It has long been known that depressive illnesses can run in families, but until fairly recently it was not fully known whether people inherited a susceptibility to these illnesses or if something else such as the environment was the true culprit. Those who research depression have been able to determine that to some extent depressive illnesses can be inherited. What appears to be inherited is a vulnerability to depression. This means that if we have close relatives who have clinical depression, we may inherit a tendency to develop the illness. It does not mean that we are destined to become depressed.
Genes that we inherit from our parents determine many things about us such as our gender and the color of our eyes and hair. Our genes also determine which illnesses we may be vulnerable to at some point in our lives. Every cell in the human body contains somewhere between 50,000 and 100,000 genes. They are all made up of something called deoxyribonucleic acid, or DNA. Genes are located on chromosomes within the nucleus of each cell. All of the cells in the body, except sex cells, contain 46 chromosomes, and genes are typically located in a specific place on a particular chromosome. Except for identical twins, no two people in the world have the exact same genetic makeup.
Research on the heredity of depression within families shows that some individuals are more likely to develop the illness than others. If you have a parent or sibling that has had major depression, you may be 1.5 to 3 times more likely to develop the condition than those who do not have a close relative with the condition. You would also have a higher chance of developing bipolar disorder. Because close relatives of those with clinical depression have such a vulnerability to developing the condition themselves strongly suggests that it can be an inherited illness.
Bipolar disorder has a strong genetic influence. Of those with bipolar disorder, approximately 50% of them have a parent with a history of clinical depression. When a mother or father has bipolar disorder, their child will have a 25% chance of developing some type of clinical depression. If both parents have bipolar disorder, the chance of their child also developing bipolar disorder is between 50% and 75%. Brothers and sisters of those with bipolar disorder may be 8 to 18 times more likely to develop bipolar disorder, and 2 to 10 times more likely to develop major depressive disorder than others with no such siblings.
Twin Studies
Much of what we know about the genetic influence of clinical depression is based upon research that has been done with identical twins. Identical twins are very helpful to researchers since they both have the exact same genetic code. It has been found that when one identical twin becomes depressed the other will also develop clinical depression approximately 76% of the time. When identical twins are raised apart from each other, they will both become depressed about 67% of the time. Because both twins become depressed at such a high rate, the implication is that there is a strong genetic influence. If it happened that when one twin becomes clinically depressed the other always develops depression, then clinical depression would likely be entirely genetic.
However because the rate of both identical twins developing depression is not closer to 100% this tells us that there are other things that influence a person's vulnerability to depression. These may include environmental factors such as childhood experiences, current stressors, traumatic events, exposure to substances, medical illnesses, etc.
However because the rate of both identical twins developing depression is not closer to 100% this tells us that there are other things that influence a person's vulnerability to depression. These may include environmental factors such as childhood experiences, current stressors, traumatic events, exposure to substances, medical illnesses, etc.
Research has also been done with fraternal twins. Unlike identical twins who have the same genetic code, these siblings share only about 50% of their genetic makeup and do not necessarily look alike. Studies have shown that when one fraternal twin becomes depressed, the other also develops depression about 19% of the time. This is still a higher rate of depression when compared to overall rates for the general public, again pointing towards a genetic influence in the development of clinical depression.
A Gene for Depression?
Research on the genetic causes of clinical depression has attempted to identify one or more specific genes that may lead to the development of a depressive illness. Although there have been a number of studies that appear to name a particular gene as the culprit there has been little consistency among their results. However, the outcome of some research has suggested that there may be specific genes that cause clinical depression to develop within certain families and not in others.
At this time there is much that we do not know about how genes may predispose a person to a depressive illness. Research has yet to identify a clear link between a specific gene and a vulnerability to depression in everyone. Rather than the possibility of only a single gene being responsible for the development of clinical depression, it appears to be more likely that a number of genes acting together may cause a person to become vulnerable to depression.
Just because a person inherits a gene that predisposes him or her to a depressive illness, it does not mean that he or she is destined to develop major depression or bipolar disorder. It is believed that a genetic influence is only partially responsible for causing depression. Other factors may also play a role.
Testing for Genetic Disposition to Depression
The team, based at the Neuroscience and Psychiatry Unit (NPU), in the Faculty of Medical and Human Sciences, has set up a website where would-be volunteers can see how prone they may be to depression by identifying the emotions on people's faces and taking a gambling test.
The team aims to recruit more than 1000 UK
Professor Bill Deakin explains: "Anxiety is a contagious emotion. When you see other people who are anxious, as a primate you feel anxious as well. Our brains are wired to see anxiety - it makes sure we are safe. This is a fascinating test and, during further testing, we will be able to see which parts of the brain light up, or work harder, when you see a fearful face. Depressed people are more likely to see sadness or fear in a neutral face.
"The gambling test, where volunteers choose from pairs of spinners to 'win' money, will show us which parts of the brain light up when you are working for a reward. Depressed people are less affected by reward and more likely to give up easily as the test goes on."
Volunteers for this research study will be asked to fill in a confidential questionnaire and provide a mouth swab for genetic analysis. The team will then compare the DNA with the questionnaire group data.
In the other EU NewMood centres, rats and mice are also being tested for their predisposition to depression using similar reward and anxiety measures. When offered sweet-tasting drinks, depressed animals show no preference, much as humans lose pleasure in eating and often lose weight when they are depressed. And when given the opportunity to explore a new location depressed animals are more wary and take longer to emerge from dark corners, much as depressed humans avoid social situations.
