Neuron-pruning gene linked to schizophrenia

January 28, 2016 12:33 PM

After

the collection of DNA from more than 100,000 people, detailed analysis of complex genetic variation in more than 65,000 human genomes, development of an innovative analytical strategy, examination of postmortem brain samples from hundreds of people, and the use of animal models to show that a protein from the immune system also plays a previously unsuspected role in the brain

researchers have concluded that a complex variant of the C4 gene is a major risk factor for schizophrenia. C4 is involved in synaptic pruning, which helps explain why the disorder often begins in adolescence or young adulthood.

The gene was hidden in the dauntingly complex and variable area of the genome which controls much of the immune system, which had made it invisible to previous genome-wide association studies and led some previous researchers to propose that schizophrenia might be an auto-immune disorder.

"The finding... will not lead to new treatments soon, experts said, nor to widely available testing for individual risk."

posted by clawsoon (30 comments total)

Trepanation --> Lobotomy --> Topiary
posted by fairmettle at 1:15 PM on January 28, 2016 [2 favorites]

Sequencing the first human genome was a world-wide effort that took years. And now this one project has sequenced 65,000 people? Not even the computer industry has logged that rate of progress.
posted by Chocolate Pickle at 2:58 PM on January 28, 2016 [1 favorite]

I interviewed Beth Stevens when she won the Macarthur genius grant earlier this year—she's pretty dang smart. During grad school, she discovered that glial cells, which people thought were just immune cells, also prune synapses. Anyway, she is a real powerhouse and it's cool to see her work here as well. I love that scientists are realizing more and more that the body often does double-duty with cells-it's like an entire layer of scientific discoveries possible over the one they've already discovered.
posted by mynameisluka at 3:00 PM on January 28, 2016 [12 favorites]

Chocolate Pickle: Sequencing the first human genome was a world-wide effort that took years. And now this one project has sequenced 65,000 people? Not even the computer industry has logged that rate of progress.

Current sequencing is made somewhat faster by using the results of those first multi-year sequencing efforts. This page has pretty good explanations; look for the parts on alignment and re-sequencing, where they talk about how much easier it is to sequence a genome if you've got a reference genome (e.g. the one from the Human Genome Project, for Homo sapiens) to compare it to. De novo sequencing of a new species always takes much longer.

However, yes, there have been some amazing technical advances that have sped things up, too.
posted by clawsoon at 3:18 PM on January 28, 2016 [2 favorites]

They didn't actually get this result by sequencing 50K genomes; that's still financially prohibitive. They looked at copy number of a targeted region of the genome (the C4 locus). They did leverage some existing large genome-wide association studies to come up with the hypothesis of where to look, but even for those studies it's very rare to get whole-genome coverage; what's more typical is to look at SNPs (single nucleotide polymorphisms), which is kind of like spot-checking a smattering of single letters across the genome. It's way, way more tractable than resequencing a genome, though clawsoon is absolutely right that that's more tractable now that there's a full sequence.

Still, some of those studies that this one leveraged do have sample sizes in the tens to hundreds-of-thousands, which is pretty unbelievable (see e.g. this recent study, which actually has ancestry-matched SNP mapping, i.e., they used unaffected family members for each patient's controls).
posted by en forme de poire at 3:28 PM on January 28, 2016 [4 favorites]

This seems to fit the pattern of problems that come from processes that go out of control and can't be regulated or stopped. Allergies, PTSD, autoimmune disorders, cancer, autism.
posted by bleep at 3:52 PM on January 28, 2016 [4 favorites]

I wonder if MS is on the same spectrum with schizophrenia?
posted by elizilla at 4:06 PM on January 28, 2016 [1 favorite]

MS has also been linked to stuff going on in the MHC, so there's that.
posted by clawsoon at 4:19 PM on January 28, 2016 [2 favorites]

To explain... C4 is a gene inside the MHC. A major job of the MHC is to help the body figure out what's foreign, which is certainly suggestive of possible mechanisms for a bunch of things (allergies and autoimmune disorders very likely, autism who knows? cancer, which is well understood compared to the rest of them, probably not).
posted by clawsoon at 4:29 PM on January 28, 2016 [3 favorites]

Interesting, to go along with bleep's point, I was just indexing a paper that described the higher prevalence of allergies in people with autism. (Epidemiological, not mechanistic, but yeah.)
posted by gaspode at 5:09 PM on January 28, 2016 [1 favorite]

Having such a variant, Dr. McCarroll estimates, would increase a person’s risk by about 25 percent over the 1 percent base rate of schizophrenia — that is, to 1.25 percent.

That's kinda underwhelming when we know that environmental factors increase your risk several-fold. As a counterpoint to this new finding, here's a good review of psycho-social factors.
posted by Wemmick at 6:08 PM on January 28, 2016 [5 favorites]

I don't disagree, Wemmick, but it's also worth keeping in mind that this is a single genetic polymorphism associated with a non-Mendelian disease; one of those big GWAS studies it used for hypothesis generation found over a hundred SZ-associated loci. A small effect size for a single locus doesn't mean that environmental variables outweigh genetic factors in aggregate: IIRC the SNPs with the biggest effect sizes for (e.g.) height are still small taken individually, even though height is strongly heritable. (In the scheme of things, I'd actually call a 25% risk alteration for a complex polygenic disease a surprisingly big effect IMHO.)

