Major Depression Linked to Genetic Changes

Pauline Anderson

May 01, 2015

Major depression has been linked to changes in DNA, a finding that seems to boost the biological model of depression.

Research conducted by investigators at Oxford University in the United Kingdom suggests that individuals with depression have more mitochondrial DNA (mtDNA) and shorter telomerase DNA than their nondepressed counterparts and that depression precedes these molecular changes.

Mitochondria are the major energy source for most cells, and telomere is the sequence that caps the ends of chromosomes.

"One of the tantalizing implications of this study is that we might have a biomarker, something we can now send off as a test," co–senior author Jonathan Flint, MD, professor of neuroscience, told Medscape Medical News.

As a psychiatrist, this biological marker "might help me with my diagnosis, prognosis, and treatment" of patients with depression, said Dr Flint. "We don't know this; it's just a hypothesis at the moment, but it's an interesting lead that we can follow up."

The study was published online April 23 in Current Biology.

Chance Finding

Researchers used saliva samples from 11,670 Chinese women in the CONVERGE (China, Oxford and VCU Experimental REsearch on Genetic Epidemiology) study. Approximately 50% of the cohort had severe depression; the other half were depression free.

The study included only women because the causes of depression in men may differ from that in women, and the researchers wanted as homogeneous a sample as possible, said Dr Flint.

Dr Jonathan Flint

From these samples, researchers carried out whole-genome DNA sequencing, which allowed them to "look at bits of the genome that people up to now haven't looked at."

One of these bits was mitochondria, which "are like the battery of each cell," said Dr Flint. "They have their own little genome."

While searching for genes that increase depression risk, researchers discovered "by chance" that individuals with depression had significant molecular signatures compared with individuals who do not have depression.

For example, major depression (MD) was associated with shorter mean telomere length (odds ratio [OR] for the contribution of normalized measure of mean telomere to the risk for MD, 0.85; 95% confidence interval [CI], 0.81 - 0.89; P = 2.84 x 10-14).

There was also a highly significant association between MD and mtDNA (OR for the contribution of normalized amount of mtDNA to the risk for MD, 1.33; 95% CI, 1.29 - 1.37).

Stress-Driven Changes

The authors note that there was a negative correlation between mtDNA and telomerase DNA.

"If you get more mtDNA, you tend to have less telomerase," said Dr Flint. "But it's not clear whether the telomerase gets smaller as the amount of mtDNA increases, or whether it's the other way around. Or it might be a common factor affecting both."

Researchers replicated the association between MD and increased amounts of mtDNA in a European case control study of 216 individuals, which included both men and women, in which the DNA was extracted from blood instead of saliva.

In this analysis, the OR for the normalized measures of mtDNA's contribution to the risk for MD was 1.35 (95% CI, 1.11 - 2.10; P = 8.3 x 10-5).

From the CONVERGE data, the amount of mtDNA was significantly correlated with both the total number of stressful life events and childhood sexual abuse. The association of both molecular markers (mtDNA and telomerase DNA) with childhood sexual abuse was stronger with increasingly severe abuse.

The researchers eliminated possible contributing factors.

"We wondered whether this was because of the antidepressant drugs subjects had taken, some artifact in the way we selected the people, or some problem with the way we had done the analysis," said Dr Flint. "We couldn't explain it in any of those ways."

Researchers thought that differences in saliva might explain the change in mtDNA. But although there were some differences between the saliva of those with and those without depression, this did not explain most of the increases in mtDNA.

"Only about 5% of the difference in mtDNA content could be attributed to differences in cellular composition of saliva," said Dr Flint.

The only factor that was related to mtDNA was the amount of stress patients had endured, he added.

Current Depression

In the original study, researchers did not determine whether the patients were depressed when they were interviewed. Some might have been well at the time but had suffered horrible life experiences and multiple episodes of depression in the past.

"We can't, unfortunately, distinguish those people from others who also had multiple episodes of depression, had horrible life experiences and happened to be very depressed when we saw them."

But in a subgroup of patients in whom there was such information about the presence of depression, researchers also found increased amounts of mtDNA. "So it does seem to be something that is related to being currently depressed," said Dr Flint.

