It is Time to Abandon the Candidate-Gene Approach to Depression

The candidate-gene approach to depression goes unsupported and is likely based on bad science, new research finds.

Zenobia Morrill
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Editor’s note: This post was originally published with the headline “It is Time to Abandon the Search for the Genetic Underpinnings of Depression.” A comment by the authors of the study appears below our report.

A new rigorous study, published in the American Journal of Psychiatry, closely examined 18 candidate genes hypothesized to be genetic underpinnings of depression. Despite recent claims that these genetic polymorphisms may serve as reliable biomarkers suitable for identifying later development of “Major Depressive Disorder,” the results from this study found no support for this association. Based on these findings, the research team, led by Richard Border and Dr. Matthew Keller in Colorado, call on the field to abandon the idea that depression is genetic.

“In agreement with the recent recommendations of the National Institute of Mental Health Council Workgroup on Genomics, we conclude that it is time for depression research to abandon historical candidate gene and candidate gene-by-environment interaction hypotheses.”

Photo Credit: Max Pixel

The researchers assert that previous data supporting the association are likely to represent false positive findings:

“The results suggest that early hypotheses about depression candidate genes were incorrect and that the large number of associations reported in the depression candidate gene literature are likely to be false positives.”

The researchers are referring here to numerous studies that have reported the promise of genetic biomarkers of depression. To explore this association, previous research has examined the direct effects of gene mutations, the interaction between gene mutations and environmental stressors, and the effects of different kinds of mutations within the same candidate genes.

However, these earlier studies featured small sample sizes and were underpowered. Therefore, although their results indicated an association between genetic variations and depression, this relationship may be a false positive finding.

Many researchers who are skeptical of this association have questioned the validity of these past findings of genetic markers for depression. There are several reasons for this. First, Border and team point to the significant problem posed by underpowered research, particularly in the context of the specific research approach used to identifying mutations across the genome.

“Given the small sample sizes typically employed, candidate gene research has likely been severely underpowered. This, in turn, may suggest that the false discovery rate for the many positive reports in the candidate gene literature is high,” the researchers write.

“Consistent with this possibility, targeted, well-powered genetic association studies of depression and other psychiatric phenotypes in large samples have not supported candidate gene hypotheses.”

Second, researchers have expressed concerns regarding “incorrect analytic methods and inadequate control” designs. Third, the clinical utility of identifying individual gene mutations is unclear. The authors question the application of claims that gene mutations or the interaction of gene mutations with environmental stressors thought to induce later onset of depressive symptoms might constructively shape clinical interventions.

Finally, and importantly, Border and co-authors report that there has been significant publication bias in this body of literature, especially evidenced by a review of all candidate gene and gene environment interactions between the years of 2000 and 2009.

To adequately investigate the commonly studied candidate genes and their hypothesized association with depression, Border and team employed rigorous research methods. They write:

“The present study is the most comprehensive and well-powered investigation of historical candidate polymorphism and candidate gene hypotheses in depression to date.”

They identified 18 commonly studied gene candidates that have appeared across peer-reviewed journals amid claims of their association with depression. They took on a comprehensive and thorough approach that included investigating the genetic mutations and the way they might interact with environmental stressors. An example of an environmental stressor is one’s exposure to traumatic events, they explain.

Moreover, Border and colleagues employed a liberal threshold for the cutoff to determine the association and included a wider range of diagnoses that would fall under the depression conceptualization including “lifetime depression,” “current” depression, and so on.

They sought to examine whether or not “the large data sets of the whole-genome-data era support any previous depression candidate gene hypotheses.” They found little evidence that any observed effect was larger than what would be expected by chance. When examining genetic mutations, all but one appeared associated with depression, using their liberal threshold.

No support for the interaction between genes and environmental stressors to predict depression was found. Interestingly, however, all of the environmental stressors measured were significantly associated with depression. For example, exposure to childhood trauma and recent trauma notably increased one’s risk for depression.

