
Schizophrenia not a single disease but multiple genetically distinct disorders - MBCook
http://news.wustl.edu/news/Pages/27358.aspx
======
haberman
This is promising. If you read the DSM (the Diagnostic and Statistical Manual
of Mental Disorders, published by the American Psychiatric Association), it
reads a lot like a fuzzy pattern-matching algorithm:

    
    
        (A) Characteristic symptoms: Two (or more) of the following,
            each present for a significant portion of time during a
            1-month period (or less if successfully treated):
    
            (1) delusions
            (2) hallucinations
            (3) disorganized speech (eg. frequent derailment or incoherence)
            (4) grossly disorganized or catatonic behavior
            (5) negative symptoms, ie., affecting flatting, alogia,
                or avolition.
    
        Note: Only one Criterion A symptom is required if delusions
        are bizzare or hallucinations consist of a voice keeping a
        running commentary on the person's behavior or thoughts,
        or two or more voices conversing with each other.
    

What is a "delusion?" What is "bizarre?" There is a lot of subjective judgment
here, and just generally speaking this feels more like alchemy than science.

I don't mean to criticize this approach too much though, because without a
more detailed understanding of the underlying mechanisms and causes, this
approach is the best possible way of at least clustering mental problems into
groups. That at least allows people to share data about what treatments have
worked for people in each cluster.

But if we can get a better understanding of the true underlying causes, and
isolate the causes with better granularity, it should put us in a much better
position to (I hope) provide much better and more specific treatment.

~~~
Kalium
It's worth remembering that the DSM is not intended for use by the average
person. It can and will use technical terms - like "delusion" \- that users of
the manual are expected to understand as technical terms.

~~~
haberman
Fair enough. It still seems safe to say that diagnoses based on criteria like
"meets at least two of these five symptoms" are less than an exact science.

~~~
bayesianhorse
All models are wrong, but some are useful. This model has proven useful.

These symptoms do cluster. Most people never ever experience halluzinations,
but then they also experience delusions or other psychotic problems,
relatively specific social problems, paranoia, etc.

In some sense this is a human-readable equivalent of logistic regression.
Because schizophrenia isn't as well understood as some other diseases, you can
only make "exact" models about meaningless abstractions, or create fuzzy
models which allow meaningful treatment decisions.

~~~
dragonwriter
> All models are wrong, but some are useful. This model has proven useful.

The model is clinically useful, but the assumption (which the DSM does not
itself advertise or support, which is made implicitly when its categories are
used as the basis for research) that the diagnostic categories in the DSM
represent commonality in origin is an impediment to research.

