Bad news. The short allele of the 5-HTT gene can predispose those who carry it to depression when misfortune strikes.

Getting the Short End of the Allele

Ophelia couldn't handle Hamlet's abuse and drowned herself. But others get through painful events without a lot of melodrama. Now scientists claim they've identified a gene that helps determine whether people get depressed in response to life stresses.

The gene encodes a chemical transporter called 5-HTT that fine-tunes transmission of serotonin, the neurotransmitter affected by antidepressants like Prozac. It comes in two common versions, the long (l) allele and the short (s) allele. In the 18 July issue of Science, a team headed by Avshalom Caspi at the Medical Research Council's psychiatry research center at King's College, London, reports that people with s alleles are more likely to get depressed.

The study is based on data from 847 New Zealanders the scientists have been following for more than 2 decades. The researchers counted stressful life events, such as romantic disasters and job crises, occurring between the ages of 21 and 26 and asked subjects whether, at age 26, they had been depressed in the past year. For those whose lives had gone smoothly, the probability of depression was the same regardless of their 5-HTT alleles. But adverse experiences had more negative effects among people with one s allele and more still for those with two s alleles. For the latter (17% of the group), the probability of a major depression rose to 43% among those who had been through four or more stressful experiences--more than double the risk for those with two l's. Furthermore, among the 73 subjects who had been severely abused as children, the two-s subjects ran a 63% risk of a major depressive episode after the age of 18. In contrast, abused subjects with two l's had the same average risk (30%) as the no-abuse group.

It's "absolutely spectacular" work and the biggest genetic fish yet netted for psychiatry, says psychiatrist Daniel Weinberger of the National Institute of Mental Health. The study shows that genes related to psychiatric ills don't operate all by themselves, Weinberger adds, but help determine “how one deals with the environment." Indeed, one reason the hunt for psychiatric illness genes has been so frustrating, says co-author Terrie Moffitt, is that most studies haven't looked at environmental exposure--which is like trying to find malaria susceptibility genes in a sample that includes people living in mosquito-free places.

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A previous study on violence, from the same group