Psychiatric disorders develop trough an interplay between environmental and genetic factors. Genetic vulnerability to a disorder can be moderated by environment and vice versa. However, most studies that described this interplay, or gene-environment interaction (GxE) are based on studies using single candidates. After recognizing the shortcomings, researchers started focusing on polygenic and genome-wide approaches. In this article, the authors research different theoretical concepts and unpick the difficult interplay between environment and genes in the development of psychiatric disorders.

What are examples of candidate gene-X-environment (GxE) studies?

Several studies investigated the influence of the serotonin transporter (SLC6A4), monoamine-oxidase A (MAOA), dopamine receptor D4 (DRD4) and D2 (DRD2) on the development of anxiety, depression, schizophrenia and bipolar disorder. Another example is research on 5-HTTLPR that seems to moderate the effect of depression. It was found that monoamine oxidase A (MAOA) is responsible for degrading neurotransmitters like norepinephrine, serotonin and dopamine. When this gene is mutated, this results in lower or higher levels of these neurotransmitters. Low MAOA-activity interacts with traumatic life events, people with low activity of MAOA exposed aggression and antisocial behaviour during adolescence more often than people with normal MAOA activity. No difference was found in the absence of a traumatic event. This interaction effect is moderated by gender and is stronger in boys than girls. Another study is the connection between catechol-O-methyltransferase (COMT) and schizophrenia. It was reported that a combination of the gene responsible for COMT together with cannabis use can contribute to psychiatric experiences. However, these results are inconclusive. Lastly, an important GxE study is the association between the Dopamine receptor D4 gene (DRD4) and attention deficit hyperactivity disorder. It was found that the genetic variant of ADHD is the 7 repeat allele and causes an increased risk on ADHD symptoms. Children with the DRD4 7-repeat genotype whose mother experienced prenatal stress have a higher risk on developing ADHD.

What are theoretical frameworks of GxE research?

The most commonly used framework for GxE research is the diathesis-stress model. According to this mode, adverse environmental experiences only lead to psychopathology when they are combined with an existing vulnerability. Risk factors that increase vulnerability are mostly genetic factors and biological differences. The diathesis-stress model proposes some people are more vulnerable for adverse traumatic experiences than others. These genetic or biological markers are not enough to cause the mental illness itself, but they contribute to its development. The differential susceptibility theory (DST) challenged the diathesis-stress model. This theory states that people differ in their general susceptibility to both positive and negative environmental influences. When people are more susceptible to environmental influences are more likely to develop psychiatric disorders. The vantage sensitivity framework describes that some people are likely to benefit more from positive effects of supporting experiences than others. This can be caused by several factors, including genetic makeup. This evolutionary approach may be better to account for the observation that genetic variance is common. Also, if there were gene variants that were exclusively related to an increased risk of psychopathology, it would be expected they decrease over time. However, most of these genes appear to be under positive selection. Whether a gene variant reflects a risk for psychopathology depends on the specific qualities of the developmental context.

In most reviewed studies, people carrying the risk-gene variation show fewer negative outcomes in the absence of stressful life events. This finding is more consistent with the differential susceptibility theory than the diathesis-stress model. Whether a genetic variation reflects on general sensitivity to the environment, depends on the placement on the spectrum of sensitivity. Recently, most GxE studies found more evidence for genetic sensitivity, rather then vulnerability. There are many genetic variants that could increase vulnerability for the development of psychopathology, but it might be more appropriate to consider environmental sensitivity to measure risk factors for psychiatric disorders.

What are the limitations of candidate GxE studies?

GxE studies made an important contribution to the field of psychiatry, but there are some limitations:

1. The candidate gene approach requires a strong and biological hypothesis to specify appropriate candidates for the study. The biological mechanisms that are responsible for the development of psychiatric disorders, however these are limited. This can increase the risk of selecting inappropriate candidates.

2. Most psychiatric disorders are influences by thousands of gene variants that all have a very small effect rather than fewer genes with large effects.

3. It is very difficult to replicate the candidate GxE findings because sample sized are often small and lack power. Also, there is a risk for finding false positives.

