From The Quarterly, Summer 2015

Researchers have identified more than 100 genes whose activity differs significantly between people with major depressive disorder and people who have never experienced major depression. The differences, which could stem from inherited genetic factors or from environmental influences, help point scientists toward biological pathways likely to be involved in the disorder.

While there is good evidence that a person’s genetics influence his or her likelihood of developing major depression, scientists have only just begun to uncover specific genetic variations that may increase risk. In a new study, published May 26th in the journal Molecular Psychiatry, scientists led by Patrick F. Sullivan, M.D., at the University of North Carolina School of Medicine honed in on relevant genes by measuring and comparing gene activity in the cells of more than 1,800 individuals. To date, this is the largest analysis of gene expression in people with major depression.

Dr. Sullivan is a 2010 NARSAD Distinguished Investigator and was the 2014 Lieber Prizewinner for Outstanding Achievement in Schizophrenia Research. Dorret I. Boomsma, Ph.D., a 2011 NARSAD Distinguished Investigator at the VU University Amsterdam, also took part in the research. The team’s gene expression analysis is a complementary approach to genome-wide association studies (GWAS) being conducted by the Psychiatric Genomics Consortium that Dr. Sullivan co-leads. GWAS examine many common genetic variants in different people to find out whether any variant is linked with a trait. Dr. Sullivan has estimated that finding a genetic “signal” in a GWAS study of depression may require a sample size of 100,000 people, a goal that has not yet been reached.

Using blood samples collected as part of the Netherlands Study of Depression and Anxiety, Dr. Sullivan and his colleagues measured gene expression in the cells of 882 people with depression, 635 people who were not experiencing major depression at the time of the study but had in the past, as well as a control group of 331 people who reported no current or past depression.

They found 119 genes whose activity differed between the control group and people with current depression. Many of these, they found, were genes that affect immune function. This was consistent with other lines of research that have suggested a link between the immune system and mood disorders.

Changes seen in current depression patients were small but statistically significant. In contrast, gene expression patterns in people who been depressed in the past were not significantly different from— people in the study who never had depression.

Two years after their initial analysis, Dr. Sullivan and colleagues collected additional data from a subset of the people in their study. This enabled them to compare gene activity between those who had recovered from their depression and those whose depression had continued. Of the 119 depression- associated genes they had already identified, they found 19 genes whose activity also correlated with changes in depression—in these 19 genes, expression was more likely to have returned to normal among those who had recovered from their depression.