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Gene Expression Profiling Study Finds Biomarkers Related to Suicide Risk

NEW YORK (GenomeWeb News) – RNA biomarkers in the blood may be able to identify people who are at risk of committing suicide, according to a new study in Molecular Psychiatry.

The researchers, led by Alexander Niculescu, an associate professor of psychiatry and medical neuroscience at the Indiana University School of Medicine, searched for genes that were differentially expressed in the blood of people with bipolar disorder — about one in three people with bipolar disorder attempt suicide during their life — who had suicide ideation. They further drew on other lines of evidence to narrow down their search and validated their findings in two prospective cohorts.

The top biomarker the investigators identified, SAT1, is a catabolic enzyme for polyamines, which affects cell vitality. A decline in polyamine levels can lead to apoptosis. And apoptotic mechanisms, the researchers noted, have been linked previously to mood disorders and resilience.

"Suicide is a big problem in psychiatry. It's a big problem in the civilian realm, it's a big problem in the military realm, and there are no objective markers," Niculescu said in a statement. "There are people who will not reveal they are having suicidal thoughts when you ask them, who then commit it and there's nothing you can do about it. We need better ways to identify, intervene, and prevent these tragic cases."

For this study, the investigators turned to a subset of a larger, longitudinal cohort they are studying. Here, they focused on a cohort of men with bipolar disorder whose suicide ideation states were assessed using a questionnaire during the course of three months to six months. Nine of those men had a shift in score from no suicide ideation to high suicide ideation.

To find markers associated with suicide, Niculescu and his colleagues conducted whole-genome gene expression profiling on blood samples taken from those men before and after the change to their suicide ideation states. Such an intrasubject design, the researchers noted, helps control for genetic variability, medication effects, lifestyle, and demographic effects. From this, they identified more than 860 differentially expressed genes.

The investigators also compared the suicide ideation group to others from the larger bipolar group, whose suicide ideation state did not change, whittling that number of differentially expressed genes down to about 250.

The researchers examined other lines of evidence, as well, to strengthen the connection of those putative biomarkers to suicide. Using a convergent functional genomics approach, they narrowed in on genes from their list that had been linked to suicide in other studies. For example, if they found though a PubMed search published reports of a gene showing expression changes in postmortem brains from suicide victims, they considered that additional evidence. They weighted the evidence they unearthed in the literature based on the tissue source as well as whether it was a gene expression change or other genetic link.

After those considerations, the top blood biomarker for suicide risk was SAT1, while CD24 was the top protective marker.

To validate the remaining top-scoring markers, Niculescu and his colleagues examined their expression levels in blood samples from suicide victims obtained from the coroner's office. SAT1, they found, was elevated in all nine of the suicide subjects they tested. Overall, six markers — led by SAT1 — remained significant after Bonferroni correction for multiple comparisons.

The investigators also turned to two subsets of their longitudinal cohort for a prospective validation of their markers, with a particular emphasis on SAT1. They examined the expression levels of six biomarkers in a cohort of men with bipolar disorder and in a cohort of men with schizophrenia or schizoaffective disorder, and compared those levels to the subjects' past or subsequent hospitalizations.

They determined that higher SAT1 levels were linked to hospitalizations due to suicide risk in the bipolar group, though there was a weaker link in the schizophrenia group.

Three other markers — PTEN, MARCKS, and MAP3K3 — showed similar, though weaker effects, the researchers noted.

"Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS, and MAP3K3 might be not only state markers but perhaps trait markers as well," the researchers wrote.

A number of the top biomarker genes were involved in circadian clock and inflammation pathways as well as in apoptosis pathways, the investigators noted. SAT1, for example, is a catabolic enzyme for polyamines, whose decrease is linked to apoptosis. SAT1, further, is inducible by a number of stimuli, including toxins and stressors. Additionally, the top protective marker, CD24, has a role in apoptosis.

"Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis," Niculescu and his colleagues said.

The researchers also underscored some of the drawbacks of their study, namely that it drew upon mostly white male subjects.

"There could be gender differences," Niculescu added. "We would also like to conduct more extensive, normative studies in the population at large."

He noted that he and his colleagues also plan to study whether their blood test could be combined with other clinical and socio-demographic risk factors to increase their ability to predict suicide risk.

"Suicide is complex: in addition to psychiatric and addiction issues that make people more vulnerable, there are existential issues related to lack of satisfaction with one's life, lack of hope for the future, not feeling needed, and cultural factors that make suicide seem like an option," he said.