Depressing genes

Can depression be a matter of genetic fate?

by Siobhan Mitchell

[This post is the latest installment in our I Am Mental Illness series.]

What if you could know if you were fated to be depressed? With the rise of personal genotyping services such as 23andme, almost can find out what their psychiatric ‘fate’ will be, but what do you do with this information once you have it?

When I first considered testing myself for depression genes, it seemed like a clearly good idea to find out if I am genetically at risk. As Socrates once quoted, “Know thyself.” The more knowledge I had about myself the better I could maintain my overall health, mental or otherwise. But I soon found knowing my risk for depression discolored my life, made me feel more uncertain and confused about myself and my friends’ perceptions of me.

A few years ago a fellow scientist asked me to donate some blood for her genotyping study. The test would show if I was genetically more at risk for developing depression.

The genotyping study was based on two different versions of a gene which controls the production of the serotonin reuptake transporter, a protein that is also the target of Prozac and other SSRIs (selective serotonin reuptake inhibitors). One version of the gene is short and one version is long. Researchers found that people with two copies of the short gene were more likely to become depressed while carriers of two long versions or a copy of each showed no increased risk of depression. When this discovery was first reported, the media and scientists alike proclaimed it as a gene that predisposes one to mood disorders. However, nature is not entirely in control of your personality because the same study showed that the risk became significant only when a carrier of two short genes experienced several ‘life stress events’.

Prozac

‘Life stress event’ is a clinical term for some of the major misfortunes that a person might experience, like divorce or death of a child or loss of a job. Psychologists and epidemiologists have shown that a high number of life stress events correlate to increased chance of illness or early death.

This was the information I knew when I donated blood for to see whether I had two copies of the “depression gene”. I would learn something interesting about my personality, how I might react to major life stresses (of which I have had none, knock on wood). Additionally, I would also see if others in my lab were predisposed to depression.

While I waited for the results, my colleagues who took part in the study speculated about who would have the two “bad” copies. We joked that all people who gravitated toward depression research must being doing so for personal reasons. Indeed, almost all of my co-workers had anxious personalities and dark senses of humor. Only one person in the lab struck me as depression-proof, the modern day Da Vinci in our midst: a guy who sang opera and sculpted in his spare time and was always reading some literary classic like War and Peace. He had lots of friends with a fully booked social calendar but came from a background of poverty and neglect. I thought his intellectual and artistic triumph over a hardscrabble childhood was proof that he didn’t have the ‘depression gene’. Yet, another co-worker mine pointed out that artistic types like our lab Da Vinci were almost always prone to depression, that their hypersensitivity to their own emotions made them turn to art as a cathartic outlet.

The senior member of our lab, a postdoctoral fellow, was probably the most ebullient person I had ever met, able to talk a blue streak and always making us laugh with jokes often at his own expense. Still I wondered about his almost frenetically funny personality: He seemed so driven to make everything humorous, almost as if he were afraid to let anyone stop laughing. In the rare moments when he wasn’t putting on a show, the postdoctoral fellow could sound very bitter, speaking about his future career prospects as a no-win situation. His mother had died in the previous year, and his work had been understandably slowed by this tragic event. Would he have the genotype?

Most of the people in my lab were similarly hard to read. My boss seemed on top of things: a well-paid psychiatrist on a great career path, happily married with adorable children. Yet he was a constant worrier and easily discouraged when our experiments produced poor results. And what was that old adage about psychiatrists being even more unstable than their patients?

Then there was the earnest but rather haphazard undergraduate who suffered from low self-esteem; he was always second-guessing himself and putting himself down. He was working in the lab because he wanted to be a psychiatrist and wanted to gain some research experience — yet it was obvious he didn’t have the knack for it. This student’s dogged pursuit of a mental health career made me wonder what kind of emotional turmoil he experienced which would make him think, at age 19, that psychiatry was the only vocation worth working towards.

Then there were the two graduate students who both worked incredibly hard and were both prone to obsess about their experiments. Each burned off stress in quite different ways: One partied a lot and lived the wild life while the other filled her time with lessons for sports like akido and tennis. Both were quiet and didn’t talk about their emotions or families much. They were hard to read, emotionally, but then again my colleagues probably couldn’t read me well either.

I am, for the most part, an amiable, easy-going person. However, under stress, I tend to fall apart: have crying jags, temper tantrums, and fits of hysteria. My friends and family have often commented on what a stress-bunny I was. I reasoned with myself that everyone gets stressed out and has bad reactions to things not working out, that perhaps my reactions were just more obvious than others. Still, I wondered: Did my susceptibility to stress also mean I was susceptibility to depression?