He noted that there appeared to be more mtDNA among those with depression who also had stressful life experiences.

"If a bad thing happens to you, it makes these molecular changes, but you won't necessarily see them unless you are also depressed," he said.

In other words, "the predictive power of stress on amount of mtDNA and telomere length is mediated through a history of MD."

The evidence suggests that depression increases the amount of mtDNA rather than the other way around, added Dr Flint.

To shed more light on the contribution of stress to molecular changes, researchers carried out experiments in mice. They exposed 16 animals to chronic stress during a 4-week period. From blood and saliva samples, they observed the same increases in mtDNA and the same decreases in telomerase length that they had observed in human patients.

They then returned the animals to their cages. After 4 weeks, the amount of mtDNA had returned to normal. This indicated that the effect was reversible.

When researchers injected small quantities of the stress hormone corticosterone into the mice, this, again, resulted in an increase in mtDNA and a decrease in telomerase length. This finding may support involvement of the hypothalamic pituitary adrenal (HPA) axis.

Ancient Response

Dr Flint believes that the DNA changes uncovered by the study are probably linked to an alteration in metabolism. The changes may be related to "a very ancient response to stress," he added.

For our ancestors, "getting their hands on food" was a major cause of stress, and they needed to stay awake to "not miss an opportunity to get the next meal" should it come by, he said.

"It may be that part of what we see in depression is a mechanism to cope with that particular form of stress."

He noted that a "classic feature" of depression that psychiatrists typically ask patients about is a change in appetite, as well as sleep problems.

It is not clear wheether there is a cutoff point for the amount of mtDNA that might signal depression. That is a question researchers will now try to answer, said Dr Flint.

The authors concluded that there are two trajectories, one leading from adversity to molecular changes, possibly through activation of the HPA axis, and another leading to illness.

Although adversity may itself affect both the amount of mtDNA and the mean telomere length, the extent and persistence of these molecular changes depend on one's susceptibility to MD, either from genetic or additional environmental predisposing factors, the authors note.

Fruitful Leads

Commenting on the research for Medscape Medical News, Turhan Canli, PhD, associate professor of psychology and radiology, Stony Brook University, New York, and director of the Social, Cognitive, and Affective Neuroscience Center, the involvement of an environmental factor fits with his hypothesis that a pathogen might be involved in depression.

Dr Turhan Canli

"I don't see anything here that would contradict my theory," he said.

Dr Canli believes that exposure to a pathogen such as a virus or bacteria may be a plausible explanation for depression in a subset of patients, for example, those in whom changes in brain structure or function can be identified, or those who develop depression suddenly, seemingly without a psychological explanation.

Also commenting on the research for Medscape Medical News, Ronald Pies, MD, professor of psychiatry, SUNY Upstate Medical University, in Syracuse, New York, said that although it is "interesting and potentially important, it tells us little about the causes of major depression."

He noted that the findings point to a sort of molecular "fingerprint" of major depression ― but not to a causal mechanism.

The suggestion that molecular changes are specific to persons who had been depressed and not merely exposed to stress or trauma "might prove to be a clue to the pathophysiology of some types of clinical depression," said Dr Pies.

He added that because mitochondria are the "powerhouses" of cells, the link between MD and cell energetics "is intriguing" and might be related to the common complaint of "low energy" by patients with major depression. However, he said, much more research is needed to confirm such a hypothesis.

Dr Pies stressed that MD is "a very elastic and eclectic term," probably representing many etiologies. Genetic, psychological, social, and environmental factors probably influence susceptibility to developing MD, in addition to vulnerability to stress-related disorders, he said.

"We still have much to learn regarding individual resiliency in the face of stress and trauma and the relative contributions of biological, psychological, and environmental factors in major depression. The present study does not inform us on these matters, but it does offer some potentially fruitful leads."

Dr Flint is head of the Psychiatric Genetics Group at the Wellcome Trust Centre for Human Genetics, which funded the study. Dr Canli and Dr Pies report no relevant financial relationships.

Curr Biol. Published online April 23, 2015. Full text

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