NSW researchers in depression gene find

Winston Churchill called it his 'black dog'. Abraham Lincoln suffered from bipolar disorder, as did German composer Robert Schumann, and Dutch artist Vincent van Gogh. And a slew of poets including Alfred Lord Tennyson, William Blake, Edgar Allan Poe, Lord Byron and Sylvia Plath lived with manic depression.

Geneticists have spent two decades hunting a gene -- any gene -- involved in hereditary susceptibility to bipolar disorder. The quest took them to Iceland, and Amish country in Pennsylvania, and many other places with insular populations with a history of manic depression. Every time, promising leads petered out.

But researchers from Sydney's Garvan Institute and the University of NSW are now convinced that they have the world's first, authentic, susceptibility gene for bipolar disorder.

Three independent lines of inquiry, and four independent bipolar disorder cohorts, led them to the same gene: the cellular adhesion gene FAT, at 4q35, near the tip of the long arm of chromosome 4.

The lead author of the paper announcing the discovery in this month's Journal of Molecular Psychiatry Dr Ian Blair, of Sydney's Garvan Research Institute, said the project began collecting families with a history of bipolar disorder 20 years ago.

"Our genetic studies have been going on for a decade," he said. "We started with the whole genome, and narrowed it down to a region right on the end of chromosome 4, which contains 18 genes expressed in the brain.

"We then turned to a second line of evidence -- association studies. We looked at four patient cohorts -- one in Australia, two in the UK and another in Bulgaria, and found evidence of an association between bipolar disorder and one of the 18 genes -- FAT.

"Our third line of evidence involved treating mice with two medications currently prescribed for bipolar disorder -- lithium and valproate -- to see how they affect expression of the brain-active genes on chromosome 4. Both drugs significantly change expression of the FAT gene."

Blair said that, to be "absolutely certain", his team now wanted others to replicate its study.

The international project involved researchers from the Garvan Institute, the University of NSW, Macquarie University, the University of Wales in Cardiff, and the Prince of Wales Hospital.

One of Dr Blair's co-workers, Dr Phil Collins, of the University of NSW, said it was notable that Australian researchers had discovered the first susceptibility gene, given that an Australian, Dr Ian Cade, had discovered the world's first effective treatment for bipolar disorder -- lithium salts. Cade made his discovery in the early 1950s. US psychiatrists did not begin using lithium until the early 1970s.

Collins said it is still not clear how lithium works to alleviate bipolar disorder, but it has "held up very well, in terms of efficacy" during the past half century.

The role of the FAT gene in bipolar disorder is also unclear -- as a cadherin, it is involved in the formation of physical links between neurons in the brain, but researchers are now working to determine how the high-allele alters normal brain function.

The alteration of brain function has both positive and negative effects. Collins said that the high creativity often associated with bipolar disorder suggests it may be an example of a balanced polymorphism: a gene with a deleterious effect (melancholia and high suicide risk) that also confers some advantage in survival and reproduction (artistic creativity). Many bipolar subjects have very highly developed skills in written and oral expression, including a talent for rhyming. Some of the world's most gifted poets have suffered from bipolar disorder.

Collins said that if researchers can determine how the high-risk FAT allele alters mood and brain function, it may be possible to develop new, targeted drugs that may be relatively free of the side effects of lithium and valproate.