Provided by the National Institute of Mental Health
IMany years of research have demonstrated that
vulnerability to mental illnesses—such as schizophrenia, bipolar disorder,
early-onset depression, anxiety disorders, autism, and attention deficit
hyperactivity disorder—has a genetic component. It is now clear that these
disorders are not due to a single defective gene, but to the joint effects of
many genes acting together with nongenetic factors.1,2,3 Despite the daunting
complexity, progress is being made. Researchers are hunting genes because they
are likely to be a vital key to deciphering what goes wrong in the brain in
mental illness.
Detecting multiple genes, each contributing only a small effect, requires large
sample sizes and powerful technologies that can associate genetic variations
with disease 4,5,6 and thereby pinpoint candidate genes from among the many
genes that are expressed in the human brain. And even after human disease
vulnerability genes are found, sophisticated tools will be needed to find out
what activates them, what brain components they code for, and how they affect
behavior. The prospect of acquiring such molecular knowledge holds great hope
for the engineering of new therapies.
Linkage studies are often based on the identification of large, densely affected
families so that the inheritance patterns of known sections of DNA (called
"markers") can be compared to the family's transmission of the disorder.7 If a
known marker can be correlated with the presence or absence of the disorder,
this finding narrows the location of the suspect gene.
Linkage-disequilibrium studies in isolated populations capitalize on the
likelihood that the susceptibility genes for a particular disorder probably came
from one or a few founding members.8 Whether the isolation is geographic or
cultural, there are fewer individuals in the community's genealogies and
therefore fewer variations of the disease genes within the population. This
limited variation makes the search easier. In addition, the groups of markers
that surround each of these susceptibility genes are likely to have the same
limited variation, which further simplifies identification.
Association studies depend on the investigator hypothesizing that a specific
gene or genes may influence the disorder. In this type of study, the
investigator examines whether those people with the disorder have a different
version of the gene than those without the disorder among related or unrelated
individuals.9
Evidence suggests that unaffected family members may share with their ill
relatives genes that predispose for milder, but qualitatively similar behavioral
characteristics. For example, some relatives of people with schizophrenia or
autism may exhibit subtle cognitive problems.10,11 Family members may also share
biological anomalies that could be clues to the underlying genetic component of
the illness. For example, they may share telltale chemical signatures in cells
of implicated brain circuits. NIMH-supported investigators are studying such
families to characterize these behavioral and biological traits, in hopes of
tracing the variations in the genetic blueprint that contribute to illness.
Some gene variants are likely to turn on too much or too little—or in the wrong
place. This could interfere with the way brain cells work. It may also affect
how cells migrate to other parts of the brain and connect with one another
during early development. NIMH has mounted an effort to vastly expand the set of
available tools for discovering the molecular mistakes that produce mental
illness.
A vital resource for doing this, now under development, will be a shared
scientific infrastructure called the Brain Molecular Anatomy Project (BMAP). The
goals of this multidisciplinary effort are to catalog the genes that are active
in various parts of the brain at different developmental stages, and to make
this information readily available to investigators on a Web-based map.
The mouse's brain is a major initial focus of BMAP. A Web-based digital mouse
brain atlas will offer 3-D and 2-D views of this biological blueprint, covering
different strains and ages of animals. In addition to advancing basic knowledge,
the BMAP database promises to enhance clinical science, providing new leads for
studying gene expression in post-mortem tissue, for the identification of
candidate genes, and enhanced capacity to screen for individuals who might be at
risk for developing brain disorders.
A related set of developing tools also centers on the mouse: identifying the
neural basis of complex behaviors.12 The mouse has become a critical model in
studying human disease because scientists have access to many inbred strains,
each expressing distinctive physiological and behavioral characteristics.
Researchers can now insert, knock out, or mutate mouse genes, quickly breed a
generation that expresses the change, and then see how it affects behavior. When
illness-linked genes are discovered, they will be inserted and expressed in mice
to find out what they do at the molecular, cellular and behavioral levels.
Researchers will be able to track a wiring abnormality, a cell migration
abnormality, or other anomaly that may lead to symptoms in humans.
Chromosomes, visualized here, are long molecules of DNA, the genetic material.
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For More Information
Please visit the following link for more information about organizations that
focus on the human brain.
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All material in this fact sheet is in the public domain and may be copied or
reproduced without permission from the Institute. Citation of the source is
appreciated.
NIH Publication No. 01-4600
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References
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3Risch NJ, Spiker D, Lotspeich L, et al. A genomic screen of autism: evidence
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