Finally the fateful day arrived. The scientist doing the genotyping requested that we use pseudonyms when donating the blood. We choose our pseudonyms from an old Matt Groening cartoon called “Avoid These Elves”, which portrayed a line-up of ‘evil’ elves with names like “Surly,” “Unhingey,” and “Li’l Hateful.” In the end, it was very easy to guess who was behind each pseudonym.

When I looked at my result, I felt a strange mixture of vindication and disappointment: I had the two short copies, making me at high risk for depression.

Even before seeing the results, I had been fairly certain that I would end up carrying the ‘depression genes’. But it took seeing my genotype on paper to make me think hard about it. All through my childhood, I had been moody and overly sensitive. A single cutting remark, however innocuous, could destroy my whole day. Gradually over time, I had learned to fight against the urge to panic when a slight setback occurred, like forgetting my homework or arguing with my sister. Despite my attempts to realign my personality, I often fell into bad moods that lasted for weeks.

Now I knew the reason why I so easily became downcast. It was written into my DNA that my mood would be more fragile than others. But was I going to do with this information? Should I go on Prozac right away, as a preventative measure? Or should I try to keep myself from experiencing any stress whatsoever? Get a new, less stressful but less intellectually stimulating (maybe even boring) job? Or should I just work on staying cheerful, like I had tried to do all my life? But perhaps I should just accept the fact I was always going to see the glass half empty, that it was impossible to change a personality dictated by one’s genes?

Over the course of the day, others in the lab checked for their genotype. Our lab Da Vinci had a short copy and long copy, meaning he was not especially at risk for depression, but nor was he especially resistant. Fair enough; at least he seemed relieved by his test result. As for our undergrad with poor self-image, to everyone’s surprise, he found out he had two copies of the long version, meaning he was resilient to the devastation of depression. And yet, his lack of confidence seemed to indicate to me a much higher chance for melancholy. What was going on? The gregarious post-doctoral fellow whose mother had recently died also had two long copies. That accounted for his gregarious personality. Still, if he had less propensity for depression, why was he so negative about his career and took his mother’s death so hard?

The two hard-working, quiet graduate students both had the short, depression-prone copies of the gene and instantly I felt more akin to them. They understood what it was like be overwhelmed by sadness. And yet, I was puzzled because they didn’t seem particularly afflicted with bad moods. Then I started to wonder if their intense dedication to their work and active social lives outside the lab was their way of combating depression, since I tended to stay busy as a way to avoid falling into a funk of apathy.

My boss suddenly announced that he didn’t want to know anyone’s genotype, lest he have preconceived notions of their ability to work. He went on to say that this kind of information could be disastrous in the hands of health insurance companies. After all, he knew first hand how expensive it was to have to pay for the treatment of a depressed individual. He was quite convinced about a future where insurance companies would demand to know if you carried genes for all sorts of diseases, like cancer or Alzheimer’s disease, as well as risk for mental disorders.

At first I was appalled at my boss’ attitude towards our genotype for a depression gene. How dare he think that I couldn’t be trusted to be productive if I had two short copies of the gene? Did he think that all my abilities rested in those two short stretches of DNA?

But then I realized that I was making similar assumptions about my colleagues, based on my new knowledge of their genetic make-up. Now that I knew the ebullient postdoctoral fellow had two copies of the low depression gene, I first felt surprised that took his mother’s death so hard. Yet, when I thought longer about it, what had I expected? That experiencing the death of a loved one would be easier for him than it would be for me? That he should bounce right back from such a devastating experience because he’s supposed to be resilient?

Rather than just mull over these questions, letting myself get overwhelmed by their implications, I decided to do what I was trained for: research and fact-finding. I looked up every scientific paper I could find on the serotonin transporter ‘depression gene’. It turns out a lot of other scientists like myself also wondered about the significance of this gene in mood disorders and other brain dysfunctions. There were dozens of studies on the prevalence of the short version of the gene on bipolar disorder, eating disorders, schizophrenia, even autism.

Some of the findings reported were, well, depressing: increased suicide attempts were correlated to two copies of the short version of the gene. Increased incidence of anorexia, alcoholism, and binge drinking was also linked to the short version.

On the other hand, sometimes having two long copies of the gene, linked to resilience to depression, raises the chance of having other types of mental disorders. Shyness, obsessive-compulsive disorder, and attention deficit disorder are more associated with two copies of the long version. Increased risk of chronic fatigue syndrome, addiction, and sudden infant death syndrome is also linked to the long versions of the gene.