While many people have overstated the NIMH move away from DSM categories as a
basis for research funding as something like an indictment of the DSM in its
intended role or, even more hyperbolicly, a rejection of psychiatry as a
field, it _is_ an important move that recognize that the DSM categories'
utility in their intended purpose does not imply that they represent real
commonality.

~~~
bayesianhorse
Yes, exactly this. DSM criteria do predict effective treatment, negative
consequences for the patients (both with and without treatment), and help plan
for the costs of these conditions. These factors are clinically relevant.

Neuroscience tries to get a firmer grip on how the brain works, and what goes
wrong when it doesn't. This research hardly touches the clinical practice as
of yet, but ultimately diagnostics and treatment might improve largely.

------
andrewl
I'm glad to see advances being made. Schizophrenia is extremely hard to
research. And it's devastating to the patient.

In the early nineties I worked at the University of Pennsylvania measuring
brain MRIs as part of a schizophrenia study. They knew there was a strong
genetic component, but they also knew that not everybody with a strong genetic
weighting would develop the disorder. They had plenty of records of identical
twins where one suffered from schizophrenia and the other did not.

The model then was the Diathesis-Stress model [1]. The diathesis, or
predisposition, is in the genes. They thought the stress could be one of a
number of things: maternal infection while the baby was still developing,
birth complications such as brief interruptions in oxygen flow, infections
after the baby is born, and perhaps extreme psychological trauma, like combat.

[1] [http://en.wikipedia.org/wiki/Diathesis-
stress_model](http://en.wikipedia.org/wiki/Diathesis-stress_model)

------
Eleopteryx
Most mental "disorders" seem to be just co-occurring negative symptoms
aggregated by experts in a matter that is not arbitrary but also far from
objective. The reason why e.g. anxiety and depression are typically comorbid
might be because the practical distinctions between them are artificial and
only exist to slap labels on nebulously defined mental ailments.

I believe that over time doctors will cease with the labels such as
"inattentive ADHD", and merely treat debilitating inattentiveness based on the
individual. The fact that ADHD can be hyperactive or inattentive, has always
seemed bizarre to me. One person can't sit still, but my problem is I can sit
still to a fault. But we have the same underlying disorder that's treated with
the same medications.

The number of types of clinical depression, for example, is absurd. It's not
merely depression, it's bipolar disorder. It's not merely bipolar disorder,
it's bipolar disorder type II. Seriously? Decades from now we're going to
regard this approach as highly primitive and bordering on pseudo-scientific.

Because every brain is different, trying to strictly classify these disorders
would force people outside of a category, but the other side of that is that
we have schizophrenia which seems incredibly broad "junk-drawer" sort of
classification, to the point where it's easy to imagine someone who is highly
eccentric being misdiagnosed.

I have no credentials obviously so this is all baseless conjecture.

~~~
DanBC
Depression is not a single illness; it's likely to be several different
illnesses that fall under a single umbrella diagnosis.

Please don't make the mistake of thinking bi-polar is in anyway similar to
depression. They are very different illnesses with different treatments.

And, again, as we learn more about bi-polar we may find that it's a bunch of
different illnesses that get given the umbrella diagnosis of bi-polar.

Your example of ADHD being treated with the same meds is just a function of
our lack of knowledge of ADHD. So we might not always use the same meds for
treatment.

In the future we'll have genetic testing to determine what meds will be useful
or which meds are unlikely to work.

~~~
SnacksOnAPlane
What? Depression is very similar to bipolar. Depression is a phase in most
bipolar. The same meds often work for both, with mood stabilizers added for
bipolar patients to try to arrest the manias.

~~~
DanBC
That's not true.

You don't use the same meds for bi polar and depression - it is dangerous to
do so.

People with depression should be given access to CBT with an anti depressant
if needed.

People with BiPolar should not routinely take antidepressants, especially not
if they are starting a manic phase. They should be taking lithium, valproate,
or olanzipine.

[http://www.nice.org.uk/guidance/CG38/chapter/Key-
priorities-...](http://www.nice.org.uk/guidance/CG38/chapter/Key-priorities-
for-implementation)

~~~
SnacksOnAPlane
Huh. You're right. I guess the protocols have changed since I learned about
them. Good to know!

------
mcone
This is potentially good news. My sister has schizophrenia, and not a day
passes when I don't worry about my 3 year-old son being diagnosed with this
terrible disease.

I'm not a scientist or an engineer, so maybe somebody who has read the
published article can help me out here. I wonder what the percentages mean.
How do they determine whether or not someone has a 73% chance of being
diagnosed with the disease? And what does that mean exactly?

On the other hand, this research raises even more questions. For instance, I
wonder what steps you could take to help a child with, say, a 60% chance of
being diagnosed with schizophrenia? Are the genes like switches, in the sense
that certain environmental variables can flip them on and off? If so, I guess
there is a lot that could be done to help someone who has a good chance of
being diagnosed.

~~~
tjradcliffe
This work investigates what are called "single nucleotide polymorphisms"
(SNPs, pronounced "snips"), which identify genes that make slightly different
forms of the same protein (the most common result of a SNP is to have swap one
amino acid for another in a protein, which may change its shape a little so it
won't work quite as well under some circumstances, or may bind a little more
heavily to one site vs another.)