“Despite the high statistical power, none of the most highly studied polymorphisms within these genes demonstrated substantial contributions to depression liability,” Border and the co-researchers write. “We found no evidence to support moderation of polymorphism effects by exposure to traumatic events or socioeconomic adversity. We also found little evidence to support contributions of other common polymorphisms within these genes to depression liability…”

The findings of this study “stand in stark contrast” to the existing literature on these 18 candidate genes. What sets their study apart is the methodological rigor, including a thorough examination of depression presentations beyond just a singular conceptualization of depression.

“Perhaps most importantly,” write the authors, “unlike meta-analyses that use previously published candidate gene findings, our results cannot be affected by selective publication or reporting practices that can inflate type I errors and lead to biased representations of evidence for candidate gene hypotheses.”

Given these thorough considerations, they write that “it is extremely unlikely that we failed to detect any true associations between depression phenotypes and these candidate genes. The implication of our study, therefore, is that previous positive main effect or interaction effect findings for these 18 candidate genes with respect to depression were false positives.”

They conclude that depression may be far more complicated than originally hoped.

“Our results demonstrate that historical depression candidate gene polymorphisms do not have detectable effects on depression phenotypes. Furthermore, the candidate genes themselves (with the possible exception of DRD2) were no more associated with depression phenotypes than genes chosen at random.”

Their confidence in their findings is supported by the recognition that similar evidence has come out of well-powered investigations examining associations with candidate genes and schizophrenia.

Thus, they conclude with the suggestion that research abandon the hypothesis that gene mutations or the interaction between genes and environment is relevant to depression. They write this in the spirit of promoting good science:

“The potential for self-correction is an essential strength of the scientific enterprise; it is with this mechanism in mind that we present these findings.”

**

Comment from the study authors:

We are writing to discuss your recent article (madinamerica.com/2019/03/time-abandon-search-genetic-underpinnings-depressionon our paper in the American Journal of Psychiatry (No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples, doi.org/10.1176/appi.ajp.2018.18070881). We appreciate your interest in our work but are concerned that your post mischaracterizes some of our findings as well as our conclusions. Particularly, we do not “call on the field to abandon the idea that depression is genetic.” Rather, we argued in our paper that a particular and increasingly outdated approach to understanding the genetics of depression—called the “candidate gene approach”—has very little evidence to support it.

Like the vast majority of behavioral traits, there are heritable and non-heritable factors that contribute to liability for depression symptoms. In this sense, no behavioral traits are entirely “genetic” or “non-genetic”; nearly all result from a combination of both genetic and environmental factors. An overwhelming abundance of evidence from both family studies and studies examining genome data (e.g., doi.org/10.1176/appi.ajp.157.10.1552 anddoi.org/10.1038/s41588-018-0090-3) supports the existence of heritable factors that partially underlie depression symptomatology. The degree of converging evidence is so strong that there is a near consensus among researchers in psychiatry that genetic factors partially influence depression liability.

Similarly, there is consensus in the field that that there are a great many individual genetic polymorphisms involved in depression liability, each of which has extremely small effects and by no means determine whether any given individual will experience depression symptoms—in other words, there is no one “depression gene”, and no combination of “depression genes” that guarantees an individual will develop major depressive disorder. This has been strongly supported by recent work by the Psychiatric Genomics Consortium (doi.org/10.1038/s41588-018-0090-3), and similar well-powered studies will continue to identify variants that contribute to depression symptom liability.

Even 25 years ago, researchers knew that genetic variants would never explain all of the variation in depression liability, but they were optimistic that individual genetic variants with substantial effects could be identified based on biological hypotheses, such as the hypothesis that depression was caused by serotonin deficiencies. Thus, assays were developed to genotype-specific variants in genes known to play a role in such systems—for example, a polymorphism in the SLC6A4 gene involved in the serotonin system. The polymorphisms targeted by these assays, which we refer to in our paper as “candidate genes” or “candidate polymorphisms”, were studied with increasing frequency in small samples, with some researchers reporting large effects on depression liability.

