How Our GxE (Gene-Environment Interaction) Makes Us Who We Are

Since the 2003 study that started all the excitement and the 2009 brouhaha that brought it to a fever pitch, other studies (some not included in the damning 2009 meta-review) have replicated aspects of the Caspi-Moffitt 2003 study, while others have not. This left the field of GxE research in a near limbo until another, much larger, more definitive review came along at the end of 2010. This NIH-funded double meta-study reviewed the raw data from a total of 56 GxE studies (with the pedigrees of the Department of Psychiatry at the University of Michigan and the Human Genetics Department of the University of Würzburg, Germany) investigating whether the 5-HTT serotonin transporter modified depression, and found what they called “robust evidence that [the gene] moderates the relationship between both childhood maltreatment and specific stressors and depression.”

In light of the previous controversies about methodologies, the reasons justifying the meta-study’s conclusion were fascinating; for example, the finding that the GxE association was strongest when researchers used in-person interviews rather than self-report questionnaires. Another finding, also involving methodology, was that the accuracy of studies measuring a grab bag of different “stressful life experiences,” meaning different episodic stresses (e.g., divorce, job loss) over a long period of time suffered due to the study participants’ insufficient recall, making measurement of stresses and their impact less reliable. So, too, did the mixing of too many different types of stressful experiences.

More recent studies that zeroed in on a single type of stressful event — like experiencing a hurricane with low social support, cancer treatment, Alzheimer’s caregiving, and childhood maltreatment — showed the strongest GxE associations. With a total sample size of 27,000 individuals and an average study sample of 961, this new meta-review represents a complete validation of the original Caspi-Moffitt finding and offers the field a solid foundation from which to move forward, with clear preferences given to certain data collecting and assessment methods over others.

Two other studies demonstrate the practicality of GxE findings.

A large body of international research has shown that cannabis use moderately increases the risk of psychotic symptoms in all young people, but it has what’s called a “dose response” relationship — meaning it delivers the highest firepower — in those with an inherited predisposition to psychosis. Caspi and Moffitt were part of the research team who, in 2006, discovered the likely culprit: a risk-conferring allele that raised such a genetically loaded young person’s susceptibility to cannabis in a variation of the COMT (catechol-o-methyltransferase) gene, an enzyme which regulates the neurotransmitter dopamine. Individuals who have this allele were found to be more susceptible to psychosis by their intake of cannabis compared to those who carried another version of the COMT gene and had no family history of psychosis.

From Yale, a 2005 study offered GxE-derived insights into how a society might mitigate the harm done to young children by early maltreatment. This study, led by Joan Kaufman, compared the genotypes and emotional states of 196 children: 109 who had been physically abused and 87 non-maltreated comparison children. After taking saliva tests to document their genotypes and administering psychological tests to detect any symptoms of mental illness, researchers found a “significant three-way gene-environment interaction” between those children who had been abused and were now depressed with the presence of two genes — BDNF (brain-derived neurotrophic factor), and the same 5-HTT serotonin transporter gene featured in the Moffitt-Caspi study.

Children who had a certain allele of the BDNF gene and two short alleles of 5-HTT had the highest depression scores, but the vulnerability associated with these gene variations was only evident in maltreated children. Then the Yale researchers added a fourth factor — another environmental variable — and came up with an exception to their own rule. They found that those abused children with the vulnerable genotype who had had the benefit of social supports displayed a lower risk of depression than their counterparts who did not have the same source of emotional support in their lives.

Looking at such a result, one might say, That’s common sense. As the last decade of findings and counter-findings around the allele for depression has shown, good science looks for more; it seeks hypotheses that can be dissected and replicated. Only then can or should such guesses be applied to improving our collective human condition.

Victoria Costello is the author of  “A Lethal Inheritance, A Mother Uncovers the Science Behind Three Generations of Mental Illness.”

This article was originally published in the Spring 2012 issue of Brain World Magazine.

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