4. The majority of the GxE studies used the diathesis-stress model, which requires re-evaluation.

What are genome-wide approaches?

Because of the limitations of GxE studies, they are now moving towards genome-wide association studies (GWAS). These studies make it possible to assess the whole human genome to check for associations with psychiatric disorders. GWAS makes it possible to engage in a hypothesis-free approach that does not need a-priori assumptions about the candidates.

What are examples of genome-wide environment interaction studies (GWEIS)?

GWEIS studies can be used to study the entire genome for genetic variations that moderate the effects of the environment on the development of psychiatric disorders. All the current GWEIS studies investigated depression. GWEIS was also used to explore the use of a joint test. The approach tests both G and GxE relationships on outcomes. It increases power to detect effects that are unique for individuals exposed to a specific environmental factor.

What are polygenic score-X-environment interaction studies?

Psychiatric disorders are often polygenic, they are a result from multiple genetic variations. The risk for the development of a psychiatric disorder can be measured by a polygenetic score (PGS). The interaction between depression, PGS and childhood trauma is measured, and they found that the nature of the interaction between the three was different for all cases. There have also been PGS studies for schizophrenia, which had predictive value. People with PGS for schizophrenia exposed a greater decrease in cortical thickness when they used cannabis.

What are future directions of gene-environment interaction studies?

Recently, the shift between candidate-gene studies to genome-wide approaches was made. There is a need to collect more high-quality data to develop mental life-course approaches. There are still some difficulties, such as the aggregate effects of genotypes in polygenetic approaches or the burden of GWAS. However, for further collection of quality data on GxE interactions the following things should be considered:

1. Obtaining better quality environmental measures, multiple environmental factors should be considered instead of just a single and specific one.

2. Focus more on transdiagnostic phenotypes, intermediate phenotypes that are similar across disorders should be further investigated. Examples are emotion regulation and cognitive bias.

3. Applying a developmental perspective, the life-course approach may be needed to fully understand the position of GxE studies in the development of psychiatric disorders.

4. New analytical approaches and study designs, the diathesis-stress model, vantage resistance and differential susceptibility should be carefully chosen to get the best results.

What are new analytical approaches and study designs?

Future studies should consider the type of gene and environment interaction to determine their research strategy. There are several GxE interactions that could be considered:

1. Use of vulnerability genes, studies that investigate a specific type of vulnerability gene can benefit from approaches that reduce the burden of testing multiple times.

2. Vantage sensitivity genes, significant effects of specific genotypes can only be observed in supportive or positive environments. Cognitive behavioural therapy (CBT) presents the opportunity to conduct genome-wide GxE studies.

3. Differential susceptibility genes can be tested in monozygotic twins (MZ twins). They are genetically identical but experience a different environment. Therefore, comparing MZ twins can benefit research to the development of psychiatric disorders.

BulletPoints

• Psychiatric disorders develop trough an interplay between environmental and genetic factors. Genetic vulnerability to a disorder can be moderated by environment and vice versa. However, most studies that described this interplay, or gene-environment interaction (GxE) are based on studies using single candidates. After recognizing the shortcomings, researchers started focusing on polygenic and genome-wide approaches.

• Recently, most GxE studies found more evidence for genetic sensitivity, rather then vulnerability. There are many genetic variants that could increase vulnerability for the development of psychopathology, but it might be more appropriate to consider environmental sensitivity to measure risk factors for psychiatric disorders.

• Recently, the shift between candidate-gene studies to genome-wide approaches was made. There is a need to collect more high-quality data to develop mental life-course approaches. There are still some difficulties, such as the aggregate effects of genotypes in polygenetic approaches or the burden of GWAS.

ExamTickets

• You should know the pros and cons of the different methodologies that are being used in research to the genetic and environmental interaction in causing psychiatric disorders.

• What is the benefit of using MZ twins in researching the interaction between genetic and environmental factors in the development of psychiatric disorders?

• What is the difference between the diathesis-stress model and the differential susceptibility theory?