Sex-specific genes for depression

For the study, funded by the National Institute of Mental Health, Dr. Zubenko and his colleagues compared genetic markers from 100 men and women with recurrent, early-onset major depressive disorder (RE-MDD) and 100 people with no history of this disorder, to find out which chromosomal regions were associated with the illness. RE-MDD is a severe form of clinical depression that runs in families and impairs the health and life span of family members.

Out of 19 chromosomal regions that were associated with the development of RE-MDD, 16 were significantly associated with the disorder in either men or women - but not both. Confirmation that one of these regions, located on chromosome 2, affects the risk of severe depression among women in 81 families identified by individuals with RE-MDD is published in today's issue of Molecular Psychiatry.

"We suspected there were at least a few different genes involved in making women and men susceptible to major depression," said lead author 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. "The results of this study suggest that sex-specific genes for recurrent major depression may actually be the rule rather than the exception."

According to the authors, these findings suggest important differences in the molecular basis of clinical depression in men and women, or sex-specific differences that determine resistence to stressful events. These genetic factors may contribute to differences in the symptoms of clinical depression in men and women, differential treatment responses, and the development of additional psychiatric disorders such as alcoholism and other substance use disorders that frequently accompany major depression and run in the same families. They may also influence the risk of developing diseases that affect organs other than the brain. The deceased relatives in these 81 families died at a median age that was 8 years earlier than for the local population; over 40% died before reaching age 65. These differences in mortality statistics resulted from a shift toward younger ages at death across the lifespan, including a five-fold increase in the proportion of individuals who died in the first year of life.

This research may provide an important step toward changing the way doctors diagnose and treat major depression that affects nearly 10 percent of the population. "Studies such as this one are providing us with a better understanding of the biology of complicated disorders such as major depression, which is unlikely to represent a single disease with a unitary cause," said Dr. Zubenko. "Instead, clinical depression is probably more like anemia. Both of these disorders are defined by a collection of clinical features that result from different causes in different people. Treatment or prevention efforts are usually most successful when they are aimed at the specific causes of a disorder."

Further progress in diagnosis and treatment of clinical depression that result from these findings will likely proceed along several avenues, as explored in an accompanying editorial. "It will be important for us and others to confirm our findings using complementary genetic methods and independent populations. This will be followed by intense efforts by many investigators to identify the susceptibility genes in the chromosomal regions that are confirmed. The identification and characterization of these genes and their products will provide new opportunities for drug development and disease prevention, and new information about the biology of mood and its regulation," said Dr. Zubenko.

These developments are time and resource intensive, and that it will be unlikely for the results of this avenue of research to affect clinical care in less than a decade. However, other applications may have important implications in the nearer future. "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," Dr. Zubenko said. "In current practice, the choice of a particular antidepressant for a patient is largely a hit or miss proposition that often leads to multiple medication trials before the depression remits. Side effects are common and can be debilitating."

ARTICLE: "D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women"

AUTHORS: GS Zubenko, HB Hughes III, JS Stiffler, WN Zubenko and BB Kaplan

Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA; Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, PA; Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD

Citation source: Molecular Psychiatry, 2002, vol. 7, no. 5 pp. 460-467. doi:10.1038/sj.mp.4001121

For further information on this work, please contact George S. Zubenko, MD, PhD, WPIC, Room E1230, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. Phone:
+1-412-624-5186; FAX: +1-412-624-4421; E-mail: zubenkog@pitt.edu

Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: +1-310-825-7113; FAX: +1-310-206-6715; e-mail: licinio@ucla.edu

For a copy of this article and accompanying editorial, please contact Frank Sissingh, editorial assistant, e-mail: molecularpsychiatry@mednet.ucla.edu.

PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.