Depression Post 5: The Genetics of Depression

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.
depression cartoon.jpg


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.

Heritability

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.
Neuroticism
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.
reuptake2.gif
(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
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
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.
Cetechol-o-methyltransferase
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.
comt.gif
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.

15 Responses

  1. s/BNDF/BDNF/g
    s/may a cause/may be a cause/

  2. Have people been doing these studies mice-to-humans, or in humans-to-mice? That is, have we identified biochemical pathways, and are now looking to see if there are SNPs or alleles in genes known to be involved with serotonin and dopamine signaling… or did we model depression in mice, screen a whole slew of different strains of mice, and backcross to find the gene most responsible?

  3. Peter: what?
    becca: Almost all the studies on genetic correlates have been done in humans, but there are also studies that are being done on the SERT long/short in monkeys, which have the same variants. It’s much harder to do these genetic studies in mice, because there are so many factors that may not translate, and because rodent tests for depression are so rough, they are more predictive of whether a drug will work than whether an animal is depressed.

  4. Peter posted some regex. The first says do a global replace of BNDF with BDNF, the second says to replace a single instance of “may a cause” with “may be a cause”
    Thanks for all these posts on depression. It has been very illuminating when dealing with my own depression.

  5. Ah! Thanks Peter and CyberLizard. They should be corrected. I was a bit tired by the time I got to that part. Makes the typing fingers all woozy.

  6. Another fantastic post!! You are one lean, mean, ‘splainin’ machine!

    This enzyme, which everyone calls COMT because it’s way too hard to say otherwise,…

    LOLOLOL!!

  7. I feel compelled to add this for your consideration but first I must admit to only understanding the general sense of your article. While I have no background in science I have far too much first-hand knowledge of depression.
    I am one of seven sibs and each one has suffered from depression (and, I believe it is fair to say, continues to.) My three brothers are recovering alcoholics. The disease has also found its way down to the next generation, in one case quite severely.
    This would seem to argue strongly for a genetic predisposition. However, the missing piece here is the nurture part which, in my case, *strongly* reinforces the genetics. It is believed that my mother blessed everyone with the problem; so don’t you have to also assess the fact that she provided the perfect environment for realizing this propensity towards depression in each of her children? In other words, if you took those same seven children and raised them in an environment with cheerful, optimistic parent, who were adept problem solvers, don’t you have to account for that as part of evaluating the children? Or, can you draw *any* conclusion *independent* of the environmental factors?
    I hope that observation makes sense so that you can comment (or anyone else for that matter.)
    Many thanks.

  8. Once More, with Feeling …
    s/Cetechol-o-methyltransferase/Catechol-O-methyl transferase/

  9. BTW, VERY GOOD JOB, despite woozy fingers!

  10. I can tell I’m learning something here, because every time I think “I’ve got it!” you write more and I realize “um… no I don’t.” That’s a compliment, btw. As soon as I think I’ve got a slight grip on all the stuff I had to go look up, I’ll come back and read this one (the entire series, in fact) again and again.

  11. macmarine: thanks.🙂 I find COMT particularly hard to spell correctly, actually, and of course spellchecker is NO good for that stuff.
    Donna: No no!!! I am upset that you should have to look up stuff! This means I haven’t explained it well…:( What parts confused you? Sci is glad to explain.

