A research team in the Pitt School of Medicine has found six chromosomal regions, or loci, that may harbor risk genes for suicide. This represents the first time scientists have been able to pinpoint locations where at least some of the genetic risk for suicide resides and could lead to a breakthrough in our understanding of the underpinnings of suicidal behavior and its treatment and prevention.

The researchers discovered that these suicide risk genes are deadliest when they work in concert with specific mood disorders. One of the risk genes resides on the X chromosome; women—who attempt suicide more often than men—could have two copies of the gene.

“These genetic loci influence the emergence of suicide attempts in patients with severe depressive disorders in a sort of lock-and-key relationship,” said principal author George S. Zubenko, professor of psychiatry in the Pitt School of Medicine and adjunct professor of biological sciences at Carnegie Mellon University. “Some suicide risk loci influence the development of suicidal behavior among patients with one psychiatric disorder, or subtype, but not another. These findings may provide opportunities for designing better treatments and early intervention strategies that reduce the prevalence of this tragic outcome of mental illness, alcoholism, and drug abuse.”

The study results were selected for rapid online publication July 6 in the American Journal of Medical Genetics and will appear in the Aug. 15 print edition.

Suicide was the 11th leading cause of death among Americans in 2002, claiming the lives of more than 30,000 people, a rate nearly double that of homicides. The suicide rate is highest among the elderly, but also is a leading cause of death in adolescents and young adults between the ages of 15 and 24.

Research studies done over many years show that more than 90 percent of people who attempt or complete suicide suffer from a psychiatric disorder, such as depression or bipolar disorder. Despite the fact that suicides most often occur in people with mental illness, the vast majority of people with mental illness, even those illnesses with the highest risks of suicide, do not attempt to kill themselves. According to Zubenko, this observation has suggested the existence of an independent predisposition that contributes to the emergence of suicidal behavior through an interaction with a psychiatric disorder.

Findings from family, twin, and adoption studies provide strong evidence that the predisposition to suicide comes from a genetic connection.

The lock-and-key description of the relationship between the suicide risk genes and mood disorders is complex. In this study, the greatest increase in the risk of suicide attempts occurred when specific suicide risk loci were coupled with recurrent major depressive disorder or depression spectrum disorder. Depression spectrum disorder includes alcoholism and drug abuse disorders as well as antisocial and labile personality disorders.

Previous efforts to identify genes that affect the risk of suicidal behaviors have focused on “candidate” genes that mediate the effects of serotonin, but these studies have yielded inconsistent and usually negative results. In contrast, the Pitt team employed a genome-wide linkage analysis of 81 families that were densely affected by depressive disorders.

“Our experimental approach did not rely on preconceptions about which genes might contribute to the development of suicidal behavior,” said Zubenko

This collection of 81 families previously enabled Zubenko and his colleagues to identify susceptibility loci for depressive disorders. In fact, the six suicide risk loci reported in the current study are distinct from the 19 chromosomal regions previously reported to influence the development of depressive disorders among these family members.

“The lack of overlap in these two groups of susceptibility genes provides molecular evidence in support of an independent, heritable predisposition that contributes to the emergence of suicidal behavior through an interaction with severe depressive disorders,” said Zubenko.

The results of the previous linkage study suggested a mechanism of genetic susceptibility to mood disorders that focused on cellular communication pathways that interact with CREB, a protein that orchestrates the expression of large numbers of other genes that play important roles in the brain. CREB also has been implicated in problems with neuronal plasticity, cognition, and long-term memory, abnormalities of which commonly occur in patients with major depression; may predispose patients to the onset or recurrence of major depression; and may be related to the eventual development of irreversible dementias like Alzheimer’s disease in some patients. Numerous genes that fulfill this description reside within the suicide-risk regions identified in the current study.

“This observation suggests that genes that interact with mood disorders to influence the risk of suicidal attempts may participate in the same or related signaling pathways that contribute to the pathogenesis of mood disorders themselves,” said Zubenko.

This study was supported by grants from the National Institute of Mental Health, with additional support from the U.S. Public Health Service. Genotyping was provided by the Center for Inherited Disease Research, which is fully funded through a federal grant from the National Institutes of Health to the Johns Hopkins University.