After completing an enormous study, scientists have dismissed claims that single gene variants, or even a small group of them, can dictate susceptibility to depression. Instead, they suggest that any genetic risk for depression likely arises from very large numbers of variants, each contributing a small effect.

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A group of scientists has debunked the ‘candidate gene hypotheses’ for depression.

Researchers at the University of Colorado Boulder (CU Boulder) reviewed hundreds of investigations that, over the last 25 years, had singled out “candidate genes” for depression. They found that 18 such genes had featured at least 10 times in previous studies.

Then, using data from hundreds of thousands of people, they showed that the influence the 18 candidate genes had on depression was no stronger than that of genes they could pick out at random.

In an American Journal of Psychiatry paper, the team concludes that early theories about “depression candidate genes” are wrong and that studies identifying them have likely done no more than produce “false positives.”

The findings dispel the notion that people will soon be able to take a test that identifies a few genes for depression, and then it is just a matter of drug developers producing new medications that target them.

“This study,” says first study author Richard Border, who is a researcher and graduate student in CU Boulder’s Institute for Behavioral Genetics, “confirms that efforts to find a single gene or handful of genes which determine depression are doomed to fail.”

Scientists working in the field of genetics rejected “candidate-gene hypotheses” years ago, adds senior study author Matthew C. Keller Ph.D., who is an associate professor of psychology and neuroscience at the university.

Meanwhile, others in fields including psychology, he adds, have continued to pursue the idea of “depression genes” and seemed to find evidence to support it.

For example, one of the 18 “historic candidate depression genes” is SLC6A4, which codes for a protein that has to do with transport and recycling of serotonin in the brain.

About 20 years ago, researchers had suggested that having a particular, shorter variant of SLC6A4 could put people at greater risk for depression, especially if they had experienced trauma during childhood.

Dr. Keller explains that the evidence linking candidate genes to depression often came from studies in which the sample sizes were too small. He likens it to the Hans Christian Andersen story of the “emperor’s new clothes.”

“There’s just nothing there,” he adds, “I hope this is the final nail in the coffin for those kind[s] of studies.”

Feeling sad, lonely, or down is part of everyday life, particularly during times of high stress or loss. Depression, however, is a psychiatric illness in which these symptoms, and others, are severe and persistent.

Depression has many forms and, while each has its own pattern of symptoms, there are also some similarities.

Major depression is the most common type of depression. The symptoms can be so severe that it stops people being able to work, study, and interact socially.

In the United States, depression is the main cause of disability in those aged 15–44 years. In 2016, around 16.1 million adults in the U.S. had had at least one episode of major depression in the previous 12 months.

Dr. Keller and his team analyzed “data from large population-based and case-control samples” that ranged from no less than 60,000 to in excess of 400,000 individuals and totaled more than 620,000. The data came from sources such as 23andMe, UK Biobank, and the Psychiatric Genomics Consortium.

The researchers looked for links between any of the 18 depression candidate genes and depression and also with depression in combination with environmental factors, such as “sexual or physical abuse during childhood, socioeconomic adversity.”

However, they write that “no clear evidence was found for any candidate gene,” neither with depression or with depression associated with environmental factors.”

“The study results,” conclude the authors, “do not support previous depression candidate gene findings, in which large genetic effects are frequently reported in samples orders of magnitude smaller than those examined here.”

Dr. Keller and his team emphasize that they are not suggesting that researchers should stop looking for links between genes and depression.

What they are saying is that the relationship between genes and depression is not as straightforward as many earlier studies may have claimed.

Research on the risks of diseases such as Alzheimer’s and cancer can reveal strong links with individual gene variants, and tests for those are medically useful for screening and choosing treatment options.

However, it is more likely that predictions of genetic risk for depression will involve “polygenetic scores” that take into account the effect of very large numbers of genes.

We are not saying that depression is not heritable at all. It is. What we are saying is that depression is influenced by many, many variants, and individually each of those has a minuscule effect.”

Matthew C. Keller Ph.D.