Now that there is a hint of a molecular mechanism, I think it'll be interesting to see whether other associated variants end up converging on the same pathway.
posted by en forme de poire at 6:47 PM on January 28, 2016 [4 favorites]

During grad school, she discovered that glial cells, which people thought were just

By the way, if anyone tells you that there's a cell type in your body that just does one thing, they are probably underestimating evolution's total disregard for elegant design.
posted by a snickering nuthatch at 6:49 PM on January 28, 2016 [4 favorites]

(allergies and autoimmune disorders very likely, autism who knows? cancer, which is well understood compared to the rest of them, probably not).

I didn't mean to imply that I think they all have the same actual physical cause; they just all seem related to a "too much of a good thing" theme. The system has no way to stop itself.
posted by bleep at 7:03 PM on January 28, 2016

By the way, if anyone tells you that there's a cell type in your body that just does one thing, they are probably underestimating evolution's total disregard for elegant design.

Because evolution also laughs contemptuously at your attempts to come up with generalizations about it: name a second function of the human spermatozoön.

This is cool! It's been a very, very long time since immunology, so although I recognized complement (enzyme cascade, innate immunity, sticks stuff to pathogens so phagocytes swallow them, that's all I got), I had no idea it was involved in neuron pruning. Neat!
posted by gingerest at 10:34 PM on January 28, 2016 [1 favorite]

I'm gonna predict this will also be linked to people who are prone to conspiracy theories and religiosity. And that it gets worse as you age.
posted by fshgrl at 11:17 PM on January 28, 2016 [1 favorite]

Metafilter: laughs contemptuously at your attempts to come up with generalisations about it
posted by Segundus at 11:30 PM on January 28, 2016

I think this is extra fascinating because a couple of years ago there was research that linked autism to a lack of synaptic pruning, and this posits the exact opposite problem in schizophrenia. This in two disorders that, for a large part of the 20th century, were thought to be basically the same disorder because of some similarities in symptomology. I'd love for someone with expertise in this area to write about this - is this opposite mechanisms in the same area producing similar symptoms?
posted by Vortisaur at 1:44 AM on January 29, 2016 [4 favorites]

This is fascinating - but isn't it the case that all explanations of schizophrenia are slightly problematic because it's not really clear that schizophrenia is itself a well-defined clinical entity?
posted by Segundus at 2:41 AM on January 29, 2016 [1 favorite]

Could someone please put en forme de poire's comment in layperson's terms?
posted by bardophile at 6:51 AM on January 29, 2016

Could someone please put en forme de poire's comment in layperson's terms?

A lot of genes have a small effect individually, but when you add them all up they have a big effect.

And sometimes when you discover that one gene associated with a problem causes the problem by doing a specific thing, you find a bunch of other genes that also cause the problem by doing more-or-less the same thing.
posted by clawsoon at 7:24 AM on January 29, 2016 [1 favorite]

Thank you!
posted by bardophile at 10:09 AM on January 29, 2016

but isn't it the case that all explanations of schizophrenia are slightly problematic because it's not really clear that schizophrenia is itself a well-defined clinical entity?

Right, the DSM schizophrenia criteria are such that two patients with no symptoms in common can both be diagnosed with the disorder. The category is disjunctive. For example, it's not clear if someone with disorganized speech is suffering the same problem as someone with hallucinations. If they have distinct causes, "schizophrenia" is a scientifically invalid construct. (Issues like this are one reason Thomas Insel advocated reorienting NIMH research away from DSM categories.) Or perhaps "schizophrenia" exists on a continuum with even "normal" people occasionally having psychosis-like experiences.

Here's more by John Read, one of the authors of the paper I linked earlier.

Full disclosure — Read and some of the other researchers like Richard Bentall focusing on psycho-social processes are somewhat in the minority for schizophrenia research, but I don't think that's a mark against them. Since so much research is either paid for or indirectly influenced by the pharmaceutical industry, non-biological explanations receive much less attention.
posted by Wemmick at 10:35 AM on January 29, 2016 [2 favorites]

Schizophrenia is devastating; progress is welcome.
posted by theora55 at 11:14 AM on January 29, 2016 [1 favorite]

Another implication of en forme de poire's comment: One thing we've found with cancer is that we have 4 or 5 genetic pathways that protect against it. If you have a mutation in just one or two of those pathways, your cancer risk only goes up a little bit. However, once all four or five pathways have mutations in them, cancer risk shoots up to the point that it's almost inevitable.

It's possible - not guaranteed, but possible - that we'll find something similar with schizophrenia and other disorders. This mutation by itself only raises your risk from 1% to 1.25%, but maybe it's only one of a critical group of mutations which, if you have all of them, suddenly puts your risk up to 20% or 30% or 50%.

