Local researchers are closing in on the first susceptibility gene for depression in women, a feat that could one day lead to a better understanding of the disease and individualized treatments.
Dr. George Zubenko, professor of psychiatry at the University of Pittsburgh School of Medicine and adjunct professor of biological sciences at Carnegie Mellon University, said his research team has tracked the gene down to a small region on chromosome 2 that makes up 1/100th of the entire human genome.
That neighborhood, which contains perhaps eight genes, happens to house a likely suspect: the gene that makes a protein called CREB1, which regulates other genes and proteins that play important roles in the brain.
"I hope the next time you hear from us we'll be telling you that we've proven it's CREB1," Zubenko said. "It will be the first identified susceptibility gene for the second most common cause of disability worldwide."
Other scientists have previously uncovered alterations in CREB1 activity in the brains of patients who died with major depression and in experimental animals treated with antidepressant drugs.
It is possible that another gene in that region is playing a role in the development of recurrent, early-onset depression, Zubenko said. But identifying the susceptibility gene and the biochemical pathways it affects will ultimately improve understanding of the disease and influence the development of treatments.
Gene mutations could cause the over- or underproduction of proteins or the creation of abnormal proteins that in turn lead to alterations of brain chemistry and mood disturbances. The specific mutations will likely vary among individual patients.
So "it's very likely some medications will work better in people who have one type of etiology for depression than another," Zubenko said.
The research, reported yesterday in the American Journal of Medical Genetics, builds upon earlier findings that men and women have genetic markers for depression in different chromosomal regions. The area on chromosome 2 showed the most noteworthy difference between women with severe depression and healthy counterparts, so Zubenko's team focused their follow-up work on it.
There are indications that CREB1 interacts with estrogen receptors in some biochemical pathways, so that may help explain why depressed men do not share this marker, Zubenko said.
The researchers will continue to map out the marker region, both to identify the gene and the mutations that may be involved. They will also look at cases of familial depression that do not carry the chromosome 2 markers, paying particular attention to the possibility of other susceptibility genes influencing CREB1 pathways.
"How many genes like this for depression are there likely to be?" he said. "Nobody really knows the answer to that question. But I tell you, after you find the first one, the second and third and fourth will be easier to find."
Anita Srikameswaran can be reached at anitas@post-gazette.com or 412-263-3858.
