There is a genetic component to early-onset clinical depression, a new study suggests.

Genetics of Recurrent Early-Onset Major Depression (GenRED), a study coordinated by Dr. Douglas Levinson, professor of psychiatry and behavioral sciences, has shown that a gene in a small region of Chromosome 15 is probably responsible for increasing the risk of early-onset clinical depression, despite the influence of environmental factors.

The study, a joint effort between Levinson’s Stanford-based group and five other research teams at Columbia, Howard, John Hopkins, Rush and Iowa universities, was the culmination of two decades of scientific work on the genetic influence on psychiatric diseases. The study’s findings were published in two papers in the February issue of the American Journal of Psychiatry.

The primary research technique used in the study was “positional cloning,” an approach in which the exact sequence of a gene is located using its position on the genome. This technique is necessary for diseases like depression, which are difficult to diagnose and have unknown causes.

Levinson said that he became interested in the genetic approach to studying psychiatric disorders when scientists began looking at the similarities between twins separated at birth. Striking similarities, like the tendency to dress alike, were probably genetic and are easy to observe.

But there are also genetic similarities that are harder to observe, and it is through the linking of the invisible to the observable that Levinson has been able to trace the genetic origins of diseases like schizophrenia and depression.

“That reality blew me away,” Levinson said. “It just fit what I was seeing.”

In positional cloning, genes are located using their proximity to known “markers” in the genome. The “markers” are like the obvious similarities that Levinson uses to track the invisible genes that cause diseases. Use of different markers has allowed scientists to become increasingly precise over time. The original markers were known genetic variations like blood type, which could be assessed clinically, but Levinson’s team turned to single nucleotide polymorphisms (SNPs or “snips”).

“You’re looking for direct correlation between having DNA sequence variation and getting sick,” Levinson said.

Earlier research on psychiatric diseases using positional cloning focused on disorders like schizophrenia or Alzheimer’s that were widely thought to be influenced by genetic rather than environmental factors. Depression, Levinson said, is influenced by so many variables that finding a genetic link is like looking for a needle in a haystack.

SNPs allowed scientists to form genetic maps detailed enough to track even the weak genetic influence exerted by diseases like depression. But they did so only in conjunction with extremely large sample sizes.

“This wasn’t possible just four or five years ago,” Levinson said.

Levinson’s study relied on funding from the National Institutes of Mental Health (NIMH) and on recent science that allows researchers to build a library of human genetic data for use in studies like GenRED. The technique enables white blood cells to regenerate after being frozen and stored.

“The GenRED study was one of the initial studies funded in order to develop the [NIMH] repository program,” Levinson said.

According to Levinson and Dr. Jennifer Johnson, who executed most of the Stanford GenRED team’s clinical work, the sample size needed for the depression study to be statistically significant was 1,000 participants. Each participant had to demonstrate recurrent episodes of unipolar (rather than bipolar) depression that occurred by age 30 and a family history of unipolar depression. Participants also had to be over the age of 21.

Johnson said the study used brochures in clinics and radio announcements to advertise, but she added that most participants seemed happy to help.

“One of the things that is most striking in interviewing these subjects is that they’re not doing it for the money,” she said. “I hear time and time again that these people say, ‘My parents had depression, my grandparents had depression...I’m scared to death that my children are going to have depression.’”

“They really want to do something to contribute,” she added.

Genetic samples and clinical information from the study are permanently stored at the repository at NIMH, labeled with identification numbers so that participants’ identities are protected.

In the future, Levinson said, increasingly accurate genetic information may lead pharmaceutical companies to develop more advanced drugs to treat depression. Alternatively, scientists could control for known genetic factors to isolate environmental variables that contribute to the likelihood of depression. Levinson is planning to run another study, this time with an even larger sample size.

Levinson said that the findings could eventually lead to advances in the treatment of early-onset depression. This particular form of depression, he said, affects three to four percent of the population and can lead to suicide. Patients with depression, he said, describe “losing a sense of enjoyment in things.”