Image of a man suffering from depression leaning against a doorjamb, gazing wistfully into space.  The view is framed through another doorway in monochrome; the man has a hint of colour.

A powerful piece of medical dogma is the notion that depression has genetic roots.  Talk to many doctors and they’ll tell you that the reason for taking antidepressants to restore the “chemical imbalance” in the brain caused by the genes responsible for depression.  Sound familiar?

Surprisingly, it turns out that depression is not strongly influenced by genetics, contrary to years of medical ‘wisdom.’  This iconoclastic conclusion comes from an exceptionally powerful new study into the genetics of depression.  For decades, scientists have been trying to identify a small set of genes that they believed rendered carriers highly susceptible to developing depression.  Turns out we were wrong!

One gene in particular, the serotonin transporter gene SLC6A4, got a lot of attention.  Caspi et al. published a now famous paper in 2003 which they believed provided “evidence of a gene-by-environment interaction, in which an individual’s response to environmental insults is moderated by his or her genetic makeup.”  This idea was so well received that the Caspi paper has been cited 8529 times, as of the time of writing this blog. 

However, Caspi and colleagues were wrong, as were hundreds of other researchers who published thousands of papers in the belief that they had found evidence to show a linkage between genetics and depressed mental space.  That idea was turned on its head by Richard Border, Matthew Keller and colleagues from the University of Colorado Boulder who debunked the notion that depression is caused by or aggravated by genetics.

How did they reach this remarkable conclusion?  Border et al. used multiple large samples ranging in size from 62,138 to 443,264 people, in total drawing data from 621,214 individuals.  That’s very impressive!  Sample sizes of that magnitude have the statistical power to answer the questions about genetics and depressed mood and avoid false positive results (type I errors).  By comparison, Caspi et al. had a sample size of 847 subjects.

DNA strand, which doesn't cause depression

To ensure that their study was not limited by narrow definitions of depression, Border et al.  measured depression in many different ways, including diagnosis, current severity, lifetime symptom count, duration of depression, the presence of recurrent symptoms, and so on.  To be certain that they identified all and any associations between depression and genetics, they used very liberal criteria for statistical significance.

They then examined the interaction between their various definitions of depression and the 18 most commonly researched genes suspected to be linked to depression, but they found nothing significant.  In fact, they found that the association between depression and suspect candidate genes was the same as the association between the condition and randomly selected genes.  Basically, this means that the previously reported associations were chance findings.

As common sense would predict, they did find an association between exposure to psychological trauma and depression, but they did not find any gene-environment interaction between candidate genes and psychological trauma.  Nor did they find any association with common single nucleotide polymorphisms across each of the candidate (suspect) genes. 

Border and colleagues carefully point out the inadequacies of previous research that suggested that depression is moderated by genetics.  They demonstrate that the previous findings were, in fact, false positives.  They conclude “that it is time for depression research to abandon historical candidate gene and candidate gene-by-environment interaction hypotheses.”

A little girl who appears to have depression

The findings of Richard Border and colleagues highlights the danger of a knee-jerk approach to scientific reductionism in combination with small sample sizes.  As anyone who has suffered from depression knows, depression is a highly complex emotional space and is influenced by a multitude of factors, internal and external.  Senior author, Prof Matthew Keller, an associate professor of psychology and neuroscience, summed it up nicely by saying, “We are not saying that depression is not heritable at all. It is. What we are saying is that depression is influenced by many, many variants, and individually each of those has a minuscule effect.”

Personally, I think that these are liberating findings.  Many depressed patients and their treating healthcare professionals have been caught in the mental trap of believing that the patient’s low mood was strongly driven by genetic factors.  On that view, patients were doomed to a lifetime of depressed mood by their DNA and only antidepressant medication could help to ease the pain.  Border’s findings position the cause of depressed mood where it belongs; in the mind.  The good news is that this means that there is hope that depression can be treated by psychotherapy.  That is not to say that it is easy to treat depression, but it is easier to shift entrenched mental habits than it is to change DNA (with apologies to all the CRISPR-Cas9 editing fans out there).

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