There's no DNA in "Disease"

Neuroskeptic iconNeuroskeptic
By Neuroskeptic
May 10, 2011 10:30 PMNov 5, 2019 12:15 AM


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Back when I was a mere first year biology student, the first thing we were taught was this:

DNA makes RNA makes Protein.

This is the Central Dogma of Molecular Biology, and it describes the intricate and beautiful process by which genes influence living things. The whole thing really is remarkable.

Unfortunately, some people in psychiatry seem to have forgotten this. Reading some of the literature, you would think that:

DNA makes DSM Diagnoses

Or if you're feeling especially adventurous and concious of the fact that diagnoses are not necessarily real entities

DNA makes Symptoms (which add up to make DSM Diagnoses)

In fact, DNA has nothing to do with symptoms either, not directly. DNA makes proteins. Proteins interact with each other, and with all kinds of hormones and other signalling molecules, to control the growth and function of cells. Cells don't get symptoms. People get symptoms - and people are very complex systems made of billions of cells.

So it would be extremely weird if a particular genetic variant only ever caused one specific disease. That would mean that, whenever you have that variant, and regardless of any other variants or environmental factors, it will always mess up cell function such that it causes the same ultimate symptoms.

That does happen. There are lots of single-gene disorders - or to put it another way, single-disorder genes. But they may well be the exception. Rather, as Matthew State says in a short paper just out in Biological Psychiatry, the latest research suggests that genes that are linked to one psychiatric disorder are usually linked to lots of them, sometimes ones with quite different symptoms.

I previously wrote about the case of "The ADHD Gene" that's actually a gene for lots of stuff including, sometimes, ADHD. State focusses on the example of the gene CNTNAP2, variants in which have been linked to (deep breath): epilepsy, mental retardation, autism, social anxiety, schizophrenia and Tourette's. Sometimes the same variant causes multiple different disorders in different people. Sometimes one variant causes one thing and protects against another, related, thing. Hmm.

As State says, one possibility is that any given mutation always causes the same symptoms, it's just that our diagnostic categories are imperfect so the same symptoms get labelled as many different things. That's certainly true but as he points out, there's a more radical possibility: the same variant might cause genuinely different symptoms.

mutations at single gene or locus may carry significant risks for truly divergent neurodevelopmental outcomes, neither demonstrating specificity for a clinically observable phenomenon nor conferring any reliable overlap among disparate behavioral phenotypes.

How? Well, suppose there was a variant, "pinker", that codes for a fluorescent protein that makes half of your brain cells glow bright pink. By itself, that wouldn't cause symptoms. No-one would even know.

Yet imagine another variant, "pinkophobe", that made cells refuse to communicate with pink cell. That wouldn't cause any symptoms either, by itself. But in conjunction with "pinker", where it would cause serious problems: half of your cells would be effectively out of action.

But suppose you carried "pinker" and yet another variant, "welovepink", that made your cells respond much more strongly to pink cells. Then, you would have the opposite problem. Half of your cells would be super-responsivie to the other half, and that would probably cause epilepsy, amongst other things. You'd get symptoms, but they would be completely different symptoms from people who had "pinker" and "pinkophobe".

So what symptoms does "pinker" cause? It doesn't cause symptoms. It's just a gene. The symptoms come much later. "pinker" would be associated with all kinds of stuff, even though it has a very specific role. It just codes for one protein. Genes are pretty simple folk. The complexity comes later.

This is a silly example, but maybe not so far fetched after all. Neurons don't glow pink, but they do release neurotransmitters, and they don't have color preferences, but they do have receptors that respond to transmitters.

State MW (2011). The Erosion of Phenotypic Specificity in Psychiatric Genetics: Emerging Lessons from CNTNAP2. Biological psychiatry, 69 (9), 816-7 PMID: 21497679

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