Sydney researchers identify bipolar gene

Researchers at Sydney's Garvan Institute have identified a gene coding for a cell-adhesion molecule in the brain as a strong risk factor for bipolar disorder, or manic depression.

Dr Ian Blair and his colleagues -- Dr Peter Schofield (now at the Prince of Wales Medical Research Institute), Dr Philip Mitchell (Black Dog Institute), and Dr Jenny Donald (Macquarie University) -- have linked a variant of the cadherin gene FAT, on chromosome 4, as a contributor to susceptibility to bipolar disorder.

Blair told the recent Lorne Genome Conference on Victoria's Phillip Island that family pedigree studies have produced many promising leads for manic depression susceptibility genes, but most have turned out to be false positives. Promising leads in Icelandic and Pennsylvanian Amish pedigrees in the early 1990s led nowhere.

Blair said identical twin studies show that while bipolar disorder does not have a simple, Mendelian pattern of inheritance in affected families.

But bipolar disorder is strongly inherited - genes, rather than environmental factors, account for about 75 per cent of the risk, and linkage studies have indicated that important susceptibility genes lie on chromosomes 4, 12, 12, 18 and 22.

Blair said that, while for the general population the lifetime risk of developing bipolar disorder is around 1.5 per cent, it is much higher in families with a history of the disorder.

During the manic phase, individuals with bipolar disorder -- the sexes are affected equally -- tend to become hyperactive, over-talkative and euphoric, and have inflated self-esteem.

They require little sleep, and indulge in impulsive behaviours such as overspending. They may become irritable, exhibit hypersexual behaviour, and suffer delusions and hallucinations.

During the depressive phase, subjects become moody and withdrawn, suffer from insomnia and a lack of sexual desire, and lose their appetites.

Blair's team decided to pursue the lead on chromosome 4, and traced the suspect gene to a 5-megabase segment just before the telomere 'cap' on the lower arm the chromosome.

The region is gene-poor; the Garvan team sequenced all genes in the region, and used the data to make predictions about the structure of their proteins.

Using known single-nucleotide polymorphisms (SNPs) from the region, they ran a comparative analysis of SNPs in affected and unaffected relatives in their extended family pedigrees.

When the analysis detected no consistent differences, they sequenced each exon, and the flanking sequences, from all 22 genes from an unaffected individual and used it as a template to identify SNPs in their cohort. They identified 84 SNPs, one of which featured consistently in the FAT cadherin gene in those with bipolar disorder.

"It could still be a false positive, but we have identified the sameassociation [with the FAT polymorphism] in two UK cohorts and a Bulgarian cohort," Blair said. In the Bulgarian cohort, and one UK cohort, a number of patients have suffered severe psychotic episodes throughout their lives.

All the polymorphisms cluster at the 3' end of the gene, within a 9-kilobase block, that codes for the 'tail' of the FAT protein -- this domain anchors the FAT protein to beta catenin, a protein that forms part of the cytoskeleton of the cell.

The same tail region of FAT is also involved in sequestering other proteins involved in intercellular signalling, suggesting that the FAT-beta catenin interaction has an essential role in the surface dynamics of cells.

Blair's team has begun preliminary function studies with real-time PCR and microarray analysis, to determine whether the expression of FAT and its associated proteins differs in bipolar and normal patients.

Blair said that, in a mouse model of bipolar disorder, therapeutic doses of the widely used anti-manic drug lithium, which regulates gene transcription, down-regulate the FAT gene. He suspects reduced FAT expression may loosen the connections between nerve cells.

Significantly, the lithium-induced downregulation of FAT takes about 1-2 weeks to kick in -- matching the typical delay between lithium medication and mood improvement in bipolar patients.

Blair said the identification of FAT as a bipolar susceptibility gene could allow clinicians to discriminate between patients who were likely to respond to lithium, and those who would benefit from other anti-manic drug