Are some people hardwired to get the blues? Scientists have long believed that a tendency toward melancholy runs in families, much like dimpled chins and blue eyes. But the tricky part has been figuring out which genes are involved and how strongly they are correlated with a risk for developing depression.
A new study published on June 16 in the Journal of the American Medical Association (JAMA) now threatens to send researchers back to the drawing board. The meta-analysis of 14 prior studies concludes that the so-called depression gene a variant of a serotonin-transporter gene called 5-HTTLPR may not be associated with an elevated risk for depression, as many researchers had believed. "Knowing whether or not you have this gene is irrelevant," says the study's co-author Kathleen Merikangas, a genetic epidemiologist at the National Institute of Mental Health, who adds that future studies of genetic risk factors for depression should broaden their scope and consider the interactions of many genes rather than the actions of just one.
The discovery by Duke psychologist Avshalom Caspi of a "depression gene," which was among the first to be associated with mental illness a notably difficult class of diseases to pin down, genetically speaking inspired dozens of similar studies. While many researchers had suspected that 5-HTTLPR played a significant role in depression risk, Caspi was the first to establish an association by studying depressed people who had also experienced a stressful life event, such as the death of a child or sudden unemployment. What Caspi's 2003 epidemiological study, published in Science, found was that people with one or two copies of the short allele of the gene appeared to be more vulnerable to depression after a stressful event than people without the gene. Subsequent studies have looked at 5-HTTLPR's role in related conditions such as posttraumatic stress disorder, anxiety and neuroticism with mixed results.
But the new JAMA study, which reviewed 14 studies involving 14,250 participants on the interaction between the serotonin-transporter gene and stressful life events, found no such association with depression risk. The study goes on to caution that any potential use of 5-HTTLPR as a screening tool for depression risk would be invalid. Currently, no such test exists, although several genetic-testing companies, including 23andME and Navigenics, do use genetic markers to tell customers which antidepressant drugs they are more likely to respond to.
"My concern is that [these tests] are being marketed to the public as if there is no question about it," says Merikangas, speaking generally about direct-to-consumer genomic tests that purport to offer people any truly predictive health advice. "Some people might understand that it is not a death sentence to them, but to others who are struggling, it could lead them not to have children or get married."
Merikangas' meta-analysis has plenty of its own detractors, particularly among the scientists whose work it refutes. "This article ignores the complete body of scientific evidence," says psychologist Caspi, who sent TIME.com an e-mail appended with 22 citations of studies that support his findings. "In the past six years, extensive research in experimental neuroscience using both animals and humans has validated the original report by showing that the 5-HTTLPR short allele-carriers are excessively vulnerable to stress," he says.
"Meta-analyses can be a steamroller," says Alexandre Todorov, a genetic epidemiologist at Washington University in St. Louis, Mo., whose 2007 peer-reviewed study was included in the JAMA piece. (While Todorov's study found an association between the gene and depression, it was based on a different variant the long allele as opposed to the short one.) "If you have three studies and two find nothing and the third finds something significant, that does not mean that the third study is not real."
Where most genetics researchers do agree, however, is on the fact that uncovering the genetic roots of depression and most diseases, for that matter is a complex task. "We have about 30,000 genes, and it is hard to pick just one and analyze it," says Dr. Hans Joergen Grabe of Ernst-Moritz-Arndt-University of Greifswald in Stralsund, Germany. Although his 2005 study also found a correlation between the 5-HTTLPR gene and depression among the unemployed, "the magnitude of the effect is very small if the effect does really exist, it will only produce depression in very rare cases, about 5 or 10 out of 1,000." Grabe is now studying genes involved in the function of the "stress axis" of the body (the hypothalamus, pituitary and adrenal glands), since those are known to go haywire during major depression.
So what does this mean for anyone who is struggling with depression? The science of linking specific genes to the disorder is still in its infancy, so no one should worry that their genes alone doom them to a life of sorrow. And while no single treatment works for every patient, there are many including simple physical exercise or strengthening social relationships that can help to lift the blues.