Gene Links Early Death, Early Depression

When major depression strikes a person at age 25 or younger and then recurs, chances are good that it has a strong genetic input, research has shown.

Now 19 genetic regions have been identified that seem to play a role in this kind of depression.

The finding comes from George Zubenko, M.D., Ph.D., a professor of psychiatry at the University of Pittsburgh School of Medicine, and his colleagues. Their research is in press with the American Journal of Medical Genetics.

The focus of the study was 1,323 subjects consisting of 81 persons who had experienced early-onset, recurrent major depression and their 407 first-degree relatives and 835 extended relatives.

The researchers used a technique called linkage analysis to hunt for depression-causing genes in these subjects. Linkage analysis is a statistical technique that explores whether the transmission of a particular piece of DNA is associated with the transmission of a trait of interest—say depression—to a statistically significant degree, that is, at a rate greater than would be expected by chance alone.

Zubenko and his colleagues found 19 different regions of genetic material that could be linked with early-onset, recurrent major depression to a statistically significant degree. The regions were on chromosomes 1, 2, 5, 8, 10, 11, 15, 18, and 19 and the X chromosome.

The genetic region that was linked to early-onset, recurrent major depression to the most significant degree was on chromosome 2 and contained a gene called CREB1. The gene makes a protein called CREB. The protein CREB in turn is a lynchpin in a variety of cell-signaling pathways that regulate the downstream expression of genes that participate in many important cellular processes. For instance, CREB regulates the expression of genes that make neurotransmitter receptors.

It is also possible that the 19 genetic regions linked with early-onset, recurrent major depression have some control over human longevity, because deceased family members of the families studied were found to have died on average eight years earlier than people in the general population. In fact, over 40 percent died before age 65.

One might expect that many of these family members died at earlier ages because they were extremely depressed and committed suicide. “But the fact is,” Zubenko told Psychiatric News, “that whether people got depressed or not didn’t seem to matter in these families. Those individuals who never got depressed died just as early as did those who were depressed.”

Further, most of the premature deaths were due not to suicide, but to natural causes such as heart disease, cancer, and stroke. So putting all these pieces together, they suggest that there is something else shared in those families besides an elevated rate of depression that is contributing to the accelerated death rate. “And we speculate that it might be some of the genes that are segregating in these families and that were detected because they contribute to depression,” Zubenko said.

Indeed, one of the depression genes that might be shortening lifespan could be the one on chromosome 2 that makes the protein CREB. The reason? “CREB is an important regulatory protein that is expressed ubiquitously in all human tissues,” Zubenko explained. “In fact, it is expressed in a wide range of species, so it has been a ubiquitously conserved protein throughout evolution.”

Thus, if a person inherits an abnormal form of CREB, it might not only be able to trigger depression but also a host of bodily illnesses that could lead to premature death.

When Psychiatric News asked Zubenko whether any other researchers have confirmed these findings, he replied: “This is the first genome-wide survey for susceptibility genes for depression. And it only took us about 15 years to do this. So I wouldn’t be too disappointed if we didn’t get to see a replication quickly. However, one part of our results has also been found by another group of researchers—the association of genetic markers in the region of CREB with early-onset, recurrent depression.”

The study was funded by the National Institutes of Health and U.S. Public Health Service.

An abstract of the study, “Genome-Wide Linkage Survey for Genetic Loci That Influence the Development of Depressive Disorders in Families With Recurrent, Early-Onset Major Depression,” will be posted on the Web at www.interscience.wiley.com/jpages/0148-7299 after publication. ▪