The concept of gene-environment interaction (GEI) is both intellectually and clinically appealing. It proposes that genes act on risk of illness in part by modulating the response of the organism to environmental stressors. A number of prior studies, using twin and adoption methods, have found evidence for GEI for a range of psychiatric disorders using traditional latent-variable models.

“People differ in a reliable manner in their capacity for coping with adversity. That is, some people are more sensitive to the depressogenic effects of stress than are others.”

Given this context, the two Science articles of Caspi and coworkers demonstrating interactions between specific genes and specific environments impacting on the risk for antisocial behavior—14560: A. Caspi, J. McClay, T. E. Moffitt, J. Mill, J. Martin, I. W. Craig, A. Taylor, and R. Poulton, "Role of genotype in the cycle of violence in maltreated children," Science 297 (5582):851-854, 2002—and depression—14737: A. Caspi, K. Sugden, T. E. Moffitt, A. Taylor, I. W. Craig, H. Harrington, J. McClay, J. Mill, J. Martin, A. Braithwaite, and R. Poulton, "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene," Science 301 (5631):386-389, 2003—generated a high level of interest in the psychiatric and psychology communities.

However, given the prior track record of gene-finding studies for psychiatric disorders, where high-profile positive reports were followed by multiple non-replications, there was a lot of anticipation waiting to see if other groups could replicate these findings. Furthermore, the original Caspi report on the serotonin transporter and depression had some methodological limitations, especially in their assessments of stressful life events, that we were able to address.

The new finding in this report—I would hesitate to call it a "discovery"—which should still be viewed as tentative, is that variation at the serotonin transporter shifts sensitivity to adversity. Individuals with two short alleles have a substantial elevation in risk for major depression after modestly stressful life events that do not impact at all on depressive risk in individuals with other genotypes at this locus.

People differ in a reliable manner in their capacity for coping with adversity. That is, some people are more sensitive to the depressogenic effects of stress than are others. We already knew from prior studies that part of this difference in stress-sensitivity is genetic. This study, in replicating, at least in part, the prior report of Caspi and coworkers (14737), suggests that we are now able to begin to identify the specific genetic variants that may be responsible for these differences between individuals.

I went to medical school and decided to become a psychiatrist because I was deeply interested in the workings of the human mind and felt that we were just beginning to have the scientific tools to enable us to explore these questions in a rigorous manner. I was attracted to psychiatric genetics in the late 1970s, while still a resident in psychiatry, because of the strength of the research findings.

Psychiatric disorders run strongly in families and twin and adoption studies have consistently shown that most of this tendency is due to genetic factors. I was also then increasingly disenchanted with the very simplistic neurochemical theories for psychiatric illness. When I began working in this area, none of us could imagine the explosion of knowledge and techniques that would emerge with the advent of molecular genetics.

It has been a wonderful career. For me, it has been and remains a major challenge to conduct high-quality research in psychiatric genetics, which requires a synthesis of my clinical skills and knowledge of psychiatric illness, expertise in statistical genetics, and my modest knowledge base in molecular genetics that I constantly struggle to keep up with.

Equally important, this study and nearly all good work done in psychiatric genetics, is deeply collaborative. My coauthors made critical contributions to this work, especially Brien Riley, Carol Prescott, and Jonathan Kuhn.

Psychiatric illness is a major cause of suffering (or, more technically, morbidity and mortality) in our society and around the world. The science of psychiatry is young and still maturing. We have increasingly powerful tools and the hope is that if properly funded from government and private sources, we can, over the next several decades, make important advances in our understanding of the major psychiatric disorders—such as schizophrenia, depression, and alcoholism. These advances have the possibility of substantially increasing our ability to treat and hopefully prevent these disorders. As our understanding increases, we can hope that the stigma of psychiatric illness, which still prevents many from seeking treatment, can be lessened.