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A genetic defect that exaggerates all sensations (including pain)

 •  • by Paul Ingraham
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Got widespread chronic pain? There’s a respectable chance you could be identified by your genes alone. The largest study of the genetics of chronic pain patients to date found 76 genes that are independent risk factors for it (see Johnston). Interestingly, almost half of these genes are also risk factors for severe depression, and there’s also substantial genetic overlap between chronic pain and schizophrenia, body-mass index, rheumatoid arthritis, and post-traumatic stress disorder, amongst others.

But blah blah blah: “it might be your genes” is vague and inevitable science news these days. Things get more interesting with the discovery that a DNA blooper can mess you up in a specific, bizarre, and painful way. And so I think this might be the most interesting pain science of the year so far: chronic pain may be caused by a common genetic defect leading to low levels of the neurotransmitter serotonin (see Khoury et al.).

A common genetic defect, mind you. Not rare. At ten percent of the population, it’s about five times more common than red hair.

The study was trolling for genetic common denominators in people with a certain kind of chronic pain. They started with data on people suffering from chronic jaw pain. In that big group, they flagged some for further study: several dozen people who also suffered from excessive body sensations. And they found that those people were all running on serotonin fumes.

Why so little serotonin? Because they all had a glitchy gene that codes for an impaired, sluggish version of an enzyme, critical for serotonin production, specifically “the minor allele of rs11575542, located in the DDC gene,” which is on chromosome 7. If you must know. This gene has an important job: it swaps “an arginine to a glutamine at position 462 close to the C-terminus in the AADC protein.” But the glitchy version does it… way… too… slowly. Oops. There are also genetic variants that result in complete failure to make the AADC protein, and that’s a biological disaster. This slightly impaired gene still works, it just makes slow AADC.

I feel everything — somatic awareness and chronic pain

What does a chronic shortage of serotonin do? The AADC protein is widely used in the body, so the effects of its impairment are complex and largely mysterious (and probably variable, buffeted by other factors). But low serotonin is definitely a measurable consequence, and in turn it appears to exaggerate bodily sensations — “somatic awareness” — which is rich soil for chronic pain to take root in.

Patients with unexplained chronic widespread pain are notorious for having many, many other odd complaints — uncomfortably strong sensations of all kinds. Indeed, the pain often just seems to be the tip of an iceberg of abnormal sensations. All of these feelings in a body are high-potency hypochondria fuel that can really freak people out, which is probably why such patients often seem like “drama queens” and are considered “difficult.” Amped up somatic awareness is a bizarre phenomenon. It’s hard for anyone — patients and pros alike — to believe that there is an obscure organic cause for totally indiscriminate sensory excess. And that is why the phenomenon of somatic awareness has always been widely regarded as psychosomatic, driven by psychological hypervigilance, and a prominent feature of the so-called “fibromyalgia personality.”

Unsurprisingly, this rather unflattering interpretation is probably wrong, and people with heighted somatic awareness are probably not difficult drama queens. Or another way of putting it: maybe they are, but they obviously have a good reason for it. Everyone alive has, at times, gotten unpleasantly fixated on an uncomfortable sensation, but try to imagine that happening much more often and more intensely than it “should.” See how calm you are. (And how much is too much? There is a 54-question quiz that can grade the intensity of the phenomenon, which is exactly how the study identified people with somatic awareness).

Implications for the all-in-your-head stigma

Science news like this serotonin story is catnip for patients beseiged by suspicion that their troubles are all in their heads. Their own suspicions as well as the condescending assumptions of so many healthcare professionals.

Psychogenic illness is real (short video), and many chronic pain patients have made their peace with the fact that it can never really be eliminated as a possible explanation for their misery. Consider the well-known example of functional neurological disorders (FND, formerly known as “conversion” disorders), which involve serious symptoms like paralysis and blindness and seizures, but are actually behavioural (and yet routinely occur in people who are completely sane and have zero awareness of any psychological issue). So we usually can’t rule out a psychological origin for chronic pain any more than we can rule out a pathological one.

But it also seems like everyone, for decades, has been underestimating the sheer number of pathologies that can make people hurt for no obvious reason. People almost certainly seem “crazy” more often than they actually are, and the sluggish AADC enzyme is one of the best single examples of why I have seen so far.

I have good news and bad news: the double-edged sword of somatic awareness

Heightened awareness of sensations in the body might never be a problem for some people, or even a source of pleasure. Imagine the effect it might have on how people experience pleasant somatic delights like massage therapy. It probably even partially accounts for the puzzlingly extreme variations in how much people enjoy massage — some people really could not care less about that experience, while others find it extremely delicious. I’ve never really understood that difference.

As long as the extra sensation seems safe and pleasant, somatic awareness might be a bit of a superpower. But it undoubtedly takes a dark turn in more ominous and uncertain circumstances.

Pain is fundamentally a threat detection system. The brain uses all kinds of sensory data and contextual clues to decide what hurts and how much. Somatic awareness gives the brain a lot more sensory noise to try to interpret, which could throw a monkey wrench into the pain system. It’s obviously not inevitable, but it is probably common. Excessive sensory data is not inherently threatening, but it could quickly become threatening when challenged by a mysterious illness or alarmingly stubborn back pain. In that scenario, every sensation is a possible symptom or complication, and of much greater concern to a paranoid brain — and all brains are paranoid when it comes to threat assessment.

Anti-depressants, chronic pain, and serotonin

Humanity has a surprising capacity to grope our way to medical solutions we don’t understand, just by trial and error. For many years now, anti-depressant medications have been used, with some success, to treat conditions related to somatic awareness, like fibromyalgia. And that tends to reinforce the stigma against these patients. Successfully treating chronic pain with a pill for depression has an “optics” problem. Many have assumed that it must work because pain is just a complication of the real problem: depression.

The discovery of a genetic cause for low serotonin and somatic awareness suggests a new and better understanding. All the classic anti-depressants have the same basic mechanism: they slow down the rate at which nerve cells slurp up loose serotonin, which means more serotonin floating around, which is about as direct and specific a treatment for hyposerotonemia as you could hope for.

Maybe anti-depressants are more relevant to somatic awareness and chronic pain than they are to depression, because they can actually treat a well-defined pathology — unlike their generally lacklustre performance with depression. That would be impressive irony.


I have added new sections based on Khoury et al to my articles about fibromyalgia and anxiety. It’s also a perfect new addition to my steadily growing collection of surprising causes of pain.

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