21 Jul 2003

Some foods only reveal their flavor after you add a dash of salt. Similarly, say the authors of an article in the July 18 issue of Science, some genes only show an association with disease when environmental factors are taken into account.

Terrie Moffitt and colleagues in England, the U.S., and New Zealand asked why stressful experiences lead to depression in some people and not others. They found that a functional polymorphism in a serotonin-related gene will only show an association with depression in response to adverse life events. Apropos the venerable question of nature vs. nurture, genes vs. environment, these results suggest that psychiatric geneticists need to think more about how the "salt" of environmental factors brings out the "flavor" of certain genes.

A common polymorphism in the promoter region of the serotonin transporter (5-HTT) would seem to be an obvious bet for modulating depression, given the powerful effects of serotonergic therapeutics in the disorder. Yet, previous research had failed to detect such an effect. In the current study, Moffitt and colleagues studied this polymorphism in the light of events such as unemployment, homelessness, relationship problems, or physical or sexual abuse, which do influence depression. The researchers found that people with one or two copies of the short version of the 5-HTT promoter-which results in less total 5-HTT-were significantly more likely to experience depression in the aftermath of stressful life events, compared to people with two long alleles. This correlation held true for various measures of depression symptoms, diagnosable depression, and suicide.

Beyond the possible diagnostic implications for depression, the study addresses the question of why it has been so difficult to find or confirm genes that cause complex psychiatric or neurodegenerative diseases. This is a problem that besets AD genetics, in particular. That there is a genetic contribution to these diseases is quite clear, and a common assumption has been that, most likely, many genes, each with very small contributions, make up the sum genetic contribution. But the authors suggest that variations in fewer genes-"whose effects are conditional on exposure to environmental risks"-may be the nature side of the nature/nurture equation.

For example, the authors note, "incomplete gene penetrance, a major source of error in linkage pedigrees, can be explained if a gene's effects are expressed only among family members exposed to environmental risk. If risk exposure differs between samples, candidate genes may fail replication."—Hakon Heimer