A MUTATION has been discovered that almost always causes severe depressive disorders in women who have it. The finding shows that in at least some cases, genes can play a key role in determining our mental state.
The mutation, in a gene known as CREB1, is rare, but 9 out of the 11 women in whom it has been discovered so far suffer from episodes of severe depression, a team at the University of Pittsburgh in Pennsylvania reports. That is the strongest link between a genetic mutation and a mental illness ever reported. 鈥淭he Huntington鈥檚 disease gene is rare, but if you have it, you develop the disease,鈥� says lead researcher George Zubenko. 鈥淭his isn鈥檛 100 per cent, but it鈥檚 knocking on the door.鈥�
The team made the discovery after studying 1200 individuals from 81 families with a history of depressive disorders. The mutation stops one protein binding to a 鈥減romoter region鈥� and switching on production of the CREB protein, probably causing a drop in overall CREB levels. It does not alter the sequence of the protein.
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Another CREB1 mutation, this time in an area of non-coding or so-called 鈥渏unk鈥� DNA, has the opposite effect. It seems to protect against depression: none of the women found to have it suffered from depressive disorders.
It is thought that genetic factors play a role in up to two-thirds of cases of severe depressive disorders, and the team estimates that mutations in CREB1 could account for up to 10 per cent of cases in the families they studied. But understanding how it has this effect is not going to be easy. The CREB protein helps regulate the activity of several other genes and appears to have numerous functions in all sorts of tissues. It is thought to play a role in basic processes such as the sleep-wake cycle that are disrupted in depression.
There is also evidence that part of the protein interacts with oestrogen receptors, and so helps determine how cells respond to oestrogen. That could be why men with the CREB1 mutation do not suffer from depression, and it might also help explain why women are twice as susceptible to depression as men.
Zubenko鈥檚 theory that disruption of CREB production is what causes depression in women with the mutation fits well with other studies, says Bruce Cohen of McLean Hospital at Harvard University. 鈥淚t is exactly the level of CREB expression, the amount of protein made, that seems to figure in animal studies.鈥� If this is the case, it might be possible to find new ways to treat severe depression by working out which genes CREB switches on or off, and then finding drugs that can do the same thing.