In 2003, Caspi et al released a revolutionary paper in Science, linking the “short short” genotype of the serotonin re-uptake transporter promoter with a much greater risk of developing depression *if* one had significant exposure to childhood trauma. After some controversy, the findings were replicated many times and in different ethnic populations. That’s all quite interesting, but the real question is why? How does a change in the expression of a serotonin transporter increase risk of depression? And not only depression…the short genotype modulates the risk for suicide, anxiety, substance abuse…which makes sense, as all of these psychiatric issues have a shared risk factor, emotional stress. Soon after the Caspi paper was published, scientists went on search for answers, looking at all sorts of aspects of stress response in people with different genotypes.
For a full primer, read my prior blog post, but if you don’t have a minute, the TL:DR version is there are three genotypes in the population for the serotonin re-uptake transporter promotor gene (also known as 5-HTTLPR), two longs, two shorts, and short + long. Folks with the long long genotype seem to be more resistant to depression after childhood trauma than folks with the short short genotype, with short long folks at intermediate risk.
If stress is the shared risk factor for all these problems, then it makes sense to look at how people with the different 5-HTTLPR genotypes react to stress. We already know that the serotonin system in the brain can modulate our response to stress. Serotonin is involved in activating the first step in the hormonal cascade leading, eventually, to our adrenal glands producing cortisol, our major stress hormone. Serotonin can also modulate the cortisol response almost every step of the way in the complicated communications between the brain and the glands that make hormones. Cortisol in the short term can make us more alert, stronger, and faster to improve survival under stressful conditions. In the long term, however, our cortisol response system can more or less burn out with too much activation, leading to exhaustion, depression, anxiety, and many other symptoms of clinical depression and other stress-related disorders.
So how do folks with the different 5-HTTLPR genotypes react to stress? One set of researchers took a 185 healthy individuals, genotyped them, measured saliva cortisol levels, then subjected the people to stress, measuring more cortisol levels along the way. The stressors used were making speeches and doing math problems in front of an audience. The control was doing the same without an audience. Turns out the people with the short short genotype had significantly more cortisol activation in front of the audience than those with the long genotypes (the paper is free full text if you want more details). Other studies using women with a family history of depression and women with depression had similar results with cortisol measurements.
Researchers have also used neuroimaging to check out the stress response in people with the different genotypes. The amygdala is a part of the brain that reacts to stressful situations with fear. Folks with the short short genotype have more reactivity in their amygdala under stressful situations than those with the long long genotype.
So now we have several replications of two different sets of data that shows people with the short short genotype tend to have a stronger stress reaction than those who don’t. You could definitely see how this could be a genetic advantage and how it was maintained in the population…a strong acute response to a dangerous stressor could save your life. And stress in general isn’t bad per se…cortisol activation gets us up in the morning. A little anxiety helps us to remember to pay the rent and finish our homework. There’s a delicate balance, however, where too much stress tips us over the edge. The right amount of stress makes us maximally functional, but too much stress makes us brittle and have a hard time functioning. It would seem that a certain segment of the population, based on genotype, is more primed to respond physiologically to stress.
The consequences of these differences could mean improved functioning in certain conditions, but greater vulnerability to anxiety, depression, and even suicide if the stress becomes too much. Greater understanding of these differences could help us figure out how to help folks who have clinical depression or anxiety, and also help us prevent them in the first place.
Copyright Emily Deans MD