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Researchers Find Genes for Depression
May Shorten Lifespan
July 2, 2003 - The first survey of the
entire human genome for genes that affect the susceptibility of
individuals to developing clinical depression has found that these
subjects do not live as long as the general population.
The survey was done in 81 families
identified by individuals with recurrent, early-onset, major
depressive disorder (RE-MDD), a severe form of depression that runs in
families. The University of Pittsburgh team's findings are published
today in the American Journal of Medical Genetics.
George S. Zubenko, M.D., Ph.D.,
professor of psychiatry at the University of Pittsburgh School of
Medicine and adjunct professor of biological sciences at Carnegie
Mellon University and his team have located a number of chromosomal
regions they say hold the genetic keys to a variety of mental
illnesses, including major depression and certain addictions.
Of equal interest is a secondary finding
that – longevity in the families who carry these genes is
significantly reduced.
Remarkably, deceased members of the 81
families died at an age eight years younger than the general
population and over 40 percent died before the age of 65. This
difference in mortality was spread across the lifespan, including a
five-fold increase in the proportion of children who died in the first
year of life and several-fold increases in deaths by suicide, homicide
and liver disease.
However, most premature deaths occurred
from "natural causes" including heart disease, cancer and stroke.
"Tracking down the risk genes in these regions is an obvious priority,
and we expect that the research will connect clinical depression and
other medical disorders at their most fundamental levels," said Dr.
Zubenko.
Finding the genetic roots of depression
is important for many reasons. Depression is the second-leading cause
of disability worldwide, affecting nearly 10 percent of the
population. And while scientists have made significant progress
developing new drugs to treat it, studies that identify specific risk
genes may lead to even more effective drugs designed to target
depression in specific individuals.
Twin studies have demonstrated that
genetic factors typically account for 40 to 70 percent of the risk for
developing major depression, but finding those genes has proven to be
a challenge because, as in most diseases, there are likely numerous
genes involved and only individuals with certain combinations of those
genes develop the disorder.
The survey revealed 19 loci – small
regions on chromosomes where genes reside – that appear to influence
susceptibility to depressive disorders. The results extended the
investigators' previous finding that a small region of chromosome 2q
containing the CREB1 gene affects the vulnerability of women to
developing depression. And at least some of the 19 depression
vulnerability loci appear to work in concert to affect a person's risk
of developing depression.
According to Dr. Zubenko, "Greater
scrutiny of the chromosome 2 locus has provided stronger evidence for
the role of CREB1 as a risk gene for depressive disorders among women.
In addition, five of the new genetic loci appear to interact with the
CREB1 region to affect the risk of developing clinical depression in
these families.
"Women are twice as likely as men to
develop depression, and genetic differences appear to account for some
of that disparity," said Dr. Zubenko. Sex-specific loci were common
and preferentially affected the vulnerability of women to developing
unipolar mood disorders. Evidence of at least one male-specific risk
locus also was found. The sex-specific effects of particular risk
genes for depression may result from the interactions of these genes
and their products with sex hormones.
These findings suggest there are
important differences in the molecular pathophysiology of mood
disorders in men and women, or in the mechanisms that determine
resistance to stressful stimuli. They may also help explain the
vulnerability of women to depression during times of significant
hormonal fluctuation including puberty, menstrual cycling, pregnancy
and childbirth and menopause. Conversely, age-related reductions in
hormone levels may contribute to a reduced proportion of familial
cases of depression among depressions that arise later in life.
CREB1 is a gene that encodes a
regulatory protein called CREB that orchestrates the expression of
programs of other genes that play important roles in the brain and the
rest of the body. The widespread importance of CREB as a genetic
regulator may influence the development of additional psychiatric
disorders related to depression, such as alcoholism and other
addictions, as well as medical conditions outside of the nervous
system that are associated with depression. For example, three of the
new linkage regions affected the risk of developing a spectrum of
depressive disorders including alcohol and other substance use
disorders.
Information provided by the Human Genome
Project is enabling the investigators to make important progress
toward this goal. In 18 of the 19 newly identified genetic regions,
the authors found candidate genes that participate in cell signaling
pathways that converge on CREB. These observations provide an
important new perspective on the biology of depression and its
treatments that focuses on cell signaling pathways rather than
particular neurotransmitters.
"The identification and characterization
of susceptibility genes and their products will provide new
opportunities for drug development and disease prevention, new
information about the biology of mood and its regulation, and new
insights into the interactions of mental illness and the human life
span," said Dr. Zubenko. "Genotyping markers in chromosomal regions
that harbor susceptibility genes may provide more immediate advances
in the treatment of major depression. For example, individuals with
particular genetic markers in these regions may respond better to
particular current treatments than others. This strategy may enable
clinicians to use genetic markers to better match individual patients
to treatments to which they will optimally respond, while minimizing
side effects."
Other researchers involved in this study
include: Brion S. Maher, Ph.D.; Hugh B. Hughes III, M.S.; Wendy N.
Zubenko, Ed.D., M.S.N..; J. Scott Stiffler, B.S.; Barry B. Kaplan,
Ph.D.; and Mary L. Marazita, Ph.D.
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The study received funding from the
National Institute of Mental Health.
For more information on the Molecular
Neurobiology and Genetics Lab at the University of Pittsburgh, please
see http://www.zubenkolab.pitt.edu/. |
