The Schizophrenia Gene

It's not nearly as complicated as you'd think.

A gently embellished transcript of a “Lightning Talk” I gave at Frontier Neuro (un)Conference in San Francisco on May 16th, 2025.

---

I have identified the gene responsible for schizophrenia.

Now, if you know anything about the genetics of schizophrenia, I’m sure you’re thinking to yourself: “Bull shit.”

Because of course, if you know anything about the genetics of schizophrenia, you know: there is no schizophrenia gene! This is the great puzzle in the field, right? Because the disease is very clearly heritable: Having close relatives with schizophrenia is the strongest predictor that you’ll have schizophrenia yourself. If one of your parents has it, there’s about a 13% chance you will, too—more than 40 times the risk of someone whose parents are both mentally healthy.

But it’s squirrelly, somehow. Most people who get a diagnosis of schizophrenia are the first ones in their families; it sort of crops up out of nowhere most of the time. If you have an identical twin and they have schizophrenia, the odds are pretty high—30 or 40%—that you will too. But that’s for two people who have the exact same genome—which means that most of what determines whether or not you get this disease is non-genetic.

And researchers have run GWAS after GWAS in an effort to find the genes responsible, and time and again they come up with…scraps. Dregs! 1% here, half a percent there. This paper from 2013—one of the more recent big efforts¹ estimated that, if you look at 8,300 different spots in the genome, you can account for up to 32% of risk.

This is, of course, the definition of an overfitted model. With 8300 parameters, you could probably build a genome-based classifier that tells you whether or not someone is named “Karen” with 32% accuracy.² And while nobody could argue with a straight face that Karen-ness is genetic, the field of biological psychiatry is still largely shackled to the idea that schizophrenia is just “highly polygenic”, involving so many different genes, each with such a small effect size, that there’s no hope of figuring out how it works until we have a billion schizophrenics whose genomes we can study.³

So how do we square this? How do we explain something that’s clearly heritable, clearly biological, and clearly not-just-genetic?

Well, ten minutes isn’t a lot of time, so I’ll cut the theatrics. It’s in the gut microbiome.

See, many of the bacteria in your gut right now are strains that you picked up from your parents, back when you were still crawling around on the ground and putting everything in your mouth, picking your nose and eating it, and so on.

If you think you didn’t do this as a kid, ask your parents. They remember.

Those bacteria have stayed with you most of your life, eating the food you eat, reproducing faster than you can shit them out. If you have kids, you will pass those same heirloom strains on to them.

Heritable. Biological. But not genetic.

So I am not bullshitting you when I say I have found the gene responsible for schizophrenia. It’s just not a human gene.

One Gene.

See, in 2023, some researchers finally took a good look at the gut microbiome in schizophrenia, and they found that a bacterium called Ruminococcus gnavus is—on average—about forty-five times more abundant in the guts of schizophrenics than in mentally healthy controls. If you look just at treatment-resistant schizophrenia, it is over one-hundred times more abundant.

This would be remarkable in and of itself. But what’s even more remarkable—and what the authors of that paper did not seem to know—is that one of the defining features of this species, Ruminococcus gnavus, is that it possesses a promiscuous aromatic amino acid decarboxylase enzyme.

Now, my PI back at MIT used to object to the use of the word “promiscuous” in this context. She would say: I prefer “versatile”, when referring to an enzyme that can accept multiple substrates, and while ordinarily, fine, cute, I agree—in this case we are absolutely slut-shaming this enzyme. It’s got a real loose substrate-binding pocket and we are all the worse for it.

See, it takes tryptophan in the gut and turns it into tryptamine, and takes phenylalanine and turns it into phenethylamine.

Now, I love this crowd because, if this were a microbiology conference, I would have to spend the remainder of my time explaining what that means—but I expect everyone here has experience with tryptamines and phenethylamines, either on a personal or professional level.

But that means you probably know: if you just eat tryptamine or phenethylamine, they won’t do much to you. They get destroyed by monoamine oxidase (MAO) as they pass through the liver on their way into the bloodstream. This is why ayahuasca has two key botanical ingredients: one contains the hallucinogenic tryptamines like DMT, and the other contains a beta-carboline—a natural MAO inhibitor to run interference with your liver. Likewise, if you wanted an orally active phenethylamine, you might modify it chemically, attach a methyl group on the alpha carbon to protect it from MAO—and then you’d have alpha-methyl-phenethylamine, or amphetamine for short.

