Large Rigorous Study Debunks Popular Gene-Environment Theory of Depression

A large and rigorous meta-analysis fails to find support for the gene-environment interaction theory of depression.


A new meta-analysis, representing the most extensive study to date, examined the hypothesis that a particular genetic predisposition, related to serotonin, is linked to later onset of depressive symptoms when paired with stressful life events. Dr. Culverhouse and a large team of international researchers conducted this study to clarify the debate and controversy around genes (the S allele of the 5-HTTLPR serotonin transporter promoter region), stress, and depression.

Their findings, published in Molecular Psychiatry, demonstrated no evidence to support the gene-environment interaction effect, a widely-held belief in the field.

 “A hallmark of science is the ability of results to be replicated, a criterion that has been increasingly recognized in biological and psychological research. The original 2003 report of an interaction between 5-HTTLPR genotype and stress exposure on depression has remained controversial owing to inconsistent results from replication efforts,” they write.

Photo Credit: Pixabay

In 2003, a high-profile report suggested that the development of depression was attributable to an interaction between a person’s genes and their environment. Researchers proposed that certain genetic variations related to serotonin, a neurotransmitter, predispose individuals to develop depression. Specifically, the presence of a short, or S, allele of 5-HTTLPR is thought to increase one’s likelihood of depression when that person has also experienced stressful life events, such as childhood maltreatment.

This research was highly influential on the field, Culverhouse and team explain. The study was widely cited and, since its release, over one hundred articles have explored the “gene-environment interaction effect” thought to contribute to the development of “major depressive disorder,” depressive symptoms, and suicidality.

Numerous meta-analyses have sought to combine the findings of these studies to determine whether this link between genes does make one more likely to develop depression after exposure to stress. However, the results of these meta-analyses are mixed. Some have found support for this interaction while others demonstrate no evidence to support the hypothesis.

Researchers have pointed out the methodological limitations of the meta-analyses in support of the gene-environment interaction effect. For example, some have pointed out that previous reviews were restrictive in their inclusion criteria resulting in misrepresented support. Others have called attention to specific statistical considerations such as the inclusion of studies that observed outcomes other than depression as well as other inconsistencies that likely resulted in erroneous support.

In this study, Culverhouse and a team of researchers conducted a meta-analysis that addressed these shortcomings. They combined the results of studies that have explored the connection between the genetic variation and life stress on the development of depressive symptoms.

In this process, a variety of studies were included to increase the power of their findings. However, they sought to reduce the risk of inconsistencies by avoiding heterogeneity in their inclusion criteria and their analytical approach. Instead, they sought to include only studies that were relevant and focused. Culverhouse and team write:

“Our goal was to include data from as many pertinent studies as possible. However, analyses based on a small number of samples can be statistically unstable, a problem that is exacerbated in models involving multiple covariates and an interaction term. For these reasons, we required participating studies to have genotyped at least 300 individuals for 5-HTTLPR and to have assessed depression and stress for inclusion.”

By engaging in intentional methods and correcting for the limitations of previous analyses, the researchers assert that they employed proper rigor to investigate the interaction effect: “With this approach and the large number of contributing samples, we are well positioned to clarify the relationship between 5-HTTLPR, stress, and depression.”

Across all of the subgroups included, their results found there to be no evidence in support of the gene-environment effect for depression. In their analyses, life stress was represented both through the presence of childhood maltreatment and other life experiences as stressors. “Current depression” and “lifetime depression” were examined to account for the notion that depression can be recurring. Studies included featured samples sizes both of participants of all ages and young adults.  In addition to this, they utilized different methods to code the genetic variation.

In addition to this, they even included data from the original Caspi et al. (2003) study in their meta-analysis. Despite these efforts, none of their analyses generated any “compelling evidence that the 5-HTTLPR S allele increases the risk of major depression in individuals exposed to stress.” In other words, the idea that a genetic predisposition contributes to depression was not supported in this combined dataset that observed 43,165 participants and numerous studies. They write:

“Importantly, our meta-analyses do not support the hypothesis that in subjects exposed to stress, carrying S alleles for 5-HTTLPR confers a differential and increased risk for either lifetime or current depression compared with the impact of carrying S alleles in subjects who were not exposed to stress. In fact, when the outcome is current depression, the point estimates for the interaction terms are all in the direction opposite of the hypothesis.”

The results of this study put a prevailing belief on trial by suggesting that the existing combined evidence fails to support the gene-environment interaction effect for depression.

“Based on our findings, we conclude that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not a broadly generalizable effect, but must be of modest effect size and only observable in limited situations.”



Culverhouse, R. C., Saccone, N. L., Horton, A. C., Ma, Y., Anstey, K. J., Banaschewski, T., … & Goldman, N. (2018). Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Molecular Psychiatry23(1), 133. (Link)


    • Good question. And I do believe you are correct, the fraud based, wildly over-utilized in practice, bio-bio-bio only believing, all distress is caused by a “chemical imbalance” in your brain, resulting in a “life long, incurable, genetic mental disorder” lie, was the “rationale for prescribing SSRI’s” to millions of people, I do believe.

      And when it comes to today’s new psychiatric/psychological theology that adverse childhood experiences create “mental illnesses,” since over 90% of “borderline” blasphemed are in reality mislabeled child abuse survivors. And over 80% of those stigmatized as “depressed,” “anxious,” “bipolar,” and “schizophrenic” today are mislabeled child abuse survivors.

