Common Risk Genes for Major Depression: Why Have We Not Found Them Yet?

Common Risk Genes for Major Depression: Why Have We Not Found Them Yet?

Posted: November 10, 2014

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Among all the psychiatric disorders, major depressive disorder (MDD) affects the greatest number of people and is responsible for the greatest burden of disability. In 2012 the World Health Organization estimated that 350 million people worldwide suffer from depression, making it the number one cause of disability among illnesses of all kinds. Every person has an estimated 15 percent to 20 percent risk of becoming depressed at some point.

In view of MDD’s vast impact, it is reasonable to ask: why have researchers so far failed to identify common gene mutations that contribute to risk for MDD? This is precisely the question recently put to a group of leading authorities on psychiatric genetics by the editor of the journal Biological Psychiatry. The question is particularly poignant in view of the fact that important discoveries recently have been announced for hundreds of gene mutations that confer risk for both schizophrenia and bipolar disorder.

Seven experts responded to the question in a commentary appearing in the October 1st issue of the journal. Among them were Douglas F. Levinson, M.D., of Stanford University, and Patrick F. Sullivan, M.D., of the University of North Carolina and the Karolinska Institute, Sweden. Both are recipients of 2013 NARSAD Distinguished Investigator Grants; recently, Dr. Sullivan was honored as co-recipient of the Foundation’s 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research. He is founder and lead investigator of the Psychiatric Genomics Consortium, in which 300 scientists from 70 institutions in 19 countries are conducting mega-analyses involving 90,000 participants. Using these analyses, the researchers hope to learn more about the genetic risk for schizophrenia, depression, autism, bipolar disorder, and attention-deficit hyperactivity disorder.

In explaining why at least eight studies to date have failed to find common gene variants that rise to the level of what scientists consider “statistical significance” in MDD, Drs. Levinson, Sullivan, and colleagues expressed confidence that such variants are likely to be found in future studies.

They made clear that the type of gene variations they are discussing are common ones––single-DNA “letter” variations from the standard human reference genome that show up in at least five percent of the population. These so-called common “SNPs” (single-nucleotide polymorphisms) are not to be confused with rare variations of single “letters” and rare variations in both larger and smaller genome segments, such as those recently found in people diagnosed with autism spectrum disorder.

Common SNPs have been identified in both schizophrenia and bipolar disorder, the experts note, so why not in MDD? First, they explain, many more subjects are needed to reveal risk variants in MDD, a much more prevalent illness. The experts refer to an “inflection point” in the number of people studied, beyond which one can expect to find risk genes at a consistent rate. In other words, the more people studied, the more genes will be uncovered. This inflection point in schizophrenia is 13,000 to 18,000 study subjects. In studies larger than this, four new SNPs consistently are found per 1,000 new study participants.

In MDD, the inflection point appears to be about 75,000 to 100,000 study participants, the experts estimate, which explains why the largest studies to date have failed to uncover any significant risk variants: the first large Genome-Wide Association Study (GWAS) for common MDD variants included only 9,500 cases. However, sophisticated analysis reveals “there is a signal buried in the [mathematical] noise” in this and subsequent studies.

When will the signal emerge? Compared with GWAS studies of schizophrenia, MDD studies need to be three to five times larger. The populations of patients sampled (whose genomes are compared with those of healthy individuals) needs to be more rigorously limited to people who are likely to have the same kind of depression. The latter is vital because the power of massive GWAS studies evaporates if the people being compared have similar illnesses that have very different underlying genetic profiles. People with MDD might be grouped according to sex; whether or not they have recurrent depression; age at onset; symptom patterns; whether or not they were abused or under chronic stress early in life, for example.

“Half of the battle” in finding common gene variants for MDD “is knowing what needs to be done,” Drs. Levinson, Sullivan and colleagues wrote. “Now, we need to do it.”

Read an abstract of this research.