Gene variant increases depression risk for abused children

Scientists at the University of Melbourne have produced further evidence linking a particular variant of the brain’s serotonin transporter (SERT) gene to an increased risk of severe depression in individuals who suffered sexual or physical abuse as children.

In their study of 333 middle-aged Victorians, published in the The British Journal of Psychiatry in September, Dr Chad Bousman and his colleagues from the Melbourne Psychiatry Centre uncovered a seemingly paradoxical effect: individuals who inherit the same SERT gene variant, but do not experience abuse as children, are significantly happier as adults than the rest of the population.

Dr Bousman’s team tracked the life trajectories of their subjects for five years, using a verbal rating scale to assess any depressive symptoms.

Dr Bousman says the SERT gene comes in two basic forms, or alleles — short (S) and long (L) — which are inherited in Mendelian fashion. From their parents, people variously inherit either a long/long, long/short or short/short combination.

He says the short and long alleles of the SERT gene differ in the length of their promoters, the DNA sequence that regulates the gene’s expression. Both code for the same receptor protein, but the short promoter results in lower expression of SERT in the brain. Compared to the brains of individuals with the LL and SL genotypes, individuals with the SS combination have fewer serotonin receptors.

At a mechanistic level, after a neuron releases a pulse of serotonin into the synapse (the tiny gap between neurons), the mood-regulating neurotransmitter is rapidly recycled — the serotonin transporter traps the molecules and returns them to storage vesicles in the neuron that released them.

The class of modern antidepressants called selective serotonin reuptake inhibitors (SSRIs) targets the SERT receptor. By inhibiting SERT, they prolong the time that serotonin remains active in the synapse.

Dr Bousman says that, despite being at greatest risk of severe depression after suffering sexual or physical abuse as children, those with the SS genotype are more resilient and happier as adults, despite life’s slings and arrows.

He says his team’s findings challenge traditional thinking about depression and those who are at greatest risk of depression as adults.

“Our findings suggest that as children, individuals with the SS genotype are more sensitive both to good and bad environmental events.”

Dr Bousman says psychiatry has two competing frameworks to explain susceptibility to depression — the first, which suggests certain alleles that confer an increased risk of depression, fails to explain his team’s findings.

The second suggests that there are plasticity alleles that cause the individual’s brain to react more strongly both negative and positive life experiences — in childhood, the brain is highly plastic and more susceptible to being ‘rewired’ by life experiences.

If childhood experiences are positive, the individual is more likely to be a happy adult. But if they are negative — if, for example, a child is sexually or physically abused — the brain is more likely to be rewired in a way that makes the person susceptible to depression in adulthood. The brains of individuals with the SS SERT genotype are the most plastic — and most susceptible to ‘negative’ rewiring.

Asked if his findings might lead to better diagnosis and treatment for adults suffering from severe depression as a result of childhood abuse, Dr Bousman said, “I’d like to say yes, but we’re not there yet. The SERT gene is one piece of a very complex puzzle.

“It’s only one polymorphism, and not yet diagnostic — it’s one of the low-hanging fruits. We are working to identify polymorphisms in other genes implicated in depression that we could integrate to produce a polygenic measure of a person’s genetic susceptibility to depression.”

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