Biotech looks for bipolar genes

Geneticists have nothing to show after more than a decade hunting for genes involved in bipolar disorder, or manic depression -- even in depression-haunted families in Iceland, and among Pennsylvania's Amish, the quarry has remained elusive.

But a Sydney research team believes it may have cornered a gene that causes susceptibility to manic depression that could provide the long-sought entry point into the biochemical maze underlying the disorder.

Prof Peter Schofield of the Garvan Institute of Medical Research, geneticist Dr Jennifer Donald of Macquarie University, and psychiatrist Prof Phillip Mitchell at the Prince of Wales Hospital have received a $780,000 NHMRC project grant to isolate the gene, which linkage studies have traced to the lower end of chromosome 4.

The Sydney team's approach will be to identify candidate brain-function genes, then check for single-nucleotide polymorphisms (SNPs), or single-letter variations in the gene's code, that consistently appear in affected individuals in the families that they have been studying.

Geneticists have recently used a similar approach to identify four candidate genes involved in susceptibility to the similarly enigmatic brain disorder, schizophrenia.

The auditory and visual hallucinations of schizophrenia appear to involve spontaneous activity in the brain's sensory systems. All four genes are players in the excitatory neural circuitry coordinated by the neurotransmitter N-methyl D-aspartate (NMDA) -- abnormal excitation of these sensory pathways would explain these symptoms.

"Suddenly, some biology is starting to emerge from genetic studies of schizophrenia, so researchers can start asking therapeutic and diagnostic questions," Schofield says. "You may then think about moving to preventative strategies."

"We don't have that with bipolar disorder -- nobody has yet found a susceptibility allele."

There's a tendency, particularly by the media, to think of inherited disorders in terms of 'good' genes, and 'bad' or mutant genes, says Schofield. But most patients are relatively normal between the euphoric highs and black depths of manic depression.

The disorder may involve variants of several genes that are otherwise 'normal', but in combination, cause the extreme mood swings of manic depression, with the severity depending on the luck of the genetic draw.

Schofield and his colleagues were gratified that their project received a Category 6 rating in the NHMRC assessment process. "Most of the highly-ranked projects were substantially supported -- we got everything we asked for," he says.

A decade ago, after a long search, geneticists found a gene involved in Huntingdon's disease hidden among so-called 'junk' DNA in the gene-sparse telomeric region at the top end of chromosome 4.

Telomeric regions are difficult prospecting territory for genes, says Schofield, and it will be "hard slog" to isolate and investigate candidate manic depression genes.

About 0.8 per cent of the population suffers from manic depression, a disorder that has both inspired and haunted many of history's great artists, composers, poets and comedians -- people like Vincent van Gogh, Robert Schumann, Alfred Lord Tennyson, Australia's Henry Lawson, Spike Milligan, Tony Hancock and actor Robin Williams.

"To me, one of the intriguing issues is that while we are undertaking this study because manic depression is a serious illness with a high social cost, there will be spin-offs," Schofield says.

"Finding the gene would allow us to find out how the brain normally works, and why there is such a strong association between manic depression and creativity."