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Gene More Than Doubles Risk Of Depression Following Life Stresses
Last Updated: Dec. 1, 2003
Among people who suffered multiple stressful life events over five years, 43% with one version of a gene developed depression, compared to only 17% with another version of the gene, say researchers funded, in part, by the National Institute of Mental Health (NIMH).
Those with the "short," or stress-sensitive version of the serotonin transporter gene were also at higher risk for depression if they had been abused as children. Yet no matter how many stressful life events they endured, people with the "long" or protective version experienced no more depression than people who were totally spared from stressful life events. The short variant appears to confer vulnerability to stresses, such as loss of a job, breaking up with a partner, death of a loved one, or a prolonged illness, report Drs. Avshalom Caspi and Terrie Moffitt, University of Wisconsin and King's College London, and colleagues, in the July 18, 2003 Science.
“We found the connection only because we looked at the study members’ stress history,” Moffitt noted. She suggested that measuring such pivotal environmental events — which can include infections and toxins as well as psychosocial traumas — might be the key to unlocking the secrets of psychiatric genetics.
Although the short gene variant appears to predict who will become depressed following life stress about as well as a test for bone mineral density predicts who will get a fractured hip after a fall, it’s not yet ready for use as a diagnostic test, Moffitt cautioned. If confirmed, it may eventually be used in conjunction with other, yet-to-be-discovered genes that predispose for depression in a “gene array” test that could help to identify candidates for preventive interventions. Discovering how the “long” variant exerts its apparent protective effect may also lead to new treatments, Moffitt added.
Everyone inherits two copies of the serotonin transporter gene, one from each parent. The two versions are created by a slight variation in the sequence of DNA in a region of the gene that acts like a dimmer switch, controlling the level of the gene’s turning on and off. This normal genetic variation leads to transporters that function somewhat differently. The short variant makes less protein, resulting in increased levels of serotonin in the synapse and prolonged binding of the neurotransmitter to receptors on connecting neurons. Its transporter protein may thus be less efficient at stopping unwanted messages, Moffitt suggests.
Moffitt and colleagues followed 847 Caucasian New Zealanders, born in the early l970s, from birth into adulthood. Reflecting the approximate mix of the two gene variants in Caucasian populations, 17% carried two copies of the stress-sensitive short version, 31% two copies of the protective long version, and 51% one copy of each version.
Although carriers of the short variant who experienced four or more life stresses represented only 10% of the study participants, they accounted for nearly one quarter of the 133 cases of depression. Among those with four or more life stresses, 33% with either one or two copies of the short variant — and 43% of those with two copies of the short variant — developed depression, compared to 17% of those with two copies of the long variant.
The stressful life events led to onset of new depression among people with one or two copies of the short gene variant who didn’t have depression before the events happened. The events failed to predict a diagnosis of new depression among those with two copies of the long variant.
The researchers suggest that effects of genes in complex disorders like psychiatric illnesses are most likely to be uncovered when such life stresses are measured, since a gene’s effects may only be expressed, or turned on, in people exposed to the requisite environmental risks.
Source: National Institute of Mental Health (NIMH)
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