Based on the available evidence from well-powered genome-wide association studies (GWAS), where nearly all common polymorphisms in the genome are measured and tested for a relationship with a trait, we now know that it is highly unlikely that such candidate polymorphisms exhibit large effects compared to “non-candidate” (i.e., less commonly studied) polymorphisms. In our paper, we show that these candidate polymorphisms have zero or near-zero effect sizes, making them impossible to reliably assess in sample sizes typical of previous candidate gene studies. Thus, we argue in our paper that previously reported positive candidate gene findings were likely false-positives and incompatible with our modern understanding of the genetic and non-genetic epidemiology of depression. As a result, we urge depression researchers to abandon historic candidate gene hypotheses. Contrary to the article’s assertion, we do not urge researchers to abandon searching for the genetic factors that contribute to depression, and we certainly do not believe there are no genetic factors that influence depression liability

We hope you’d be willing to either modify your original post to reflect our point of view, or, alternatively, to include our response. Please let us know if you have any further questions or concerns.

Sincerely,

Richard Border, Luke Evans, Emma Johnson, Matthew Keller

****

Border, R., Johnson, E. C., Evans, L. M., Smolen, A., Berley, N., Sullivan, P. F., & Keller, M. C. (2019). No Support for Historical Candidate Gene or Candidate Gene-by-Interaction Hypotheses for Major Depression Across Multiple Large Samples. American Journal of Psychiatry, appi-ajp. https://doi.org/10.1176/appi.ajp.2018.18070881

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Zenobia Morrill
MIA Research News Team: Zenobia Morrill is a graduate of the dual master’s counseling psychology program at Columbia University. As a doctoral student and researcher at the University of Massachusetts in Boston, she seeks to understand the context informing psychology research and the underlying social factors that influence individual psychology. She is currently involved in projects examining the impact of structural violence.

17 COMMENTS

  1. This is the sort of thing that happens when you treat a syndrome like it was an actual unitary disease. No wonder these alleged researchers are confused- they haven’t teased out members of the many sub-groups of the depressed, so all these groups are combined into one population instead of the heterogeneous groups they actually are.

    • Yes. Because panic attacks have never been shown to be caused by one thing only. They are caused by many different things, including physiological (like insufficient oxygen), psychological (such as reactions from childhood abuse), social (as happened to me when I retired, sold my house and bought a huge camper to live in), and spiritual (such as losing faith in God and not knowing what happens when one dies). There are as many causes as there are individuals, and the idea that genetics would cause such a temporary and conditional situation is actually so unlikely as to approach zero probability. And to date, there is absolutely not one iota of evidence, despite decades of research, to suggest a genetic cause to ANY “mental illness.”

      We should look at what is going with each individual and stop trying to blame normal emotions like anxiety on “bad brains” with zero evidence that it is true.

      • I started getting panic attacks as a side effect from the psych drugs I was taking at the time, started about 36 years ago, a year after starting these drugs. I did not realize this at the time, I had no idea what this terrifying and painful experience was, but I figured this out years later, after coming off the drugs, and eventually the panic attacks disappeared.

        But in the meantime, I was prescribed the usual benzos for this, at one time up to Xanax, Ativan, and eventually Klonopin was added. All leading up to big breakdown to where I had to ditch all of the drugs, and start over with all this, from a fresh and streamlined perspective.

        Eventually, I learned that regardless of what life experience triggers us into a panic attack, it translated into adrenal overactivation. So on top of having panic attacks, it also led to adrenal exhaustion, which is that “tired but restless” feeling, which is a state of physical imbalance.

        http://antianxietys.com/adrenaline-and-panic-attack-connection-what-you-need-to-know

        I addressed this in many ways over the years but identifying this as an adrenal issue is what led to my turning a corner. There are herbs very specific to overactive adrenal glands and adrenal exhaustion, for which I saw a very well trained herbalist and Chinese Medicine practitioner. In Chinese Medicine, this is all about “Chi” which is our vital life force energy, and this is what gets depleted with panic attacks.

        The herbs, accupuncture, Qi Gong, and grounding meditation all help to calm our nervous system and adrenal glands, so that our bodies don’t become flooded with adrenaline from stress, and in turn, our bodies become better equipped to handle stress when we are grounded and in chi balance.