But because this is not a microbiology crowd, I want to clarify something: When I say “gut bacteria”, I am not talking about your stomach, I am not talking about your thirty feet of small intestine. The overwhelming majority of the microbial metabolic activity in your GI tract is happening in the final stretch, the large intestine and colon.

And what is so special about the colon? Chemicals absorbed in the colon skip first-pass metabolism! This is why the most truly dedicated degenerates boof their drugs, right? It’s a direct line into the bloodstream, for metabolites produced by your gut bacteria—more akin to smoking or injecting a compound than eating it.

Now, I want to be clear: this is not just theoretical. I have personally reanalyzed the data from a published meta-analysis of ten different metabolomics/metagenomics papers—that is, looking at associations between the chemicals in the bloodstream and the bacteria in the gut, and throwing out any signals that didn’t replicate across at least three independent studies.

And in this meta-analysis, the strongest association between any microbiome feature and any serum metabolites—the very top of the thirty-thousand row table in their supplementals—is the correlation between the amount of Ruminococcus gnavus in your gut and the amount of tryptamine and phenethylamine in your bloodstream.⁴ The more of this bug, the more of these chemicals.

Now, tryptamine is a full agonist at the 5HT2A receptor—that’s the trippy one. Nanomolar affinity. Phenethylamine acts a lot like amphetamine, which is known to induce delusions, hallucinations, paranoia, and psychosis after prolonged exposure. In fact, this is one of the better ways to model psychosis in animals, if you need to test out a new antipsychotic drug; dose ‘em up with enough speed that they don’t sleep for a few days, and pretty soon they display a hallucinatory phenotype that can be reversed by dopamine antagonists.

But just as interesting as the effects of the compounds themselves is the body’s response to them. Phenethylamine induces neuroinflammation, so in response to it your brain up-regulates expression of monoamine oxidase B, to clear out what the liver couldn’t handle. And this does a pretty good job of getting rid of the phenethylamine, but in the process it also gets rid of serotonin, dopamine, and norepinephrine.

And since we all know what happens when you’re short on your monoamine neurotransmitters, you’d expect this to lead to a syndrome of anhedonia, avolition, flat affect, depression—in other words, the negative symptoms of schizophrenia…punctuated by episodes of delusions, hallucinations, and psychosis—the disease’s so-called positive symptoms—whenever the rate of tryptamine and phenethylamine production overwhelms the body’s capacity to remove it.

So there you have it, ladies and gentlemen: Schizophrenia in seven minutes or less. One gene! And even if you’re not totally convinced, you have to admit, it's a lot cleaner than “look at these 8300 SNPs, most of which are noncoding”.

Even so, there are a few more pieces to the puzzle worth mentioning.

One: A number of species in the genus Enterocloster, which sits not far from Ruminococcus gnavus on the phylogenetic tree, are similarly elevated in schizophrenia. Some Enterocloster species also express that aromatic decarboxylase, and these are among the only other common gut bacteria which do. But get this: in that big metabolomics meta-analysis I mentioned, Enterocloster is also tightly correlated with serum levels of N-acyl ethanolamines, endocannabinoid-like compounds that signal via the dorsal root ganglia to downregulate expression of MAO in the brain.⁵ In people without much tryptamine-production capacity in their gut, this may be a good thing, as it seems to be associated with motivation and athleticism. But since that enzyme is also the brain’s last line of defense against rogue tryptamines and phenethylamines, suppressing it in someone with high background amounts of those compounds sounds like a recipe for a manic or psychotic episode.

Two: After Ruminococcus gnavus, the two microbes most differentially enriched in schizophrenia are Eggerthella and Flavonifractor. These are known for their ability to dehydroxylate and otherwise tear apart catechin and similar flavonoids. That’s all fine when it’s the tannins in your tea that they’re breaking down, but the B ring of catechin looks an awful lot like the aromatic end of dopamine, norepinephrine, and adrenaline—this is why they’re called the catecholamines, after all. In 2020, it was shown that Eggerthella can in fact dehydroxylate dopamine and similar compounds, in the process of using them as electron acceptors. It probably means something that bacteria which can undo the rate-limiting step in the biosynthesis of key neurotransmitters are so heavily enriched in a disease involving severe dysregulation of those neurotransmitter systems, although without more data I’m hesitant to speculate as to what.

