Public understanding of gene science

An important contribution from research into gene-environment interaction is the elucidation of erroneous genetic assumptions. In the twentieth century, as a result of findings about heredity, it was implied that non-genetic factors did not play a role in mental health and behavior. It was also thought that one's future behavior could be predicted by looking at one's genes. The latest findings about the interaction between genes and the environment provide more realistic public beliefs about the causes of behavior in which some genetic effects depend on the choices that people make during their lives.