        This is a lovely and brief (7 minutes) meditation which I found online called “Meditation for Panic Attacks/Emergency Anxiety Relief.” When we practice this enough, we are in essence training our neural pathways toward thoughts of calm, relaxing, and safe. Then, we can become our own self-healing agent during stress.

        https://www.youtube.com/watch?v=sz-cNBAK7Qs

        I of course still can feel anxious and get nervous about speaking publically, performing, facing certain life challenges, and some thoughts can still trigger anxiety if I dwell on them, being human and all. But I have not had a full blown panic attack in years and years.

        Getting off the psych drugs, balancing my energy through herbs and chi exercises, and also GROUNDING (vital for any kind of anxiety, especially panic) is what healed me from years of hair trigger panic attacks, and it also healed my nervous system in general, from a lot of trauma. It’s all very natural and self-healing, with good support from the Earth.

        That’s what grounding is, to the Earth. The way electrical appliances must be grounded so as not to short-curcuit. Same thing. Humans short circuit, too, if we’re not grounded.

  2. The researchers are unable to replicate any support for genetic causation of depression consistent with their inability to replicate any genetic causation for any “mental illness”; the inability to replicate is the story here. Jay Joseph has written books and blogs on this subject; genetic research is bad science based on failure to do “double-bind studies” and control for the confirmation bias (besides failure to replicate). Depressive experiences cause depression; unfortunately, researchers cannot quantify this hypothesis nor falsify it.

    • Well Steve. This is what happens when you try to treat syndromes as real diseases. “Mental illnesses” aren’t real diseases unto themselves, but syndromes- collections of signs and symptoms that can (and likely do) have multiple origins and multiple treatments, depending on the causative agents. Naturally, it should be no surprise that there isn’t genetic simplicity or constancy for everyone with the same syndrome.

  3. To search for genetic cause of depression is not science, it is psychopathy, or theology in medical disguise. Because we assume that happiness is obligatory and depression or psychosis is unnecessary.

    Psychopathology is either evil or sin. Depression, psychosis is neither evil nor sin, it is a necessity.
    Szasz and Hillman were heroes of freedom of thought, beyond Plato’s cave. And psychiatry is a blind giant in Plato’s cave.
    Victims of psychiatry are also those free, beyond the darkness.

    I am myself, that is not enough – Sylvia Plath.
    Psychiatry has got no connections with wisdom. Death has. Sylvia Plath has.
    I have respect for death, I have respect for suffering. But I have no respect for theology in medical disguise. Or people who think that religious dogmas, medicine or science, means more than human psyche, death and so on.This is arrogance of authoritarian mind.This is Apollonian hatred of psyche. This is spiritual negation of psyche. Fundamentalism of any kind is evil.

    And psyche is seen as a great evil in monotheistic world. Because psyche belongs to polytheistic reality. Apollonian ego is a monotheistic giant.

    • ‘Those who are able to see beyond the shadows and lies of their culture will never be understood, let alone believed, by the masses.’ -Plato

      Szasz, Hillman were rejected, P.Getzsche was punished, P.Breggin is unknown in Europe, many people writing here, are not heard. Victims of psychiatry are deliberately unseen victims. Because apollonian ego is a blind giant in Plato’s cave. And we are those few, beyond.

      Be proud, whoever you are. Because we are those beyond the cave, and we know what’s going on.
      The rest is sleeping and happiness is their sleeping pill.

  4. “exposure to childhood trauma and recent trauma notably increased one’s risk for depression.” This is the cause of most “depression,” as well as most “anxiety,” “bipolar,” “schizophrenia,” and “borderline.”

    “the prevalence of childhood trauma exposure within borderline personality disorder patients has been evidenced to be as high as 92% (Yen et al., 2002). Within individuals diagnosed with psychotic or affective disorders, it reaches 82% (Larsson et al., 2012).”

    “It is Time to Abandon the Search for the Genetic Underpinnings of Depression.” It is also time to abandon the search for the genetic underpinnings of “bipolar” and “schizophrenia.” Since it’s stupid to search for genetic underpinnings for illnesses we already know have iatrogenic etiologies.