      I’m quite certain the real problem leading to all this misdiagnosis of child abuse survivors, with the DSM disorders, is that the “mental health professionals” can not bill insurance companies for helping any child abuse survivor ever, unless they first misdiagnose the child abuse survivors with the billable disorders. Because child abuse is not an insurance billable DSM disorder.

      Perhaps this systemic problem with the DSM should be addressed? And our “mental health professionals” should get out of the business of turning millions and millions of child abuse survivors into the “mentally ill” with the psychiatric drugs? Especially since covering up child abuse is illegal, as well as morally repugnant, behavior.

      Or better yet, perhaps it’s time to finally flush the DSM altogether. Given the reality that all the DSM disorders were confessed to be “invalid” over five years ago, by none less than the head of the National Institute of Mental Health.

      How long will it take?

      Report comment

      • Someone Else–

        The NIMH article you cite does suggest getting rid of the DSM, but what you neglected to mention is the alternative they propose.

        The alternative diagnostic procedure is heavily dependent on biomarkers that are yet to be found.

        This pushes it into the medical model camp, and is perhaps even worse than the DSM, in my opinion

        Report comment

  1. Depression is still the great enemy. More personal energy is expended in manic defenses against, diversions from, and denials of it than goes into other supposed psychopathological threats to society – addictions, psychopatic criminality….

    As long as we are caught in cycles of hoping against despair….as long as our actions in regard to depression are ressurrective, implying that being down and staying down is a sin, we remain Christian in psychology.

    Our stance toward depression is a priori a manic defense against it….

    Because Christ resurrects, moments of despair, darkening, and desertion cannot be valid in themselves…Our model insist on light at the end of the tunnel,,,therapy more or less consciously imitate this program.

    James Hillman

    The problem is that we do not want to see the need of depression. Apollonians or people beyond the state of depression do not believe in depression or darkness per se, they believe in resurrection and light. So identity + depression is not a real one for them, no one believe in our depression, they believe that it is a sin.

    This is theology, not psychology – to cure state which is beyond the world of body sickness, beyond medicine. This is impossible. Theological pseudo medicine and the terror of health is not an answer for/to human depression. Courage and the truth is the answers.

    Report comment

    • The difficulty starts with the fact that “depression” is not caused by one thing, but tons of different events and effects. For that reason, calling “depression” the problem is both misleading and confusing, and as long as psychiatry starts from this false premise, it will continue to come up with one wrong answer after another.

      Report comment

        • I can’t entirely agree with this anymore. I used to think the rich had a different medical care system until I learned more about Lyme. Watch the video of Avril Lavigne crying saying they treat Lyme patients as psychiatric patients “they treat you like you’re crazy” she said. Many celebrities (and/or their children) have or had battles with Lyme. Tommy Hilfiger’s daughter was sick for more than ten years, eventually woke up on a psych unit. She wrote poignantly about that betrayal by her family when they gave up on her in her book Bite Me. Kelly Osbourne was sick for a long time. Shania Twain’s career was derailed by Lyme. I wonder if Kate Spade who took her life this year had untreated Lyme. What about Anthony Bordaine? He certainly would have had many chances for exposure to Lyme and associated diseases that effect neurocognition and behavior. Adam Lanza had chronic Lyme and while it may shock the senses for some to defend him given how heinous his actions were, I think it behooves both patients and the medical system to understand how Lyme and associated diseases affect neurocognition and behavior especially with as armed and dangerous as American society is.

          Report comment

          • You do make an excellent point. Robin Williams, Marilyn Monroe, Stevie Nicks, Ernest Hemmingway, Judy Garland, Heath Ledger, … the list goes on of rich and famous people whose lives were damaged by “mental health treatment” in the form of prescribed psychiatric drugs. They can afford better “treatment”, but can they find it, or do they even know enough to look?

            Report comment

    • No. To look for material causes of depression is a nihilism. The causes of depression are purely psychological. Materialists think theologically about psychology which is a fallacy and a crime against
      LOGIC and psyche, crime against death.

      They think that when sb is rich, he or she, must be also happy – this point of view actually shows their ignorance and stupidity.
      And completely non psychological attitude.
      Either childish thinking or theological negation. Grow up, apollonian people. Just grow, up.

      The reason of happiness and unity is psychological blindness. Depression means psychological awakening.
      Psychosis also is sth beyond material reality, it happened in strictly psychological reality which is not real for apollonian fundamentalists/materialists.

      Report comment

  2. I fell asleep watching a lecture on late Lyme in psychiatric patients by Jane Marke (a psychiatrist with Lyme and whom treats neuro Lyme patients in NYC), and a study was shared that took a snapshot of the inpatient population on a particular hospital unit and showed that 89% of the supposedly “bipolar” patients were seropositive (WB) for Lyme disease, and (a large percentage I cannot remember) of those with a psychosis label were seropositive. I’ll try to find the reference because it’s a lot more compelling than the long contested gene theory.

    Anyone especially who’s ever been labeled treatment resistant might be interested in watching Dr Marke’s Videos on her YouTube channel.

    The gene theory should have been published in the journal of irreproducible results. Why do these theories become so pupilar *before* they are replicated? Before they have any validity? How is it this has become almost common knowledge and yet it’s so very wrong just like the chemical imbalance theory?

    How is it that people with known etiologies like severe trauma or infections with bacteria that are known to easily cross the BBB are still having to defend their brains? Punishing my bad brain didn’t work for me and it doesn’t work for an awful lot of others.

    Report comment