  12. Very nice article.
    One thing that I would be interested in seeing within your excellent series of articles on depression is an in-depth analysis of persistent viruses and other pathogens in the etiology of depression. This would nicely complement this present article on genetic susceptibilities to depression.
    Borna virus one example, but there are many other more common persistent viruses that can cause depression, such as Epstein-Barr virus, coxsackie B virus, human herpes 6 virus, cytomegalovirus, influenza A, West Nile virus, as well as other pathogens. Some like Epstein-Barr and herpes 6 are found in around 90% of the adult population.
    One mechanism that explains how such viruses cause depression is through the effects interferon-alpha: Chronic infection with any of these viruses can lead to raised interferon-alpha levels (interferon-alpha is secreted by cells of the the immune system as it tries to control the virus), and it is now known that interferon-alpha can significantly affect the serotonin system.
    See here for info on interferon-alpha and depression:-
    http://www.ei-resource.org/news/mental-&-emotional-problem-news/important-immune-chemical-associated-with-serotonin-deficiency-and-depression/
    However, this is not the only way that a persistent viral infection can cause depression. Certain types of depression originate in the hypothalamus, which can be dysdregualted by viruses such as coxsackievirus B, which have a particular affinity for, and disruptive action on, the hypothalamus. Thus viruses can damage the brain directly.
    And another very powerful (but indirect) mechanism through which persistent viruses can cause depression is by raising glutamate levels in the brain (high glutamate levels are linked to depression). The excess glutamate in this case comes from the activated microglia cells (microglia are specialized macrophages permanently resident in the brain). When the microglia are activated in response to a persistent infection in the brain, these microglia produce lots of glutamate, which can then lead to both depression and anxiety disorders as a result of this neurochemical imbalance.
    IN SUMMARY: It is quite possible that many cases of depression are ultimately viral in origin, through one or more of these mechanisms. We are just beginning to uncover the complex biochemistry behind the way pathogenic infections cause diseases such as depression.
    In my own case, powerful depression and anhedonia states were kicked of by a chronic viral infection, that also caused many other mental and physical symptoms.
    My own story can be found here:
    http://chronicsorethroat.wordpress.com/
    Best wishes

  13. Very nice article.
    One thing that I would be interested in seeing within your excellent series of articles on depression is an in-depth analysis of persistent viruses and other pathogens in the etiology of depression. This would nicely complement this present article on genetic susceptibilities to depression.
    Borna virus one example, but there are many other more common persistent viruses that can cause depression, such as Epstein-Barr virus, coxsackie B virus, human herpes 6 virus, cytomegalovirus, influenza A, West Nile virus, as well as other pathogens. Some like Epstein-Barr and herpes 6 are found in around 90% of the adult population.
    One mechanism that explains how such viruses cause depression is through the effects interferon-alpha: Chronic infection with any of these viruses can lead to raised interferon-alpha levels (interferon-alpha is secreted by cells of the the immune system as it tries to control the virus), and it is now known that interferon-alpha can significantly affect the serotonin system.
    However, this is not the only way that a persistent viral infection can cause depression. Certain types of depression originate in the hypothalamus, which can be dysdregualted by viruses such as coxsackievirus B, which have a particular affinity for, and disruptive action on, the hypothalamus. Thus viruses can damage the brain directly.
    And another very powerful (but indirect) mechanism through which persistent viruses can cause depression is by raising glutamate levels in the brain (high glutamate levels are linked to depression). The excess glutamate in this case comes from the activated microglia cells (microglia are specialized macrophages permanently resident in the brain). When the microglia are activated in response to a persistent infection in the brain, these microglia produce lots of glutamate, which can then lead to both depression and anxiety disorders as a result of this neurochemical imbalance.
    IN SUMMARY: It is quite possible that many cases of depression are ultimately viral in origin, through one or more of these mechanisms. We are just beginning to uncover the complex biochemistry behind the way pathogenic infections cause diseases such as depression.
    In my own case, powerful depression and anhedonia states were kicked of by a chronic viral infection, that also caused many other mental and physical symptoms.
    My own story can be found on my blog: “Chronic Sore Throat / Mood Virus”

  14. Thanks for these articles SciCurious. As a neuropsychologist in training as well as being someone who suffers from depression myself, I found them very interesting.
    I think I knew most of the information, although the history of the MAO/5HT hypothesis of depression was new to me and very interesting to read. Also, I’d always assumed the theory came from mechanisms of drugs that are 5HT2a agonists (known for producing happiness and giggles).
    Its good to read all the depression genetics stuff in one article. Up until now I’ve read this kind of info all over the place, so its really good to read a summary where the points are considered together.
    At the moment I’m suffering from a depression, although I’m starting to feel that I’m coming out of it. I’m self medicating with 5HT and DA precursors 5-HydroxyTryptophan and L-Tyrosine. Also, I’m supposed to be exercising, so will get running and back to my Kung Fu class very soon.
    Of course, as a psychologist I know a lot about the psychology of depression, which is ironic considering I often fail to consider this or put this knowledge in to practice. I’m actually thinking of using this weekend to write up a summary of what I know about the psychology of depression, as well as psychological methods to treat it. If you’re interested and find the article informative, might you like to publish it as a guest article on your blog? It might be a good follow up to the biological take of your first 5 articles.

  15. […] treatment for depression, which we’ll also be talking about, you can see my tutorials here , here, and […]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: