Found Rare Genetic Mutations to be a Factor in Schizophrenia Risk

[manuelm...@gmail.com]

For several decades, scientists have known from studies of identical
and fraternal twins that schizophrenia has a strong genetic component,
which has been estimated to account for about 80 percent of risk. But
they have searched largely in vain for commonly occurring gene
mutations that would explain the prevalence of the disease in the
general population -- about one in every 100 people. It has been
widely assumed that a relatively small number of commonly occurring
gene mutations, each producing a small effect but assumed to be acting
in concert with one another and also with environmental factors,
triggers many cases of schizophrenia.

The new study, led in part by Pamela Sklar, M.D., Ph.D., a two-time
NARSAD Young Investigator and recipient of an Independent Investigator
award, suggests another important genetic factor contributing to risk
for schizophrenia. Based on genome scans of 3,391 patients and 3,181
healthy controls, the study found that patients were more likely to
have rare gene mutations of a particular kind, called copy number
variations, or CNVs.

CNVs are segments of the genome, sometimes but not always containing
one or more genes, that for unknown reasons are either deleted or
repeated in a person. CNVs can be inherited or occur “spontaneously,”
in a child whose parents do not have the missing or repeated genome
segments. Certain instances -- but not all -- of these “structural
variations” of the chromosomes are theorized to disturb gene
expression, perhaps triggering serious illness.

CNVs Are More Common in Patients Than Controls

After comparing genome scans of healthy people and people with
schizophrenia, the scientists noted a key pattern: people who had
these rare chromosomal deletions and duplications were more likely to
have the illness.

As Dr. Sklar -- of Massachusetts General Hospital, Harvard University
and MIT’s Broad Institute -- and her colleagues in the International
Schizophrenia Consortium reported last week in an advance online
edition of the journal Nature, the increased schizophrenia risk
associated with possessing a rare CNV is “subtle” -- 1.15 times the
risk of people who don’t have this type of structural mutation in
their genome.

When they counted only instances where CNVs contained a gene, the team
found a larger difference in risk between patients and healthy people:
patients had such mutations 1.41 times as often as people in the
control group.

CNV-Disease Link Is Not Understood

One question raised by this research concerns the precise nature of
the relation between CNVs and biological processes that contribute to
schizophrenia. “Exactly how” the additional risk associated with
having CNVs “translates mechanistically into illness in a given
patient is currently unknown,” the scientists noted. They added:
“Similarly, we do not know how environmental risk or protective
factors might act in concert with specific CNVs” to cause illness.

The consortium’s scientists, like researchers who have found CNVs in
other schizophrenia populations, are intrigued by the fact that some
of the genes in the deleted or repeated areas have separately been
associated with other neurobiological disorders, including mental
retardation, psychosis, bipolar disorder and autism.

Researchers have begun the difficult task of determining how specific
CNVs affect the expression of genes, which, in turn, may be parts of
networks that might affect function of the brain and other aspects of
the human system. Such changes, in turn, could have an impact on risk
for schizophrenia and other mental illnesses including autism and
bipolar disorder.

Study Also Links Three Specific Deleted Regions to Schizophrenia

The International Schizophrenia Consortium’s genome scans also
identified three deleted regions in the genome that it specifically
linked to schizophrenia, including an area on chromosome 22 that has
been identified in other studies. The other two deletions, though, had
not been previously implicated in the disease: large sections of DNA
on chromosomes 1 and 15 were missing more often in patients with
schizophrenia than in controls. In another study appearing in the same
issue of the journal Nature, a team of researchers led by scientists
at deCODE Genetics found that the same three deletions conferred risk
for the disorder, in effect an independent confirmation of the
consortium’s finding.

“In light of these new findings,” Dr. Sklar commented on the work on
CNVs, “there no longer needs to be an argument that this type of
variation plays a role in some of the risk” for schizophrenia. “The
task now is to understand how rare structural variation, together with
other kinds of genetic variation and environmental effects, work
together to produce schizophrenia.”