Three: In a recent mono-colonization study of mice, Ruminococcus gnavus alone didn’t induce neurological symptoms, but the combination of R. gnavus and liver damage did. Now, if you look at the pathway-level analysis of bacterial genes in the schizophrenic gut, it suggests that alcohol is being produced. And if you look at the gut microbione in NASH (non-alcoholic steatohepatitis, what used to be known as “fatty liver disease”), you'll find that it is not quite as non-alcoholic as the name would have you believe. A number of the same microbes elevated in schizophrenia—including R. gnavus, Enterocloster, and Streptococcus—are also elevated in NASH. They produce ethanol in the gut, and it looks like this is what drives the liver damage in that condition, so it wouldn’t surprise me if that’s a component at play here as well.

Four: In the discussion after my talk, another attendee informed me that her former lab had identified DMT as a metabolite in fecal samples, and that antibiotics could suppress its production—suggesting that it can come from bacteria. There are known enzymes in fungi (and likely in bacteria as well) called HyoA which take tryptophan and repeatedly N-methylate it, resulting in N,N,N-trimethyl tryptophan, or hypaphorine. I am not a good enough chemist to say whether this could plausibly still interact with an aromatic amino acid decarboxylase, but the product of this hypothetical reaction would be trimethyltryptamine, or TMT (“tryptoquat?”)—which sounds like a wild time. I think hypaphorine itself is only possible because the quaternary amine has a carboxyl group nearby to steal charge from, so the more likely possibility to my mind is that tryptamine could also interact with a HyoA-like enzyme, which would stop after two N-methylations. HyoA-like enzymes can be found in the genome of E. coli, and—although that isn’t saying much, because practically any damn thing can be found in the genome of E. coli—it’s worth mentioning that this is another bacterium differentially enriched in schizophrenia, being 16-fold more abundant in the schizophrenic gut than in healthy controls.

Now before I open the floor for questions, I want to point out: these bacteria are present at some level—typically below 1%—in the guts of about half the global population, and they’re linked to a host of other diseases like anxiety, depression, cardiovascular disease, and IBS. It’s the closest thing I've ever seen to an actual, literal demon.

At the beginning of this year, I started a company, to turn ideas like this one into solutions. So far it's just me, but I'm looking for backers and collaborators, so if you'd like to help me wrestle the devil himself and get him in a headlock, find me at the break.

—🖖🏼💩

1. Because, in the intervening decade, people have largely given up trying

2. It’s fun to imagine how this classifier would work: knock out anyone with a Y chromosome and you’re already doing twice as well as random chance. Tyrosinase-dependent traits like fair skin and light hair would probably add weight to the Karen Risk Score. But even bits of the genome that literally don’t do anything could help: The name is Danish in origin, and there are probably countless mutations common to people of Danish heritage scattered among the non-coding regions of the genome. Unfortunately, none of what you learn from studying these genomic patterns would help anyone stop being a Karen.

3. If anyone would like to coauthor a very ambitious grant with me, I’m confident we can achieve the dream of One Billion Schizophrenics by 2050.

4. This is a great example of one of the reasons why microbiome science is hard. The paper on the fecal metagenomics of schizophrenia says “Faecalicatena” gnavus is the most differentially enriched feature. If you don’t really know your shit, you might not recognize that this is the same genus that’s called Ruminococcus_B in the metabolomics<>metagenomics table, or that it’s also sometimes known as Mediterraneibacter. Likewise, Enterocloster—mentioned further down in this piece—used to be part of Clostridium, then Lachnoclostridium, and is also known as Clostridium_M in some metagenomics databases. These are the kind of details that make it next-to-impossible to use things like “AI” for discovery in this space, unless you already know in advance what you’re looking for (in which case, what’s the point?). It’s also why I have sworn vengeance upon a guy named Mark Pallen, but that’s a story for another day.

5. If you read my post on exercise, cannabinoids, and the microbiome, this may sound familiar: that piece was coverage of the article where they worked out that N-acyl amides influence MAO expression, and that this is how gut bacteria impact animals’ motivation to exercise. Interestingly enough, R. gnavus gets a shoutout in that paper as well. However, I've since grown skeptical of any findings around N-acyl amides after learning that they're used in the manufacture of polyolefin plastics—like the kind you make test tubes out of—under trade names like “optislip”.