A team led by Terrie Moffitt, of the Institute of Psychiatry, King’s College, London, looked at the development of depression after stressful life events among 847 people who had been enrolled in the Dunedin Multidisciplinary Health and Development Study. This representative birth cohort of New Zealanders has been studied in detail for almost 30 years. Moffitt’s group looked at their experiences of stressful life events between the ages of 21 and 26 and their experience of depression in the year before the study. They also grouped the subjects according to their genotype, in particular their alleles of the promoter region of the serotonin transporter gene 5-HTT. A short version of the promoter is associated with less-efficient transcription of the gene, and in experimental animals is linked to more fearful and anxious behavior. In humans, drugs that increase the amount of serotonin alleviate the symptoms of depression.

In the study group, 17% were homozygous for the short allele, 51% were heterozygous with one short and one long allele, and 31% were homozygous for the long allele. While there was no difference among the groups for the number of stressful life events experienced, there was a clear effect on depression. People with two short alleles were much more likely to suffer a major depressive episode than people with two long alleles. Heterozygotes fell roughly in the middle. The effect on thoughts of suicide was even stronger.

"It was such a wonderful result we all thought it couldn’t possibly be true," Professor Guy Goodwin, Head of the Department of Psychiatry at Oxford University, tells Science Watch. In paper #3, Crespi et al were equally circumspect. "Until this study’s findings are replicated," they wrote, "speculation about clinical implications is premature."

"Much to their surprise," said Goodwin, studies have now replicated the result. (See, for example, K.S. Kendler, et al., "The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication," Arch. Gen. Psychiat., 62[5]:529-35, 2005.)

The interaction between genotype and environment uncovered by Moffitt’s group makes sense of the failure previously to find strong links between genes and psychiatric disorders such as depression, probably because earlier studies did not look in detail at stressful life events. A gene may have effects only on family members exposed to particular events. Likewise, if different individuals in a sample experience different stresses, the effects of the gene may be masked. Moffitt suggests that the variant form of the 5-HTT promoter protects its owner from environmental pathogens, like many other variant genes present in populations at high levels. However, she extends the notion of environmental pathogens to encompass "traumatic, stressful life experiences" and speculates that some multifactorial disorders, which people had previously assumed to be caused by variations in many genes with small effects, may instead be caused by fewer genes but be conditional on environmental factors.