A GENE that leaves its carriers prone to depression works by weakening a critical circuit in the brain, according to new research that offers important clues to the commonest form of mental illness.

Changes in the way that the brain handles stress and negative emotion may explain why inheriting a particular version of a gene called 5-HTT doubles the risk of depression after traumatic events such as bereavement or divorce, scientists have discovered.

The link between 5-HTT and depression, which strikes one in five people at some point in their lives, was established two years ago by a team at King’s College London, but the biological mechanisms behind it were not previously understood.

The findings, by researchers at the US National Institute of Mental Health (NIMH) in Bethesda, Maryland, published today in the journal Nature Neuroscience, could have implications for the treatment of an illness recognised by the World Health Organisation as the fourth-largest cause of long-term disability. It may suggest new antidepressant drugs.

The 5-HTT gene controls how the brain uses serotonin, a critical signalling chemical that is strongly linked to mood. The gene comes in two types, one long and one short, and each person inherits two copies, one from each parent.

A team led by Daniel Weinberger at NIMH scanned the brains of 94 people while they watched images showing fearful faces. This is known to activate the amygdala, a brain region that processes fear, and the cingulate, which handles emotion. These two circuits, the researchers found, were “playing a duet under the baton of the depression-linked gene”. In people with two short versions of 5-HTT, the circuits were less active and were structured differently: they contained less grey matter — the type of brain tissue specialised for performing complex tasks — and had weaker connections between neurons.

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