The long and short of it is, no pun intended, is that having a depression gene does not make me any less able. I can reason this from a strictly evolutionary point of view. A gene that has nothing but negative impact on a person would not be commonly found in a diverse population. In actuality, roughly 20% of Americans carry two short versions of the serotonin transporter promoter a.k.a. the ‘depression gene’. If the short version really is such a bad variant to inherit, then people who carry two copies would’ve been too unsuccessful to reproduce offspring to carry on the gene. Although there are obviously some drawbacks, this ‘depression gene’ also may be useful in counteracting other socially disabling syndromes such as obsessive-compulsive behavior, attention problems, and addiction.

Armed with this new knowledge, I began to reassess what I knew about some of the long/long or “resilient” members of our lab, such as the unconfident undergraduate student. Sometimes the undergraduate forgot to label the media solutions he made as part of his lab duties. When I would confront him about an unlabeled bottle, he seldom acted perturbed about his mistake, asserting that the solution was mostly “X” or “Y” or perhaps “Z”. His lack of concern always mystified me, since my anxious nature would never let me use a solution that I wasn’t completely sure of. Now I saw that the undergraduate’s worry-free demeanor helped him be more resilient to stress, but it also made him a sloppy researcher.

Thus, the ‘depression gene’ could lead to both good and bad things, which is similar to the way a lot of other genes operate. For instance, people who have gene variants linked strong immune systems are more prone to autoimmune diseases. Super-efficient immune systems sometimes become overzealous and attack their own body’s tissue, often leading to serious health problems and death. Only rarely do gene variants cause primarily negative consequences, such as BRCA1, the breast cancer gene, or APOE epsilon 4, the early-onset Alzheimer’s disease gene.

If insurance companies did, in fact, try to weed out clients based on their genetic make-up, they would soon find that most gene variants that put carriers at risk for some diseases may protect them from other diseases. In fact, knowing one’s own genotype may allow more careful monitoring and prevention of a disease the gene supposedly causes. A recent study showed that people who have a genetic predisposition to Alzheimer’s disease (APOE epsilon 4) were not insurance risks, as it found hospital costs for those who test positive for a gene variant linked to the disease are no higher than expenses incurred by people who test negative.

Currently, thousands of genetic tests are available to the general public. Anyone can fork over a few hundred dollars to get their DNA tested for diseases such as diabetes. Fortunately, life insurance companies are not allowed to cancel a contract based on the results of such tests. However, health or disability insurance may become more expensive for an individuals who test positive for disease-associated genotypes. Some countries allow insurance companies to offer genetic testing as a preventive measure, rather than as a punitive one, but knowledge of genetic disease risk raises questions about what kind of prevention to recommend. With some genes, such as BRCA1, which increases one’s risk of breast cancer, preventive measures can run from benign (more frequent mammograms) to invasive (double mastectomy). In one study in which women were tested for the BRCA1 gene, over half of the positive gene carriers elected to have prophylactic surgery.

Happily I did not have to take such extreme preventive measures. But what was I going to do with the information I had about my own genetic disposition? This possibility of personality?

In the end, knowing my risk for depression did not change the way I lived my life. And, after a few months, knowing my colleagues’ risk for depression did not change the way I interacted with them. Gradually, I forgot to gauge my colleagues’ every action against my knowledge of their genetic make-up. After all, actions speak louder than genes. Each member of my lab has developed his or her own way of becoming a successful person, despite the suspect pool of genes we are all carrying. As for myself, I now have a scientific reason to cut myself some slack during times of stress. With hope, I’ll be able to take steps, in times of extreme stress, to get help. And who knows? Maybe someday I will do my own research on the ‘depression gene’ and possibly develop therapies specifically geared for people with two short copies. After all, that’s one of the reasons why scientists are trying to identify risk genes: to design better treatments for those disorders.

[Image credit: DNA, public domain image from US govt. Image of Prozac, credit Tom Varco, CC 3.0 license.]

[Siobhan Mitchell obtained a Neurobiology Ph.D. at the State University New York at Albany (SUNY Albany), followed by a post-doctoral fellowship at University of Washington, Seattle. She currently works at the Nestle Institute of Health Sciences in Lausanne, Switzerland, where she researches systems biology interrelationships between diet, genes, lifestyle and the causes of neurological diseases such as dementia, depression and stroke. She is married and has two sons.]

One thought on “Depressing genes

  1. I wonder if there’s something subtle in the expression of the gene that works better with one SSRI than another? I ask because whatever’s in my DNA, apparently my father and I do best on the same drug. We’re still dealing with depression, but we recover now instead of spending long stretches of our lives incapacitated.

    I won’t be able to find out, oh, ever, but if I did come out having drawn two short straws, somehow I think that would only be confirmation. After all, I’ve already been through the mental illness. It isn’t as if knowing would predispose me to anything because that future is my past. If it would help scientists learn how to tailor solutions to every variation of this? Sign me UP.

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