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The Genetics of Stress

By cortex on April 25, 2008.

Razib calls my attention to this new Nature study on the genetic variation underlying the stress response. The researchers focused on neuropeptide Y, an endogenous anxiolytic (it's like an anti-anxiety drug naturally produced by the brain) which is released in response to stress. They focused on a single nucleotide polymorphism (aka SNP) which "alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo."

The pertinent question, of course, is how they measured variation in vivo. The researchers used a few different, and quite interesting, techniques. The first method (the Pittsburgh sample) involved showing people "threat-related facial expressions" and measuring amygdala activity with fMRI. They found that "amygdala activation was higher in individuals with the low-NPY expression," although it's worth pointing out that this only accounted for 9 percent of the variance in fMRI response.

The second test of stress involved measuring "endogenous opioid release" with PET in response to a painful stimuli. These results were quite interesting: "highly expressed NPY diplotypes predicted significantly higher levels of stress-induced opioid system activation" throughout the brain, so that 37 percent of the variance in opioid release in the posterior insular cortex was due to the NPY diplotype. In other words, the brains of the lucky people with this SNP released more painkillers in response to pain. In theory, at least, this means that the experience of pain was less stressful. (One thing I don't understand, however, is why these endogenous opioids didn't correlate with a reduced pain response: according to the data, the NPY diplotype only accounted for 3 percent of the variance in subjective pain.)

Obviously, this study has far-reaching ramifications. The regulation of stress is a critically important function of the brain, and the breakdown of this process has been linked to everything from depression to neurogenesis to PTSD. It's pretty astonishing to think that a significant amount of the variation of the stress response is tied to a few basepairs of DNA. The next step it to see if this slight genetic variation correlates with various types of mental illness. Are soldiers with low-expressions of NPY more likely to get PTSD? Does having lots of NPY in the brain make people less likely to choke under pressure? Are the different levels of NPY expression evenly distributed in various socio-economic strata? Etc, etc.

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There was a long-term, vast study of Vietnam veterans that found that lack of a strong sense of handedness was a major flag for PTSD. I recall the theory being that someone approaching ambidexterity didn't have as definitive a split in brain functions between hemispheres and [something -- I forget details]. I wonder how those results would correlate to this new research?

Jonah,
I heard you are writing a book about the complexities of decision making. I was wondering if you have any insight into the following scenario:
I decided to break for lunch at the best sandwich place on campus and as a walked across campus I visualized my usual; turkey breast, cranberries and herbed stuffing on a French baguette--delicious! But when I got there I decided to scan the menu just to make sure I'd picked the best option and in that quick scan I took in a couple words; pasta, original recipe and mushrooms. And somehow when I stepped up to the counter I ordered that pasta instead of what I intended. When I got my plate of spaghetti and remembered that I'm not too fond of spaghetti, especially for lunch (and they had forgotten the mushroom which I was too hungry to protest), I tried to trace back the decision making process. But I just couldn't figure out how it was got from a sandwich to pasta without feeling like I really made a decision. Who really did the ordering at lunch today?
I know it�s off today�s topic but I thought you might be able to shed some light.

By Emma Leigh (not verified) on 25 Apr 2008 #permalink

Hi,Jonah:
Thanks for the lucid post with explanations for us non-biologists. I have a general question: given a genetic predisposition for stress or breast cancer or whatever, how much can an individual over-ride this tendency with 'nurture', be it mind training, nutrition, medication, or physical exercise? I met a woman yesterday whose mother at age 78 had come down with advanced breast cancer that had spread to the lymph nodes and bones in the half a year or so since her last mammogram. This disease runs in her family and the mother found the cancer during a self exam.
I'd be very worried if I were my friend. She's being and has been very attentive to her body. Is there a general plan such people can follow?

the NPY diplotype only accounted for 3 percent of the variance in subjective pain

a single locus accounting for 3 percent of the variance is a huge effect, as far as these things go. In your average genome-wide association study of height, diabetes risk, or any other complex phenotype, individual loci often account for 0.3% of the variance or less.

(for example, in height ~25 loci together account for ~3% of the variance:
http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.122.html
)