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Genetics of depression: Could a test have prevented the Germanwings catastrophe?

| May 15, 2015

The brutal death of 150 people on the Germanwings flight that crashed into the French Alps in March led to a swift investigation that shockingly concluded that the pilot, Andreas Lubitz had intentionally crashed the plane, killing himself and everyone else on board. Indeed, the New York Times reported on May 6th that the pilot had practiced the steep descent he executed on the fatal crash in a previous flight on the day of the crash.

One of the facts that came out of the investigation was that the pilot had interrupted his flight training course with Lufthansa, the parent company of Germanwings, to treat an episode of severe depression in 2009, six years before the crash. Though he was declared fit to return to training by a flight doctor, he continued to suffer from psychiatric issues which he hid from Germanwings and Lufthansa–successfully enough that his employers’ regular medical screenings did not pick up his condition.

Whether the pilot continued to suffer from depression after 2009 is unclear, but it is quite clear that he was mentally ill for a long period of time and was thinking about suicide in the days preceding the crash.

In an article on Slate, Alison Griswold asked, “Could Better Psychological Testing Prevent a Tragedy Like the Germanwings Crash?” While she concludes that Lufthansa’s system is extremely thorough and it is unlikely that toughening up testing would yield any significant advantages without bringing up too many false positives, it does bring up an interesting aspect of testing for mental illnesses like depression.

Could a genetic test disclose the presence of or even predict depression? How much do we know about the genetics of depression?

Nature and nurture

The prevalence of clinical depression or major depressive disorder (MDD) as it is called is estimated to be around 10% in the general population. It has been long recognized that depression and other forms of mental illness can and do run in families with estimates attributing around 40% of the variation in population risk for depression to genetic factors. As can be expected, among siblings of an individual with MDD, the risk is significantly higher and the risk increases even further if the individual has experienced multiple episodes of depression.

Let’s get the most obvious question out of the way first. Do we know of a single gene that is causally linked with the majority of people with depression? In other words, is there a depression gene? So far, the answer to that question is no, according Dr Douglas Levinson, a Professor of Psychiatry and Behavioral Sciences at Stanford

..many common disorders like depression, diabetes and high blood pressure are also influenced by genes. In these disorders, there seem to be combinations of genetic changes that predispose some people to become ill. We don’t yet know how many genes are involved in depression, but it is very doubtful that any one gene causes depression in any large number of people.

In fact, the situation is very much at the other end of the genetic association spectrum. A 2014 review article in the Harvard Review of Psychiatry notes that based on what we know, the genetic basis of depression may involve a hundreds of genes which have a small genetic effect on the disease, a much larger number even when compared to other psychiatric disorders that are thought to involve many genes.

As for our understanding of these risk factors, so far genetic analyses of depression have not fared very well, reported Heidi Ledford in a Nature News article.

The largest study so far — a search through the genomes of just over 16,000 patients with major depressive disorder and another 60,000 controls — has turned up just one, as yet unconfirmed, genetic association

Dr Jonathan Flint, a long time depression researcher at the University of Oxford said in the same piece that a large part of why we haven’t been able to pin down more robust genetic associations has to do with how poorly the disorder has been defined, with many different mental ailments being improperly categorized as depression. Indeed, as the 2014 review quantifies this confounding factor quite startlingly (emphasis mine)

..it is possible to meet [the] diagnostic criteria for a major depressive episode through at least 227 different symptom combinations [according to the standard manual of classification used by mental health professionals].

Another aspect that older large scale genetic studies ignored was the importance of gene-environment interactions (also known as GxE) on the occurrence of depression. It has been well established that early life trauma such as childhood abuse or neglect or extremely stressful situations in adulthood such as poverty and parental divorce significantly increase the risk for depression when coupled with genetic factors that make an individual susceptible. Newer genomic studies taking GxE into account may offer as deeper insight into the disease in the future.

Related article:  DNA as 'fortune teller'? There are limits as to what genes can predict

As the authors of the Harvard Review of Psychiatry article noted, the potential involvement of many small genetic changes that each have a small effect on its own, the strong effect of gene-environment interactions and the broad criteria currently used for diagnosis of depression mean that genomic studies will require “tens of thousands of participants,” several times the magnitude of studies involving more defined psychiatric disorders such as schizophrenia. Even that might not be enough, according to Steven Hyman, a professor of psychiatry at the Broad Institute of MIT and Harvard who suggested in a commentary in the journal Nature that to identify genetic links, studies of more than 100,000 people will be required.

Is a genetic test coming anytime soon?

As stated earlier, around 10% of people in America are estimated to have gone through depression at some point or another in their lives. That’s an alarming number, but it should be noted that diagnosis of major depression is in itself tricky, given the lack of objective criteria. Nevertheless, it also means that a genetic test for depression would be extremely useful for one of the most debilitating conditions in the world.

Such a test is likely to be extremely controversial as well and will face similar ethical, legal and social implications being faced currently in the broader realms of personal genetic testing and prenatal genetic testing. Patients and parents are unsure of what the results of genetic tests actually mean, and are stuck worrying whether they should make life altering decisions based on a ‘probable’ risk for a certain disorder.

No doubt with rapid advances in geomics technologies and analysis methods we will gather more insight in the coming decade about the complex genetics of depression. But to the question of whether we can use that knowledge to develop an objective genetic test, there are no obvious answers in the near future. And even if we do develop a genetic test, it is imperative that we be conscious of the extremely crucial role that environmental factors such as early life abuse and presence of stressful situations play in interacting with genetic susceptibility. It is easy to become reliant on a test once it becomes available as we have seen so often in the current medical system. Rather, a genetic test for depression would be most useful when considered along with other methods of evaluation such as psychological testing to make a diagnosis and guide treatment.

Arvind Suresh is a science media liaison at the Genetic Expert News Service. He is also a science communicator and a former laboratory biologist. Follow him @suresh_arvind.

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The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.

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