Article 5c: Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits

Question 1

Gene-Environment interaction (GxE)

Answer 1

The interaction between genes and the environment can explain why people can respons very differently to the same environmental factors.

Question 2

Design of the study

Answer 2

Researchers looked at variation into promoter region of the serotonin transporter gene (5-HTT) and it’s contribution to stress sensitivity. This research was conducted with:
- Human observational studies
- Experimental neuroscience studies
- Nonhuman primates studies
- Genetically engineered 5-HTT mutations in rodents

Question 3

5-HTTLPR and stress sensitivity

Answer 3

People with the SHORT allele of the 5-HTT gene showed reduced gene expression of the serotonin transporter gene, heightened neuroticism, increased amygdala activity to threats and greater susceptibility to depression (especially under stressful life conditions like childhood maltreatment).

Question 4

Human observational studies

Answer 4

The leading explanation is that the S allele underlies the personality traits affectivity and neuroticism. This causes heightened sensitivity to fear and anxiety and increased susceptibility to stress-related disorders.

Question 5

Experimental neuroscience studies

Answer 5

All fMRI studies showed that the short allele was linked to exaggerated amygdala reactivity to threat (but only in provoked stimuli and not at the baseline). The studies both showed increased magnitude and faster threat-related amygdala responses compared to the long allele. This causes heightened emotional and physiological responses to stress.

Question 6

Non-human primates studies

Answer 6

When monkeys were exposed to early life stress (maternal separation) monkeys with the short allele showed reduced active coping behaviours and heightened anxiety, stereotypic behaviour and increased HPA responses. The results suggest that genetic variation in the 5-HTT gene influence a shared corticolimbic network, influencing stress regulation, social behaviour and cognitive responses.

Question 7

Genetically engineered 5-HTT mutation in rodents

Answer 7

These rodents showed heightened anxiety-like behaviour, impaired fear extinction and increased HPA response to stress. Depression-like behaviour emerged only after repeated stress.

Dose-dependent effect of 5-HTT: over expression of this gene showed reduced anxiety.

Question 8

Ai podcast

Answer 8

Serotonin transporter gene = 5HTT: this influences how much serotonin (=happiness) is flowing around in our brain. A small change in this gene can influence how people react to stress. People with the short allele are more sensitive to stress, because they have more activation in the amygdala during stressful events. People with this short allele also have a higher chance of depression after childhood maltreatment (=stress).

Question 9

Limitations

Answer 9

Studies using questionnaires showed a weaker link, but studies using biological markers (like stress hormones) and in-depth interviews found a much stronger effect. → How stress was measured really mattered!

Question 10

Negative affectivity / Neuroticism

Answer 10

The short s allele might make people more prone to developing negative affectivity or neuroticism traits, which makes people more vulnerable to stress (people wired for negativity).

Question 11

Results AI podcast

Answer 11

• People with the short allele show way more amygdala reactivity to stress in an fMRI scan.
• The short allele can strengthen the connection between the amygdala and the prefrontal cortex (which makes it harder for people to control their emotions/ fear).
• Rhesus monkeys with the short allele showed much more stress-reaction to separation from their mother (stressful event).
• Rodent studies that were genetically modified with the 5-HTT gene were much more fearful and showed more stressful behaviour. They also showed behaviour that hints at them being more prone to negative emotions (more neuroticism and negative affectivity).
• Knocking out the 5-HTT gene does way more than just changing serotonin levels: it also can also influence other neurotransmitters (like dopamine) and rewiring of the brain communication.

Question 12

GxE importance

Answer 12

People that experienced childhood maltreatment AND had a short allele of the 5-HTT gene were most vulnerable to negative outcomes.