It's like a four-engine plane: If one engine fails, your chance of crashing only goes up a little bit. But if all four engines fail, your chance of crashing goes up dramatically. The researchers are hoping they've identified a situation here that's like one engine failing: It's a small effect by itself, but it's a significant effect, and they have a mechanism that explains why it has an effect.
posted by clawsoon at 11:58 AM on January 29, 2016 [2 favorites]

That's a good point, Wemmick. I'm reminded of a recent study which found that people with a certain mutation were happier than average people if they had a good childhood, but more likely than normal to be depressed if they were abused as children. (Previously.) But finding solutions to the social half of the problem doesn't make money for corporations with research budgets, so the vast majority of money goes into pill research.
posted by clawsoon at 12:04 PM on January 29, 2016 [1 favorite]

At the same time, doing research on patients with a particular DSM classification doesn't necessarily imply a strong commitment to the validity or uniformity of that classification. It may be that alleles associated with what we call schizophrenia ultimately affect similar processes (e.g., pruning) regardless of symptoms, but it could also be that these alleles fall into multiple distinct groups, or somewhere in between. Which of these scenarios is true can gradually be revealed over time with research, using a combination of statistical association and more in-depth, mechanistic studies. That's true even if you provisionally accept an incomplete or flawed way of categorizing patients, because the more we learn, the better we should be able to group people with similar disease processes.

Also, I think it's worth saying that some social/environmental factors are not necessarily "non-biological." In fact they can ultimately converge on similar molecular pathways as genetic mutations, similarly to how UV exposure can cause cancer by causing DNA damage, but genetic defects in the DNA damage repair machinery can also increase cancer risk. I think this is important to remember because environmental doesn't necessarily mean "easier to intervene": one of the environmental risk factors for schizophrenia is exposure to urban environments, for example, but people also have a lot of good reasons for being in urban environments, like jobs, families, and access to child care and transportation. Another is social adversity, which we should be combating for a variety of reasons, but which is also clearly a big, difficult problem to solve.

Or perhaps "schizophrenia" exists on a continuum with even "normal" people occasionally having psychosis-like experiences.

I can't remember where I read this but I think this has been shown for auditory hallucinations? As in, a lot of people report having sometimes had auditory hallucinations without ever going on to develop other symptoms?
posted by en forme de poire at 1:05 PM on January 29, 2016 [1 favorite]

(Also, it's my understanding that most basic research at this level is not pharma-funded or -adjacent. It looks like funding for this particular work, for example, came from the NIH and from private philanthropy. Pharma generally only cares about basic research when things get within sight of a new druggable target [and this usually means a drug that binds a specific protein] or a new screening test with high accuracy. Not to say that the world of government-funded basic research is ideologically pure or doesn't have its own perverse incentives, obviously, but I think these are different biases and problems that probably wouldn't go away even if you got rid of or nationalized all the pharmaceutical companies tomorrow.)
posted by en forme de poire at 5:32 PM on January 29, 2016 [1 favorite]

I can't remember where I read this but I think this has been shown for auditory hallucinations? As in, a lot of people report having sometimes had auditory hallucinations without ever going on to develop other symptoms?

I haven't read it yet, but this one has been highly cited:
Johns, L. and van Os, J. (2001). The continuity of psychotic experiences in the general population.

And yeah, I think you're right that it's more than just industry bias. Older theories of schizophrenogenic mothers heaped a lot of unjust criticism on parents, and I'm sure many well-meaning researchers in the early days of the disease model wanted to avoid anything that could look like blaming the family for their child's psychosis. Neuroscience and genetics seems more scientific, especially when you can use the latest fMRI scanners and sequencing methods. Government policy may favor biological research because social interventions like providing jobs or houses are really expensive. And there certainly may be genetic risk factors and trauma can play out through biological mechanisms. At the same time though, we have evidence of a 50-fold increase risk for children most severely effected by abuse or trauma compared to only a 25% increased risk here. I worry that the story that says schizophrenia is a heritable brain disease is likely to cause increased stigma, decreased hope for recovery, and lead clinicians to be dismissive of people's experiences and histories. Even if environmental interventions are prohibitively difficult versus drugs, I think it's still important for the public to understand the relative significance of different contributory factors.
posted by Wemmick at 6:15 PM on January 29, 2016 [2 favorites]

I agree with that largely — though not to be too contrary :), I'd also say that the paper linked there lists a 3-fold odds-ratio increase for traumatic experiences (I think the 50-fold increase is only for people who experienced the most extreme traumas; I actually can't find the 50-fold number in the paper itself but I'm skimming). More importantly, I think, the elevation in risk from having close relatives with schizophrenia is in the same range, and it varies with genetic relatedness (~50-fold relative risk increase for an identical twin with schizophrenia, vs. 5-15x risk increase for a fraternal twin, for instance). That suggests a large genetic component, which is why I wanted to make the point about genetic influence in aggregate vs. because of just this one particular variant.

But of course these are really "both-and" distinctions not "either-or"; families of course share environmental effects and genetic variation can definitely make someone more vulnerable to environmental effects.
posted by en forme de poire at 6:37 PM on January 29, 2016 [1 favorite]