    And we already know the ADHD drugs and antidepressants create the “bipolar” symptoms. And that the “bipolar” and “schizophrenia treatments,” the antipsychotics/neuroleptics, create both the negative and positive symptoms of “schizophrenia.”

    https://www.alternet.org/2010/04/are_prozac_and_other_psychiatric_drugs_causing_the_astonishing_rise_of_mental_illness_in_america/
    https://en.wikipedia.org/wiki/Neuroleptic-induced_deficit_syndrome
    https://en.wikipedia.org/wiki/Toxidrome

    Just think of how much money our country could save if we could get the doctors to stop prescribing these neurotoxic drug classes, and stop making millions “mentally ill” with these drug classes. And if we stopped wasting money looking for genetic underpinnings, for environmentally caused or iatrogenic illnesses.

    But this, of course, would mean the psychological and psychiatric industries would have to get out of the child abuse covering up business, which has always been the “mental health” industries’ primary actual societal function, despite this being illegal.

    https://www.indybay.org/newsitems/2019/01/23/18820633.php?fbclid=IwAR2-cgZPcEvbz7yFqMuUwneIuaqGleGiOzackY4N2sPeVXolwmEga5iKxdo
    https://www.madinamerica.com/2016/04/heal-for-life/

    Maybe, just maybe, having the psychiatric and psychological industries systemically aiding, abetting, and empowering the child rapists on a massive societal scale, to the point we now have pedophiles and child sex traffickers ruling Western civilization, was a bad idea?

    https://globalfreedommovement.org/putin-blasts-euro-western-culture-of-pedophilia-and-satanism/
    https://www.nytimes.com/2018/04/11/us/backpage-sex-trafficking.html
    https://www.youtube.com/watch?v=-nzi2avrKDg

  5. Depression used to be a sin, as in a choice people make. If you can not sin ( you do not have the DNA that they are looking for) you are not a human being. The sin is ingratitude to not appreciate and enjoy the gifts that God has given us, like the sight, sound, smell of things.

    • Depends on how far you get into it. But my late depression is because it stems from bitterness and lack of faith as well as ingratitude. I had a friend lie in bed and refuse to get up or let his family know he was alive because he was bitter at how his life had turned out. Anger turned inward.

  6. Depression is a feeling. Not a disease!

    Yes, I have been depressed and have been very much so lately.

    But it comes and goes like any other feeling. My life sucks– largely because of psychiatry. I have a right to feel very sad.

    Not sure it will ever go away for long. Because–oh yeah. My life stinks and will never get better!

    Psychiatrists only make your problems 10x worse and pretend your rotten life situation is irrelevant. That’s why these guys are worse than useless in solving any problems. Physical, social, or spiritual. Worthless physicians.

  7. It also occurs to me that even these “candidate genes” in the most POSITIVE light presented by biased researchers never came within orders of magnitude of the known effect of trauma and environmental stress on so-called “mental disorders.” Most likely, nutrition, exercise, sunlight exposure, change of environment, laughing, hugs, and all sorts of other things have more measurable effect than the most optimistic estimates for any gene. Yet somehow, these studies continue to get funded. It’s a total dead end, and high time the research literature stated this out loud.

  8. I have a serious problem with anxiety and depression….
    I take medication for this problem…
    I see a psychiatrist every 3 months….
    I have no problem if someone says I have a mental illness..
    and I seriously hope that they never stop looking for
    any genetic problem that might impact on this suffering…
    I believe in the bio/psy/soc model of causation….
    I don’t want anything left out that might help…

    • But all this business playing around with genes and genetic causes is a blind alley and has been for decades. This is never going to be a viable answer to the difficulties caused by what people call depression. Depression, as Rachel observed above, is not an illness but an indication that points to the fact that something is not quite right in your life, that there’s something that needs to be changed by you. This is not something caused by genetics and genes and all this mumbo-jumbo. And I do have a problem with anyone wanting to call me “mentally ill”. They can do so but it had better be behind my back.

      At least I’m glad that MIA didn’t retract anything that they said about this dubious study.