The percentages mean that if you take 100 people with a given combination of
SNPs, 73 of them will get schizophrenia. People without that combination will
have a much lower chance.

The good news for you and your son is that because they have identified multi-
gene effects, the odds of you or your son having all the same SNPs as your
sister is very low. You and your sister share half your DNA, so if there are
ten genes involved, each with a 50/50 chance of being shared, that's a 1 in
1024 chance (2^10). For your son it's one in a million (unfortunately I can't
tell from the article or the journal abstract how big the SNP sets involved
actually are, but given the difficulty in finding them I'd expect more than
four or five SNPs per set.)

With regard to your other questions, the honest answer is: nobody knows,
although there will be any number of people trying to sell you on unproven
solutions, mostly based on the demon of the moment. Twenty years ago it might
have been red meat. Five years ago it would have been gluten. Today it would
be refined sugars. Tomorrow it will be something else. The only thing we can
be sure of is that the promoters will be smug, self-assured and self-deluded
(or dishonest, but I think self-delusion is more common).

~~~
gwern
> unfortunately I can't tell from the article or the journal abstract how big
> the SNP sets involved actually are, but given the difficulty in finding them
> I'd expect more than four or five SNPs per set.

Table 1 (
[https://pdf.yt/d/rErZm8HUluBbj8xu](https://pdf.yt/d/rErZm8HUluBbj8xu) /
[https://dl.dropboxusercontent.com/u/5317066/2014-arnedo.pdf](https://dl.dropboxusercontent.com/u/5317066/2014-arnedo.pdf)
/
[https://www.sendspace.com/file/ht7shm](https://www.sendspace.com/file/ht7shm)
) list characteristics of the sets; they range from a low of 3 to a high of
32, with associated risks of 70 - 100% (!).

The size of the sets with a risk of schizophrenia between 90% and 100% is
11/11/19/4/6/3/10/6/9\. (SNP set 87\\_76 is the one with just 3 SNPs and a
risk of 95%. Very nasty.)

Unfortunately I don't think this risk information is enough to to calculate
how much predictive value SNPs would have for someone undiagnosed since you'd
need to know how many healthy people have these SNP sets as well? But I'm sure
the genomics hobbyists and anyone with 23andme data are probably looking
closely at the paper and trying to extract risk estimates...

------
tokenadult
What a coincidence. This was posted just as I was at the weekly "journal club"
on human behavior genetics at the University of Minnesota with two researchers
who used to be associated with Washington University in St. Louis (the source
of the press release kindly submitted here). Genetic research on schizophrenia
has been going on for a long time, and one of the WUSTL researchers I know
locally[1] has been conducting that research since the year I was born.
Experienced researchers on schizophrenia have always suspected that the
finding announced in the press release headline is the correct description of
reality, but it has taken a long time to do enough careful genetic research to
be sure of multiple genotypes that all lead to the same clinical set of
phenotypes that can be described as schizophrenia in current diagnostic
categorization.

As other comments suggest, research along this line may eventually lead to
more effective interventions for treating or even preventing schizophrenia. We
already know (links below) that schizophrenia does have a very strong
component of genetic risk, yet every once in a while identical (monozygotic)
twins brought up in the same household are discordant for schizophrenia, so
plainly some "environmental" risks matter too. It will be good to continue the
research program on this devastating illness.

AFTER EDIT: Irving Gottesman is looking forward to reading the journal article
by his former colleagues at WUSTL. Of course a preliminary finding like this
will have to be replicated in other data sets to become part of established
scientific knowledge. Then the hard work of matching treatments to patient
genome patterns will begin.

[1]
[https://news.ycombinator.com/item?id=4661802](https://news.ycombinator.com/item?id=4661802)

[https://news.ycombinator.com/item?id=7663622](https://news.ycombinator.com/item?id=7663622)

[https://news.ycombinator.com/item?id=8069518](https://news.ycombinator.com/item?id=8069518)

------
gwern
Fulltext:
[https://pdf.yt/d/rErZm8HUluBbj8xu](https://pdf.yt/d/rErZm8HUluBbj8xu) /
[https://dl.dropboxusercontent.com/u/5317066/2014-arnedo.pdf](https://dl.dropboxusercontent.com/u/5317066/2014-arnedo.pdf)
/
[https://www.sendspace.com/file/ht7shm](https://www.sendspace.com/file/ht7shm)
(excerpts:
[https://plus.google.com/103530621949492999968/posts/iJBeuxup...](https://plus.google.com/103530621949492999968/posts/iJBeuxupqfX)
)

------
webnrrd2k
It's been interesting to see genetics slowly get expanded to help understand
more conditions...

Just like cancer isn't caused by one thing, many of the common "psych"
diseases aren't caused by one thing. The more obvious candidates for a strong
genetic component are disorders like depression, alcoholism, and ADHD; but I'm
sure this will be broadened into other mental health areas like diet, obesity
and stress management.

There is still a strong environmental component, so I'm not trying to say that
genetics is everything, but it's still important.

