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Pitt Researchers Single Out Genes For Major Depression; Genes Implicated In Mood Disorders And Shorter Lifespan

PITTSBURGH, July 2, 2003 Researchers at the University of Pittsburgh have completed the first survey of the entire human genome for genes that affect the susceptibility of individuals to developing clinical depression.

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. 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 Pitt teams findings are published today in the American Journal of Medical Genetics.

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.

Of equal interest is a secondary finding that longevity in the families who carry these genes is significantly reduced.

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 persons 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.

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.

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.

For more information on the Molecular Neurobiology and Genetics Lab at the University of Pittsburgh, please see http://www.zubenkolab.pitt.edu/.

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