5-HTTLPR: A Pointed Review

In 1996, some researchers discovered that depressed people often had an unusual version of the serotonin transporter gene 5-HTTLPR. The study became a psychiatric sensation, getting thousands of citations and sparking dozens of replication attempts (page 3 here lists 46).

Soon scientists moved beyond replicating the finding to trying to elucidate the mechanism. Seven studies (see herefor list) found that 5-HTTLPR affected activation of the amygdala, a part of the brain involved in processing negative stimuli. In one especially interesting study, it was found to bias how the amygdala processed ambiguous facial expression; in another, it modulated how the emotional systems of the amygdala connected to the attentional systems of the anterior cingulate cortex. In addition, 5-HTTLPR was found to directly affect the reactivity of the HPA axis, the stress processing circuit leading from the adrenal glands to the brain.

As interest increased, studies began pointing to 5-HTTLPR in other psychiatric conditions as well. One study found a role in seasonal affective disorder, another in insomnia. A meta-analysis of twelve studies found a role (p = 0.001) in PTSD. A meta-analysis of twenty-three studies found a role (p = 0.000016) in anxiety-related personality traits. Even psychosis and Alzheimer’s disease, not traditionally considered serotonergic conditions, were affected. But my favorite study along these lines has to be 5-HTTLPR Polymorphism Is Associated With Nostalgia-Proneness.

Some people in bad life situations become depressed, and others seem unaffected; researchers began to suspect that genes like 5-HTTLPR might be involved not just in causing depression directly, but in modulating how we respond to life events. A meta-analysis looked at 54 studies of the interaction and found “strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (P = .00002)”. This relationship was then independently re-confirmed for every conceivable population and form of stress. Depressed children undergoing childhood adversity. Depressed children with depressed mothers. Depressed youth. Depressed adolescent girls undergoing peer victimization. They all developed different amounts of depression based on their 5-HTTLPR genotype. The mainstream media caught on and dubbed 5-HTTLPR and a few similar variants “orchid genes”, because orchids are sensitive to stress but will bloom beautifully under the right conditions. Stories about “orchid genes” made it into The Atlantic, Wired, and The New York Times.

In 1996, some researchers discovered that depressed people often had an unusual version of the serotonin transporter gene 5-HTTLPR. The study became a psychiatric sensation, getting thousands of citations and sparking dozens of replication attempts (page 3 here lists 46).

Soon scientists moved beyond replicating the finding to trying to elucidate the mechanism. Seven studies (see herefor list) found that 5-HTTLPR affected activation of the amygdala, a part of the brain involved in processing negative stimuli. In one especially interesting study, it was found to bias how the amygdala processed ambiguous facial expression; in another, it modulated how the emotional systems of the amygdala connected to the attentional systems of the anterior cingulate cortex. In addition, 5-HTTLPR was found to directly affect the reactivity of the HPA axis, the stress processing circuit leading from the adrenal glands to the brain.

As interest increased, studies began pointing to 5-HTTLPR in other psychiatric conditions as well. One study found a role in seasonal affective disorder, another in insomnia. A meta-analysis of twelve studies found a role (p = 0.001) in PTSD. A meta-analysis of twenty-three studies found a role (p = 0.000016) in anxiety-related personality traits. Even psychosis and Alzheimer’s disease, not traditionally considered serotonergic conditions, were affected. But my favorite study along these lines has to be 5-HTTLPR Polymorphism Is Associated With Nostalgia-Proneness.

Some people in bad life situations become depressed, and others seem unaffected; researchers began to suspect that genes like 5-HTTLPR might be involved not just in causing depression directly, but in modulating how we respond to life events. A meta-analysis looked at 54 studies of the interaction and found “strong evidence that 5-HTTLPR moderates the relationship between stress and depression, with the s allele associated with an increased risk of developing depression under stress (P = .00002)”. This relationship was then independently re-confirmed for every conceivable population and form of stress. Depressed children undergoing childhood adversity. Depressed children with depressed mothers. Depressed youth. Depressed adolescent girls undergoing peer victimization. They all developed different amounts of depression based on their 5-HTTLPR genotype. The mainstream media caught on and dubbed 5-HTTLPR and a few similar variants “orchid genes”, because orchids are sensitive to stress but will bloom beautifully under the right conditions. Stories about “orchid genes” made it into The Atlantic, Wired, and The New York Times.