~~~
azernik
What's even more interesting is the insight this gives into biology. When we
find a protein-encoding gene that, when mutated, causes a certain disease, it
gives a pretty good clue as to that protein's function in the body.

------
_98fj
Schizophrenia is more a catch-all term for "things are going severely wrong in
a brain" than a disease.

------
jrapdx3
I'll have to read the article to really understand what the authors have found
out, but judging from the summary the advance is dividing the huge number of
genes linked to schizophrenia into 8 groups of genes that associate or
interact more closely than with other related genes.

In many ways, this isn't surprising. It's been evident that many genes have
been linked to psychiatric disorders, but no "smoking guns" are evident,
usually a gene accounts for <2% of the variance, and dozens or hundreds of
genes have some influence.

So it's logical that it takes a cluster of many genes contributing something
to have enough effect to be clinically apparent. How genes interact is an
enormously complicated matter, and perhaps an even bigger question is the role
of gene-environment interaction.

One thing to track is with the multitude of genes shown to be clustering, an
important element is how "tight" the clustering is. I anticipate we'll find
out as it's investigated further that overlap among clusters is significant,
that is, "blends" or mixed/intermediate types are probably common. Certainly
in the real world there are seldom pure cases of any condition, the boundaries
tend to be fuzzy.

Not that the article implies at all that the new work gives "answers", but
with any luck, it will lead to new insights, shed light on the astonishingly
complex processes, and clues to making progress. Just expect the path will
have many more twist and turns on the way there.

------
tim333
On a slightly different tack I found the 2010 Discover Magazine article about
the role played by the HERV-W retrovirus in Schizophrenia interesting. Not
quite sure how that line of research is panning out these days.
[http://discovermagazine.com/2010/jun/03-the-insanity-
virus](http://discovermagazine.com/2010/jun/03-the-insanity-virus)

------
fideloper
My personal, uneducated guess about mental illness in general is that it's a
systemic issue, having to do with a person's overall health (genetic +
lifestyle/environment).

Systemic issues are likely hard to research, and so we take this scienctific
(method) approach of studying small bits in isolation. This is similar to food
science - there are too many factors to clearly study how we get nutrients
from our food, and so science has studied bits in isolation (vitamin c, vs
"orange juice with pulp and eggs").

My hope is that we'll find ways to study the overall health/status of an
individual and see how that all adds up to behavior we deem "unhealthy",
rather than being "trapped" poking at minute details (or perhaps well finally
get enough detail to see the bigger picture).

Anyway I have zero expertise in this, but this is my guess on the situation.

