|Rates of Rare Mutations Soar Three to Four Times
Higher in Schizophrenia
Multiple Genetic Glitches Disrupt Pathways Critical for Brain
People with schizophrenia (http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml)
have higher rates of rare genetic deletions and duplications that
likely disrupt the developing brain, according to studies funded
in part by the National Institutes of Health.
These tiny anomalies were found in 15 percent of adult onset schizophrenia
patients and 20 percent of child and adolescent onset patients,
compared with only 5 percent of healthy participants. Collectively,
the mutations carried by patients were significantly more likely
than those in healthy participants to disrupt genes involved in
brain development — potentially implicating hundreds of genes
in the illness, which affects about 1 percent of adults.
"This is an important new finding in the genetics of schizophrenia," said
NIMH Director Thomas R. Insel, M.D. "Identifying genes prone
to harboring these mutations in brain development pathways holds
promise for treatment and prevention of schizophrenia, as well
as a wide range of other neurodevelopmental brain disorders."
Two independent teams of researchers report on their combined
findings in an article published online in Science Express,
March 27, 2008. One team was led by Judith Rapoport, M.D., and
Anjene Addington, Ph.D., National Institute of Mental Health (NIMH),
Intramural Research Program. The other team was led by Jonathan
Sebat, Ph.D., and Shane McCarthy, Ph.D., Cold Spring Harbor Laboratory,
and by Jon McClellan, M.D., Tom Walsh, Ph.D., and Mary-Claire
King, Ph.D., University of Washington. Their research was supported
in part by the NIMH, National Institute of Child Health and Human
Development, National Institute of Neurological Disorders and Stroke,
National Center for Research Resources, and the National Institute
The prevailing genetic model of schizophrenia implicates common
variants of certain suspect candidate genes, each exerting modest
effects, in interaction with each other and environmental factors.
This hypothesis holds that risk stems from common variations in
the sequence of the genetic code that result in altered protein
About a year ago, Sebat, King and colleagues reported evidence
strengthening the case for a different kind of genetic risk (http://www.nimh.nih.gov/science-news/2007/tiny-spontaneous-gene-mutations-may-boost-autism-risk.shtml).
Many people with autism were found to have different, spontaneous
and individually rare structural variations — variations
in the number of copies of genes. These copy number variations
were scattered throughout the genome, suggesting many different
genes could be involved in autism spectrum disorders (http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml).
The new findings in schizophrenia echo those in autism, but also
broaden their implications. The results suggest a new approach
for discovering genes for schizophrenia and other mental disorders,
say the researchers. Any mutation in the hundreds of genes involved
in brain development could lead to a different set of neurodevelopmental
consequences — schizophrenia, autism, mental retardation,
or no illness at all. Each person with one of the illnesses could
have a different genetic cause for the disorder.
The functional consequences of these structural genetic variations
may differ, depending on interactions with other genes or environmental
events, say the researchers, making any gene harboring a deleterious
structural mutation a "candidate gene." Any gene harboring
one mutation likely contains others. Although each might be individually
rare, together such disease-causing variations in one gene could
explain a substantial number of illness cases, they suggest.
Among key study findings:
- Genes disrupted in patients, as opposed to healthy participants,
were significantly over-represented in pathways critical for
brain development. These included genes involved in creating
the infrastructure by which neurons communicate — and for
neuronal growth, migration, proliferation, differentiation, and
cell death. Among these were genes important for neuronal communications
via glutamate and neuregulin, both of which have previously been
implicated in schizophrenia.
- The mutations were often specific to single cases or families.
Virtually every mutation detected by King, Sebat and colleagues
was different in a sample of 150 adults with schizophrenia and
268 healthy controls.
- In families affected by childhood onset schizophrenia, Rapoport
and colleagues found that 28 percent (23) of 83 patients harbored
mutations, compared with 13 percent (10) of 77 controls. By using
the non-transmitted chromosomes of the patients' parents as controls,
the researchers were able to determine if the mutations in their
children were likely inherited or spontaneous. The majority turned
out to be inherited rather than spontaneous, some from parents
unaffected by the illness. Childhood onset schizophrenia is thought
to be a more severe and more genetically influenced form of the
The research was also funded by the Forrest C. and Frances H.
Lattner Foundation, NARSAD, the Simons Foundation, the Stanley
Medical Research Foundation, the Howard Hughes Medical Institute.
Rare Structural Variants Distrupt Multiple Genes in Neurodevelopmental
Pathways in Schizophrenia
Tom Walsh1*, Jon
Shane E. McCarthy3*,
Anjene M. Addington4*,
Sarah B. Pierce1, Greg M. Cooper5,
Alex S. Nord5, Mary Kusenda3,
Dheeraj Malhotra3, Abishek Bhandari3,
Sunday M. Stray1, Caitlin F. Rippey5,
Patricia Roccanova3, Vlad Makarov3,
B. Lakshmi3, Robert L. Findling6,
Linmarie Sikich7, Thomas Stromberg4,
Barry Merriman8, Nitin Gogtay4,
Philip Butler4, Kristen Eckstrand4,
Laila Noory4, Peter Gochman4,
Robert Long4, Amalia Dutra9,
Zugen Chen8, Sean Davis10,
Carl Baker5, Evan E. Eichler5,
Paul S. Meltzer10, Stanley Nelson8,
Andrew B. Singleton11, Ming K. Lee1,
Judith L. Rapoport4, Mary-Claire King1,5,
1 Department of Medicine, University of Washington,
Seattle, WA 98195, USA
2 Department of Psychiatry, University of Washington,
Seattle, WA 98195, USA
3 Cold Spring Harbor Laboratory, Cold Spring Harbor,
NY 11724, USA
4 Child Psychiatry Branch, National Institute of
Mental Health, NIH, Bethesda, MD 20892, USA
5 Department of Genome Sciences, University of Washington,
Seattle, WA 98195, USA
6 Department of Psychiatry, Case Medical Center,
Cleveland, OH 44106, USA
7 Department of Psychiatry, University of North Carolina,
Chapel Hill, NC 27599, USA
8 Department of Human Genetics, University of California,
Los Angeles, CA 90095, USA
9 Genetic Disease Research Branch, National Human
Genome Research Institute, NIH, Bethesda, MD 20892, USA
10 Cancer Genetics Branch, National Cancer Institute,
NIH, Bethesda, MD 20892, USA
11 Neurogenetics Laboratory, National Institute
on Aging, NIH, Bethesda, MD 20892, USA
* These authors contributed equally to this work.
# To whom correspondence should be addressed.
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