"All humans have the same genes and they are very similar to those in all mammals - we turn out differently from each other because we inherit different versions of the same genes which can vary in their activity" Professor Deakin says. "We can see what genetic traits towards depression these animals have, then compare them with the same genes in the human DNA.
"Depression is a common trait like height or body build and, just like those, we suspect there are lots of genes involved. By measuring the important possible factors that can lead to a tendency to depression across a large number of individual people, we hope to find which ones act together to cause depression. Ultimately, this will help us to develop new ways of preventing and treating this illness."
Recent Studies – Genetic Link Discovery (Chromosome 15)
Researchers announce progress has been made on discovering why some people appear to be genetically predisposed to developing severe depression. A region on one chromosome appears to offer significant promise.
The research is lead by Douglas Levinson, MD, professor of psychiatry and behavioral sciences at the Stanford University School of Medicine.
“This finding has a very good chance of leading to a discovery of a gene that could yield important information about why some people develop depression,” said Levinson.
If problematic genetic variations could be identified, it would open the door to a whole new world of investigation, and eventually, treatment possibilities.
The team’s results are reported in two papers that will be published in the February issue of the American Journal of Psychiatry.
Levinson’s group, comprising researchers from six universities, achieved this breakthrough by studying 650 families in which at least two members suffered from repeated bouts of severe depression that began in childhood or early adult life.
The first of the studies was a genome-wide scan that looked for evidence of genetic “linkage” within families between depression and DNA markers on the various chromosomes. The linkage study identified regions worthy of more intensive examination.
The second study was a more detailed look at the most suspicious of these regions, located on chromosome 15. Levinson said the team studied six DNA markers in this region in the first study, and an additional 88 in the second.
“We found highly significant evidence for linkage to depression in this particular part of chromosome 15,” he said. “This is one of the strongest genetic linkage findings for depression so far.”
“It’s an important paper,” said Peter McGuffin, MD, dean of the Institute of Psychiatry at King’s College in London
Researchers learned that depression is influenced by genetics by studying patterns of depression in twins and families. No single gene is thought responsible for determining the risk for developing depression.
Instead, multiple genes are probably interacting to create what amounts to a genetic baseline level of risk. On top of that baseline, environmental factors are likely mixed in as well, things such as non-genetic physiological problems or psychological traumas.
Some 10 to 15 percent of people suffer from severe depression at some point in their lives, and 3 to 5 percent have it more than once. Women are twice as likely to develop depression as men, although the reason is not yet known.
“We don’t think depression is entirely genetic, by any means, but there are important genetic factors,” said Levinson.
“If we can succeed in finding one or more genes in which there are specific DNA sequence variations that affect one’s risk of depression, then we would be able to understand what type of gene is it, what it does in the brain and by what mechanism it could make one more or less predisposed to depression.”
Knowing more about which genes are the major factors causing a predisposition for depression would also help researchers sort out the environmental factors that contribute to depression, Levinson said.
And knowing more about either genetic or environmental factors could help in developing more effective therapies to treat depression. “The treatments we have now are lifesavers for some people, but there are others who have only a partial response or no response at all,” he said.
“Understanding the biology would help the search for better treatments.”
Recent Studies – Genetic Link Discovery (Chromosome 12)
The mutant gene codes for the brain enzyme, tryptophan hydroxylase-2, that makes serotonin, and results in 80 percent less of the neurotransmitter. It was carried by nine of 87 depressed patients, three of 219 healthy controls and none of 60 bipolar disorder patients. Drs. Marc Caron, Xiaodong Zhang and colleagues at Duke Unversity announced their findings in the January 2005 Neuron, published online in mid-December.
“If confirmed, this discovery could lead to a genetic test for vulnerability to depression and a way to predict which patients might respond best to serotonin-selective antidepressants,” noted NIMH Director Thomas Insel, M.D.
The Duke researchers had previously reported in the July 9, 2004 Science that some mice have a tiny, one-letter variation in the sequence of their tryptophan hydroxylase gene (Tph2) that results in 50-70 percent less serotonin. This suggested that such a variant gene might also exist in humans and might be involved in mood and anxiety disorders, which often respond to serotonin selective reuptake inhibitors (SSRIs) — antidepressants that block the re-absorption of serotonin, enhancing its availability to neurons.
In the current study, a similar variant culled from human subjects produced 80 percent less serotonin in cell cultures than the common version of the enzyme. More than 10 percent of the 87 patients with unipolar major depression carried the mutation, compared to only one percent of the 219 controls. Among the nine SSRI-resistant patient carriers, seven had a family history of mental illness or substance abuse, six had been suicidal and four had generalized anxiety.
Although they fell short of meeting criteria for major depression, the three control group carriers also had family histories of psychiatric problems and experienced mild depression and anxiety symptoms. This points up the complexity of these disorders, say the researchers. For example, major depression is thought to be 40-70 percent heritable, but likely involves an interaction of several genes with environmental events. Previous studies have linked depression with the same region of chromosome 12 where the tryptophan hydroxylase-2 gene is located. Whether the absence of the mutation among 60 patients with bipolar disorder proves to be evidence of a different underlying biology remains to be investigated in future studies.
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