Saturday, March 29, 2008

What is schizophrenia? Not what we thought.

Some recent results for a study of the genetics of schizophrenia got a lot of press attention. Among other things, the studies are one more indication that the term "schizophrenia", like the term "autism", is obsolete.

First, here's the best of the coverage I read. One came from a blog, the other from the Washington Post. The rest of the coverage, including the NYT and Scientific American, was pretty bad. (Unfortunately Science does not allow public access to articles, I really wish they'd go out of business):

Schizophrenia involves an increased rate of mutations (Ars Technica)

... schizophrenics displayed a high rate (three times the expected level) of genetic mutations at the chromosomal level, where individual genes were either absent, or present multiple times, leading to over-representation. In patients with early-onset schizophrenia, this rate of mutation was four times the expected level.

The genes involved turned out to be important in brain development including neuregulin and glutamatergic signalling, along with ERK/MAPK signaling and genes that are involved in adhesion and synaptic plasticity. Interestingly, the mutations were not common across the schizophrenic patients, instead differing along familial lines...

Schizophrenia Linked to Rare, Often Unique Genetic Glitches (Rick Weiss, Washington Post)

Patients with schizophrenia are three to four times as likely as healthy people to harbor large mutations in genes that control brain development, and many of those glitches are unique to each patient, researchers reported yesterday.

The findings are forcing scientists to rethink the reigning model of how genes and environment conspire to cause the debilitating disease, which affects about 1 percent of the population worldwide.

In part, scientists said, the new view is daunting because it suggests that many people with schizophrenia have their own particular genetic underpinnings.

At the same time, the study shows that new screening techniques can find and differentiate among those various mutations. In the long run that could help doctors choose the best medications for individual schizophrenics and speed the development of drugs tailored to certain patients' needs.

"If the genetics tells us that schizophrenia is really 10 different disorders, then let's have 10 treatments that optimize the outcomes for everyone and not just use the same drugs for everybody," said Thomas Insel, director of the National Institute of Mental Health, which helped fund and conduct the study.

The work also offers evidence that autism shares some genetic roots with schizophrenia.

"Take away schizophrenia's hallucinations and delusions," said Jon McClellan, a child psychiatrist at the University of Washington and a leader of the study, published in yesterday's online issue of the journal Science, "and the symptoms that remain, the lack of social interest and withdrawal, are what we call autism. There is clearly an intersection of the brain systems involved."

... scientists [had concluded] that the mutations contributing to schizophrenia are probably common in the population but have little impact individually, and that only when several occur together is a critical mass of neurological trouble achieved.

The model emerging from the new study is quite different. It says most cases of schizophrenia may be caused by rare genetic glitches that are individually potent.

The turnaround is the result of sophisticated gene scans conducted on 233 schizophrenics, including 83 who got the disease in childhood, a more serious condition. The scans looked for rare stretches of DNA where more than 100,000 "letters" of genetic code were either missing or mistakenly present in duplicate.

About 15 percent of schizophrenics, and 20 percent of those affected in childhood, had such glitches, compared with 5 percent of healthy individuals who were also studied. Yet the glitches, including one previously associated with autism, were different in each person.

Unlike previous scans based on older technology, which could at best find general genomic "neighborhoods" where mutations associated with schizophrenia are present, the new scans pinpointed the individual genes affected...

...The genes implicated are diverse, but many are known to play crucial roles in how the brain gets wired early in life. Normally that process starts with a huge overproduction of neurons, followed by a controlled winnowing that leaves only those that have made proper connections.

"Changes in these genes could bias the way circuits get sculpted out and could perhaps lead to a brain in which signals that would normally get filtered out don't get filtered out," which could interfere with thinking and prompt hallucinations, Insel said.

The delayed onset of the disease can be explained by the fact that some genes and brain connections do not take on central roles until young adulthood, said Jonathan Sebat of Cold Spring Harbor Laboratory, one of the study leaders...

Rick Weiss of the Post did a far better job than anyone else on summarizing these results. The NYT coverage, in particular, was disappointing.

This feels big, but note that that only 15% percent of "schizophrenics" fit this pattern. This is not the whole story, but it's the biggest piece we've gotten so far.

I'll summarize the key implications:

  • Schizophrenia is not a disease. It's the name given a fairly large number of unique disorders of brain development that have, among their endpoints, social withdrawal, hallucinations, and fixed beliefs.
  • A good number of cases of "autism" and "schizophrenia" are different manifestations of overlapping sets of mutations.
  • There may be"no genes for most instances autism and schizophrenia". There are sets of large scale mutations that are similar between close genetic relatives, but similar appearances are resulting from disorders of quite different components of brain development.
  • One in twenty seemingly normal people have big, ugly looking mutations that ought to be messing up their brain development. Yet they seem "normal". Seventeen in twenty persons with "schizophrenia" do NOT have these nasty scattered "sledgehammer" mutations. (So called because it's as though something took a sledgehammer to the genome.)
  • The age onset of schizophrenia is determined by when the disordered developmental genes are activated. There's a lot of this going on in late teen years. The implication is that the same thing explains why "autism" presents around ages 2-3, and why it can seem to appear fairly suddenly. This may also explain why some conditions seem to improve at other ages. Schizophrenia syndromes often improves in middle age, for example.
  • If every person with autism has a somewhat unique disorder, then treatments and prognosis are also unique. This validates the age old practice of asking someone with a cognitive/psychiatric disorder what treatments have worked for relatives.

The puzzle is far from complete, but one part of it has been filled out. We don't know what's causing these scattershot mutations, though a viral infection in very early development is one obvious possibility. I think this picture is also consistent with my earlier speculation that schizophrenia and autism are evolutionary disorders (see also).

Incidentally, Emily reminds me that autism was once considered a childhood variety of schizophrenia.

To me one of the most amazing results of the study is that 1/20 randomly selected health individuals have major derangements of genes responsible for brain development -- yet their brains still work. That's a group I'd really like to study!

See also:

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