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Anxiety from infancy to adolescence
Polymorphisms in the serotonin transporter gene and temperament in children
Edward R. Winstead

In 1984, more than two thousand infants in Victoria, Australia, were enrolled in a long-term study called the Australian Temperament Project. The project now has data on the temperament and adjustment of hundreds of children from infancy to adolescence, and in recent years the project has collected DNA from many participants.

A goal of the project is to determine whether individual differences in temperament are associated with functional polymorphisms in genes such as the serotonin transporter gene. Polymorphisms in the regulatory region of this gene have been linked to anxiety and depression in adults. By influencing gene activity, the 'long' and 'short' variants may influence serotonin levels in the brain.

New research joins dozens of studies based on the Australian children's unique data. Anthony Jorm, of the Australian National University in Canberra, and colleagues recently analyzed the serotonin transporter gene and data on anxiety and behavior problems in hundreds of subjects. No significant associations were found at most ages. Some teenagers who reported increased anxiety had two copies of the long variant, however.

The researchers compared 660 individuals who had been assessed for temperament from 4-8 months to 15-16 years, and for behavioral problems from 3-4 years to 15-16 years. The analysis revealed an association between the long variant and higher anxiety in two age groups: 13-14 years and 15-16 years.

"These findings do not support an association of the short allele with anxiety-related traits in early life," the researchers write in the current issue of Molecular Psychiatry. They refer to a 1996 study reporting increased anxiety in some adults with two copies of the short variant—a finding that generated follow-up studies and inconsistent data. The reason for the discrepancy between the results is not clear.

As with any association study, the data need to be replicated. More significant than the result may be the process: Researchers are studying polymorphisms in gene candidates for psychiatric conditions and also the effects of these polymorphisms at different stages of development.

Gene expression is likely to vary somewhat with age, and association studies in one group may miss genetic clues that are present at other stages. Studies have shown, for example, that major changes in risk for depression occur during the early teenage years. "The advantage of the longitudinal data is that it allowed us to assess allelic associations at various stages of development," the researchers explain in their paper.

Children in the Australian Temperament Project are evaluated differently over time. For children younger than age 4, parents report on shyness. For children over age 4, parents include a report on anxiety, and school-age children also receive teacher evaluations. Children over age 10 begin self-reporting on depression. By the mid-teens, children, parents, and teachers all report on anxiety and depression.

A few years ago, researchers examined in infants the role of polymorphisms in two genes linked to temperament—the serotonin transporter gene and the dopamine D4 receptor gene. The researchers used a neonatal assessment scale to evaluate temperament in 81 two-week-old infants. Two months later, the infants were reevaluated using an infant behavior questionnaire.

An analysis of the survey data and DNA revealed, for example, that polymorphisms in the dopamine D4 receptor gene were associated with orientation and motor organization, while polymorphisms in the serotonin transporter gene were not.

On the basis of these results and the 1996 study in adults, the Australian group hypothesized that the serotonin transporter gene is associated with the temperamental trait of approach-withdrawal (shyness) and behavior problems involving anxiety or depression. The trait of approach-withdrawal in childhood has been a predictor of anxiety in adolescence, according to the researchers.

The Australian researchers have four goals for the project: determining whether polymorphisms play a role in individual differences in personality traits; determining whether associations vary with age from infancy to adolescence; assessing the specific contributions of genetic and environmental factors in behavior disorders; and elucidating the mechanisms by which 'nature' can have an effect on 'nurture.' Specifically, that means determining whether candidate polymorphisms are associated with differences in children's social environment, such as child-rearing practices or relationships with peers.

See related GNN article
»Mood, food, and anxiety: The serotonin transporter gene

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Jorm, A.F. et al. Association of a functional polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens. Mol Psychiatry 5, 542-547 (September 2000).

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