WP article: Schizophrenia linked to rare, often unique genetic glitches (ASD ref

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Note reference to autism starting in paragraph 5 ...

Schizophrenia Linked to Rare, Often Unique Genetic Glitches

By Rick Weiss

Washington Post Staff Writer

Friday, March 28, 2008; A05

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

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. "

" It's not that we're now going to be able to solve schizophrenia

tomorrow, " said Barondes, director of the center for

neurobiology and psychiatry at the University of California at San

Francisco, who was not involved in the work. " But it does present a

new way of figuring this puzzle out. "

Schizophrenia is a disease of disordered thinking and behavior.

Patients have trouble organizing their thoughts or communicating

sensibly, and many have auditory or visual hallucinations.

The disease, which typically emerges in early adulthood, used to be

blamed on " bad mothering " but has since come to be recognized as

having genetic roots.

Yet environmental factors also contribute. Pregnant women who

experience famine are at increased risk of giving birth to children

who will get schizophrenia. Childhood infections may also add to the

risk. Further muddying the picture, most schizophrenics have no

family history of the disease. That suggests that, to the extent the

disease is genetic, the mutations often arise spontaneously either

at conception or during fetal development, perhaps after having

inherited a general propensity to get such mutations.

Those and other details led scientists to conclude 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.

" It's fabulous to be able to find these mutations directly rather

than indirectly, " said - King, a geneticist at the

University of Washington who was on the team. " You just go for the

jugular. "

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 Sebat of Cold Spring Harbor

Laboratory, one of the study leaders.

" Genes have timing, " Sebat said. " They follow developmental programs

for where and when they're going to be active. "