This is post 5 in my ongoing, now-approaching-behemoth-size series of posts on depression. I’ve got other posts available on the etiology of depression, the current pharmacotherapies, studying depression in the lab, and the serotonin theory of depression, which of course you can read and refer to if you’re curious.
This post will be on what we currently know about the genetics of depression, the latest candidate genes, and what it means when scientists talk about genetic vulnerabilities and predisposition for disorders such as depression and bipolar disorder.
First of all, depression is not entirely genetic. Neither is it entirely the result of your personal experiences. But depression IS influenced by your genetics. We know that about 10% of the general population will suffer from what is known as unipolar major depressive disorder in their lifetime. But how much does this have to do with life experiences, and how much of it is due to genetic factors?
Most of the information in this post comes via various articles and reviews by the Levinson lab at Stanford, which is one of the big centers for the study of the genetics of depression. That said, I may not interpret all of his findings correctly, and of course I would welcome any additional information.
When scientists want to look at the potential heritability of something (the relative contribution of your genetics to the final result of traits that you display), they like to do twin studies. (I have read a LOT on twin studies, and I am starting to believe that, if you an identical twin, you will probably have been in at least one twin study. Most likely a lot more. If you are an identical twin raised apart from your twin, medical eyes have apparently been on you from day 1.) In the case of depression, it appears that the heritability of depression is around 50%. This means that, if you are an identical twin (sharing 100% of your DNA) with depression, there is a 75% chance that your twin will have it too. If you are a fraternal twin with depression (fraternal twins share only 50% of their DNA, the same as any brother or sister set), your twin only has a 20% likelihood of suffering from depression. Finally, if you are an identical twin raised APART from your twin, and you have depression, there is a 67% likelihood that your twin will have it, too. All these results factored together, with the addition of various other studies of families with depression, results in a roughly 50% heritability for depression from genetics alone.
BUT, that doesn’t mean you are going to be depressed, even if your identical twin is depressed. A 50% heritability is not 100% of the expression of depression. There are many environmental factors out there which can influence whether or not you exhibit depression, the most important of which, so far, appears to be stress. You might have a genetic predisposition to depression, but if you live a life relatively free from stress at critical periods (such as childhood and early adulthood), you may still be just fine. And you can still suffer from clinical depression without any genetic predisposition at all, as a result of things like severe life stress or other environmental factors. It’s all a mixture of nature and nurture.
Certain personality traits (resulting from a combination of genetics and environment) are also predictors for depression. The strongest personality trait predictive for depression is neuroticism. I’m sure that many people have heard the word “neurotic” before, but most people have only the vaguest idea of what it means. High neuroticism is a personality trait chacterized by dysphoria, anxiety, tension, and emotional reactivity. This basically boils down to a tendency to experience a negative emotional state.
Neuroticism is highly correlated with a tendency toward depression, and is also correlated with a poor response to environmental stress. A poor response to environmental stress is, of course, correlated with depression. Neuroticism is also correlated with other disorders suchs as generalized anxiety disorder, and possibly also to other problems like panic disorder and social phobia. So many of the studies that look at genetic correlates for depression or anxiety disorder will ALSO look at ratings of neuroticism.
So what genes, coding for which proteins, have been implicated?
The Serotonin Transporter
So far, the serotonin transporter is the big one. The serotonin transporter (otherwise known as the SERT) is a molecule that sits in the presynaptic membrane of serotonin synapses, taking up and recycling excess serotonin to be used again once it has been release.
(for more on the serotonin system, check out the serotonin system post)
We know that there are two functional polymorphisms of the SERT. A functional polymorphism is a slight change in the DNA coding for your protein which will alter the way that protein is expressed or how functional it is. In this case, the two available for SERT are the long and short alleles which are actually on the promotor region for the SERT gene. It has been found that the short version of the allele will lead to less expression of the serotonin transporter in the brain. So you have fewer serotonin transporters. Not only that, those you do have are less functional. This means that you might actually have MORE serotonin build up in your synapses, which sounds more than a bit odd, because that’s what serotonin targeted antidepressant therapies are supposed to do.
To try to explain this without getting TOO crazy, we think right now that people with the short SERT expression allele end up with chronically decreased serotonin signaling. Higher levels of serotonin in the synapse (due to decrease SERT function and presence) actually will signal BACK onto the serotonin neuron that released the serotonin, causing decreases in signaling. So people with the short version of the SERT expression allele may have less serotonin signaling overall. It is also thought that in those people with the short SERT expression allele, the effects of serotonin targeted antidepressants function mostly through their longer term actions on serotonin receptor levels, specifically the 5-HT1A receptor.
The 5-HT2A receptor
The 5-HT2A receptor is one of the many serotonin receptors present in the central nervous system. Stimulation of it can increase the downstream activity of a given neuron, though of course what that results in in terms of a total brain effect depends on what type of neuron it is and where it is located within the brain. There are not a lot of studies out there about the effects of 5-HT2A receptors, but it is thought right now that various functional polymorphisms may explain differences in the way people respond to antidepressants.
Tyrosine hydroxylase is one of the main enzymes required for the synthesis of the neurotransmitters dopamine (for more on dopamine, check out my dopamine post!) It is thought that certain polymorphisms in this enzyme making it more or less functional and drastically alter the amount of dopamine you have in your system. Changes in dopamine levels are known to affect mood states, and low levels of dopamine in particular may be associated with anhedonia, an inability to feel pleasure and one of the hallmarks of depression.
Tryptophan Hydroxylase is similar to tyrosine hydroxylase, only it is the rate-limiting step in the production of serotonin, rather than dopamine. As you can probably tell from the many links you will find out there on serotonin and depression, there is a hypothesis that low function of tryptophan hydroxylase, resulting in low levels of serotonin, may be a cause.
This enzyme, which everyone calls COMT because it’s way too hard to say otherwise, is found in the synapses between neurons, as well as within neurons themselves. It’s extremely important in terminating dopamine signaling between neurons. When dopamine is released into the synapse, some of it is taken up by the dopamine transporter to be used again. The rest is broken down, either by monoamine oxidase (both A and B types will break down dopamine), or by COMT.
So it is possible that alternate polymorphisms of the COMT gene, which could increase expression or function of COMT, could lead to increased breakdown of dopamine, decreasing dopamine. Alternatively, decreased COMT activity could caused increased dopamine in the synapse, which could feed back onto pre-synaptics neurons and decrease dopamine signalling. Both of these scenarios could result in lower levels of dopamine, possibly increasing things like feelings of anhedonia or changing reactions to external stimuli.
Brain-derived neurotrophic factor
At some point, I really need to do a post on the brain-derived neurotrophic factor (BDNF) theory of depression. BDNF is one of the factors in your brain which helps to control the brain’s response to stress, in particular whether neurons die in response to environmental factors. Recently, it’s been found that the death of hippocampal cells can increase symptoms of depression in animal models, and that these effects can be protected against with BDNF. There are also some reports in the literature that people with severe clinical depression have reduced levels of BDNF. Unfortunately more work still needs to be done, and other results have been mixed. But it’s possible that polymorphisms in the expression of BDNF could result in reduced expression, making your neurons more sensitive to stress.
These are the main proteins so far where polymorphisms have been related to depression. But it’s certainly not all of them. Mostly likely there is not going to be one genetic answer, and there may be many different combinations of genetic factors, all of which could predispose a person more or less to developing depressive symptoms under the right circumstances. But there are a lot of studies ongoing and planned, to try and pinpoint which genes are the most associated with the development of depression. This can not only help us determine who is at risk, but allow us to find new avenues of drug research to help with the symptoms.
Filed under: Neuroscience |