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.
The study
received funding from the National Institute of Mental Health
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