Is there a gene that leads you down the path to debilitating depression only after the fourth hard knock comes along in your life? Is there another gene conferring a higher vulnerability for schizophrenia that gets triggered only if you become the victim of vicious bullying before the age of 8 or smoke too much pot in your teenage years? Can another version of a gene protect an abused child from extreme PTSD only if she receives the benefit of a safe and caring relationship before the age of 5? A new wave of gene-environment interaction (GxE) research strongly suggests that the answers to these questions are scientifically attainable — and affirmative.
In the decade following the decoding of the human genome, genetics researchers focusing on massive gene-association studies have found dozens of promising leads but no clear answers as to causes or cures for schizophrenia, bipolar disorder, or depression. A new, more integrative approach to genetics is garnering attention inside and out of the scientific establishment. The GxE model looks at interactions of genetic traits and environmental effects that can either heighten or lower an individual’s risk for mental illness, and brings together high- and low-tech tools to produce findings that appear to offer the benefits of scientific elegance and everyday practicality.
By implication, in such a study, neither gene nor environment alone would be sufficient to create the discovered effect. When used to study and describe the causes of mental illness, a GxE effect usually comes under the banner of the “vulnerability hypothesis.” The research that supports such findings seeks to identify factors in a person’s environment — an internal infection, a natural disaster, malnourishment — that can “turn on” a person’s genetic “switch” — the gene or genes that confer greater vulnerability to a psychiatric disease.
In 2003, psychology professors Avshalom Caspi and Terrie Moffitt, pioneers in longitudinal family studies and GxE research, published a study of a Dunedin, New Zealand, population — 1,000 individuals and families who’ve allowed their health to be documented and tracked for the past 40 years. Moffitt and Caspi’s findings linked one allele (a shorter version of a gene) in the promoter region of the 5-HTT serotonin transporter gene — the gene that regulates transport of serotonin in the brain — to those in the Dunedin Cohort who showed a lower ability to handle stressful events that can lead to depression. Individuals with one or two copies of this short allele exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life-events than individuals who carried the long allele of 5-HTT. This interaction, Moffitt and Caspi reported, also showed that childhood maltreatment predicted adult depression only among individuals carrying a short allele and not among those carrying the longer allele.
It was the first study suggesting that a difference of one allele could result in someone possessing either greater vulnerability or resilience to life’s hard knocks, and one of few since showing a significant interaction between this genetic variation and both the trauma of abuse that happened long ago and episodic stresses that happened six months ago or yesterday. These short and long 5-HTT alleles are not uncommon in the population, thus this finding would seem to hold large implications. Even more provocative was the study’s concurrent finding that those study participants with the longer version of this allele had a lower chance of developing depression after facing the same kinds and numbers of stresses. For those scientists seeking tangible proof of a meaningful GxE, this discovery was the holy grail. At the end of 2003, Science magazine identified it as one of the reasons they chose mental-illness genetics as a top science breakthrough for that year.
But an article in The New York Times, “Report on Gene for Depression Is Now Faulted,” censured their research with a career-battering sentence: “One of the most celebrated findings in modern psychiatry — that a single gene helps determine one’s risk of depression in response to a divorce, a lost job, or another serious reversal — has not held up to scientific scrutiny.”
In defense of her work, Moffitt explained to me that the key difference between the 2003 study and the studies cited for the Times article. Out of the 14,000 individuals surveyed in the 14 studies reviewed in the Times story, a full 8,000 people had reported their stressful events and presence or lack of depression over the phone or through the mail, rather than through in-person interviews scheduled in advance with willing individuals who were part of a long-term studied cohort whose self-reports were corroborated by two other family members 80 percent of the time. Another deficiency in the critique, from Moffitt’s perspective, was the greater weight given to larger studies over the smaller ones, which tend to do more in-person interviewing. Interestingly, the smaller studies were also the ones that reported results closest to Moffitt’s.