Suicide-Related Gene Could Point Way to Drug Target

There is a reason to believe that suicidal behavior has a genetic component independent of the risk imposed by psychiatric disorders such as alcoholism, bipolar disorder, and depression. Some candidate genes in this domain have also been identified—for example, the serotonin transporter gene, the tryptophan hydroxylase genes, and hypothalamus-pituitary-adrenal axis genes such as BDNF, NTRK2, and SSAT.

Now another gene that may make an independent contribution to suicidal behavior has been identified. It is called the ACP1 gene and is located on chromosome 2 in a region known as 2p25.

The lead investigator of the study that identified this gene was Virginia Willour, Ph.D., an assistant professor of psychiatry at Johns Hopkins University. The senior investigator was James Potash, M.D., an associate professor of psychiatry there. The results were published online March 22 in Molecular Psychiatry.

Willour and her colleagues compared genetic material from some 1,200 subjects with bipolar disorder and a history of suicide attempts with genetic material from about 1,500 subjects with bipolar disorder but without a history of suicide attempts. Their hope was to identify snips of genetic material that distinguished the former from the latter and thus would constitute genetic risk material for suicidal behavior independently of any risk imposed by having bipolar disorder.

They found one snip that possibly distinguished those who attempted suicide from those who did not. It was located on the short arm of chromosome 2 at a position called 2p25.

Furthermore, this snip of genetic material contained four genes, one of which was called ACP1. The researchers then went on to examine the expression of the ACP1 gene in the brains of 14 subjects with bipolar disorder who had died from suicide and in the brains of 20 subjects with bipolar disorder who had died by other means. They found that expression of the ACP1 gene was significantly elevated in the prefrontal cortex of the former group. As a result, they believe that the ACP1 gene might contribute independently to suicidal behavior.

Another reason they think that such a link might exist is that the protein made by the ACP1 gene influences a biological pathway that is regulated by lithium, and lithium's ability to counter suicidal behavior is well established.

How might the ACP1 gene increase suicide risk? Possibly by contributing to impulsive aggression, Willour told Psychiatric News, "with individuals having both a psychiatric disorder and a tendency toward impulsive aggression having the greatest risk for suicidal behavior."

When asked whether their findings have any clinical implications at this point, Willour noted, "My colleague James Potash has a number of ongoing clinical and genetic research projects focused on the role of lithium in the treatment of bipolar disorder. We are hoping that our findings that relate to ACP1 and its potential role in attempted suicide might complement that work. Our results could inform the development of novel treatments that, like lithium, have antisuicidal properties."

Potash agreed: "This paper will not itself change clinical practice. But the goals of this kind of work are to make a difference for patients. There are several ways that this could happen. The most important would be that finding a gene takes us into a pathway, and then studying the pathway points us to new ‘druggable’ targets—places in the pathway where novel medications might interrupt the process that leads people toward suicidal behavior."

Willour also pointed out that the Psychiatric Genomewide Association Study Consortium—which was launched in 2007 and today includes more than 100 scientists from 11 countries—is not just attempting to identify genetic risk factors for bipolar disorder, major depression, schizophrenia, and some other psychiatric disorders, but to identify genetic risk factors for suicidal behavior. "We are eager to see whether [their results] will provide further evidence for the 2p25 candidate region and for ACP1 in particular," she said.

The study was funded by the National Institute of Mental Health and the American Foundation for Suicide Prevention.

An abstract of "A Genome-wide Association Study of Attempted Suicide" is posted at <www.nature.com/mp/journal/vaop/ncurrent/abs/mp20114a.html>.