------
tunesmith
That's really good news - if the same were discovered for bipolar and
depression (which are often diagnosed along the lines of "well, you have these
symptoms, so you probably have it") then it could help prevent a lot of
misdiagnoses and increase quality of life.

~~~
bayesianhorse
That presupposes that a treatment exists for the "correct" diagnosis. In
bipolar disorder there is a wide range of symptoms and prognosis. However, the
subgroup don't inform treatment decisions to the point that the first choice
of treatment usually works.

Any subdivision must lead to better treatment options and guidance to be
meaningful.

------
kornork
The article doesn't mention it, but I'm curious if Watson involved in this (or
similar efforts) at all.

~~~
bayesianhorse
I sure hope not. Associating genetic variations with symptoms or physiological
findings is a relatively clear-cut statistical problem. The major challenge in
whole genome association studies (or their extension to whole genome
sequencing data) is to get enough data to draw meaningful conclusions.

There is a cognitive dissonance in biology/medicine: On the one hand they
complain about too much data to process, but at publication time, the power is
too low...

~~~
pinkyand
The problem with a lot of the data in electronic medical records is that they
are not structured but in natural language. This is exactly where Watson can
help.

~~~
bayesianhorse
I don't think so. It is too expensive to enroll more than a couple of thousand
of participants for a GWA study, though they are often pooled for a broader
analysis. Anyway, genotyping will probably cost at least $100 (depending on
the technology a lot more), which puts manual entry of patient data into
perspective.

An unpaid intern can be cheaper than fancy artificial intelligence!

------
vacri
The idea that schizophrenia is a collection of different diseases is not new
at all. When I did my neuropsych degree in the early 90s, the lecturers
commented that schizophrenia was likely to be at least four different things
(this article suggests eight). Their commentary was that schizophrenia was a
sort of dumping ground where people got put if they didn't fit into a
different diagnosis, and I remember the run-down of frequency of symptoms -
the most common symptom exhibited by schizophrenics, auditory hallucinations,
was only seen in 69% of patients.

The idea of the four broad groups at the time (from _very rusty_ memory here)
stemmed from plus/minus showing cognitive/perceptual disturbances (like
auditory hallucinations) and plus/minus showing social withdrawal symptoms,
along with a couple of other things I can't recall.

It's not to cast aspersions on the article - mental health research is always
good - just to say that this idea has been bouncing around for quite a while.

------
DiabloD3
I find this research to be very interesting. It should make it much easier to
pin down the cause of the individual features of Schizophrenia, many of which
are believed to be caused or triggered by the modern Human diet (refined
sugars, grains, other (sometimes highly) processed foods et al.) by a growing
number in the scientific community.

~~~
sedachv
> many of which are believed to be caused or triggered by the modern Human
> diet (refined sugars, grains, other (sometimes highly) processed foods et
> al.) by a growing number in the scientific community.

Links to studies published in peer-reviewed journals or GTFO. "Modern diet" is
the medieval humorism of the last decade.

~~~
llamataboot
Lots of links here.

[http://evolutionarypsychiatry.blogspot.com/2013/11/gluten-
an...](http://evolutionarypsychiatry.blogspot.com/2013/11/gluten-and-
schizophrenia-again-with.html)

There is also rising evidence that gut flora correlate with various mental
health issues.

[http://www.apa.org/monitor/2012/09/gut-
feeling.aspx](http://www.apa.org/monitor/2012/09/gut-feeling.aspx)

[http://www.scientificamerican.com/article/gut-bacteria-
may-e...](http://www.scientificamerican.com/article/gut-bacteria-may-
exacerbate-depress/)

~~~
daeken
From your first link, the only study that attempted to show a causal link
between gluten and schizophrenia had no control group, no placebo, and n=2.
This isn't a study, it's a guess.

There may well be something to this whole thing, but the science just isn't
there right now, at all. Right now what we need are studies, not solutions.
The evidence is non-existent.

------
pender
Sounds like malarky to me. Sounds like a group to understand something outside
their reach; finding subjective data points to further categorize the problems
allowing themselves to believe they now have more of a handle on than they did
before. I don't believe they know anything that adds more value.

