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Science, People & Politics,Volume 1, 19.3.06.

Psychiatry and Genetics reach a cross road

by Helen Gavaghan

Depending on who you talk to, and whose work you read, the field of psychiatry and genetics is undergoing a revival, or it is in serious trouble -- or -- it is at a cross roads. What is certain is that the literature is alive with new papers containing hopeful prognostications with more papers waiting in the wings, whilst in the UK the Medical Research Council is preparing for two focus meetings on the topic this summer. In need of evaluation is whether an initiative spanning UK government funding bodies which has pumped cash into the field of brain research for four years is paying off.

Much of the research internationally, not only that in the UK, is focussed on Schizophrenia and, secondly, bi-polar disorder; two illnesses that can be debilitating and which are known to be genetically complex. They are also at opposing ends of a spectrum of overlapping psychiatric conditions with a so-called psychotic component (in my view one of the most foolish words in the medical lexicon).

As recently as October 2005 Kalpana Merchant and Gerard Marek from Ely Lilly wrote in NeuroRx, the Journal of the American Society for Experimental NeuroTherapeutics, that "Recent breakthroughs in genetic studies of schizophrenia offer for the first time, a hypothesis-driven approach for the development of disease modifying therapy for this debilitating disorder".

Inspiration for this encomium were studies stemming from a paper published in The Lancet in 2003 by Paul Harrison, a psychiatrist and researcher at the University of Oxford, and Michael Owen from the University of Wales. They listed seven genes that linkage and association studies had suggested might be schizophrenia susceptibility genes and hypothesized a pathogenesis for schizophrenia that centred on the role of these genes in synaptic formation and glutaminergic signalling in the prefrontal cortex. Other synaptic transmissions, for example dopaminergic and GABAergic, in and around the same synapses would modulate events.

The impact of impaired signalling of neurotransmitters at these synapses would plausibly be to reduce volition and complex analytic thinking, which are the negative and cognitive symptoms of schizophrenia and related so-called psychoses. The positive symptoms, hallucinations of various kinds (which can also be drug induced), are thought to be connected to dopaminergic pathways. Interactions among the pathways would mean that the seven genes identified in the Harrison-Owen hypothesis could affect positive symptoms also.

Though one of the seven genes in Harrison's and Owen's hypothesis (RSG4) has turned out, says Harrison, not to be a good schizophrenia susceptibility gene the hypothesis is, in general, holding up well and becoming more sophisticated. He is, he says, speaking with all the major pharmaceutical companies about his work and they are currently deciding their strategy within the field.

In essence the research strategy that Harrison is applying is the one which worked for John Hardy, now head of clinical neurogenetics at the National Institute on Aging , in Bethesda, Maryland in the US for the work he led on Alzheimer's Disease. Hardy himself does not think the strategy that worked for him will work with schizophrenia or bi-polar disorder, even though, he says, some of the cognoscenti thought prior to his discoveries that it would actually be Schizophrenia not Azheimer's which would yield its secrets first in the post genomic age.

Within the strategy that worked for Hardy researchers are hoping for strongly replicated studies which confirm that a susceptibility gene for a particular genetically complex illness is indeed a susceptibility gene. They would then hope to identify specific polymorphisms: that is to pinpoint variations of one base in the genetic code, and to associate that polymorphism (single nucleotide polymorphism-SNP) or, possibly, unique collection of polymorphisms or SNPs (a haplotype) with a specific biological factor that might plausibly be connected with what is known to be symptomatic of schizophrenia, say, or bipolar disorder. That done, the drug companies would have a biological pathway and steps on that pathway to turn into research targets.

The main difficulty with this approach, according to Robin Murray, a professor of psychiatry who I interviewed at the Institute of Psychiatry at King's College, London, is that in his opinion the predictive value that each of the current candidate susceptibility genes for schizophrenia has could be as little as 1 to 10 per cent. Murray, who is a world expert on schizophrenia with expertise in bi-polar disorder, argues that more and larger epidemiology studies are needed to improve the quality of linkage studies (where two segments of DNA on the same chromosome are inhertited together) and association studies.

As of now the strongest candidate schizophrenia susceptibility genes are Neuregulin, Dysbindin, DISC and COMT. Neuregulin, Dysbindin and COMT were among the original seven in the Harrison and Owen hypothesis. DISC was not. Since then Neuregulin is the gene where association and linkage studies have been replicated most strongly.

COMT is the gene about which most has been written concerning downstream biology. The gene codes for the enzyme catchol-O-methyltransferase. The enzyme degrades catecholamines which play a part in the metabolism of dopamine in the cortex. So, COMT is a putative susceptibility gene which also has a plausible biological relationship to a part of the brain and neurotransmitter known to be involved in the hallucinogenic manifestations of the illness, and, of course, the dopaminergic pathway may well have regulatory impacts on the GABAergic and glutaminergic signalling pathways which impact the negative symptoms. Hence its inclusion in the Harrison and Owen hypothesis. Perhaps it is this complexity which leads Hardy to be strongly sceptical that the research strategy that he applied to the genetics of Alzheimer's will work more generally in the field of psychiatry.

Irrespective of where the debate about the Harrison-Owen hypothesis ends up other groups are working on comparison studies which might prove to be an alternate way of identifying and/or verifying illness susceptibility genes. Ming Tsuang and colleagues from the University of California, San Diego wrote in the American Journal of Medical Genetics that the messenger RNA he and colleagues had taken from patients with definite diagnoses of schizophrenia and bipolar disorder had shown there was a uniquely expressed genome signature for each disease state.

That paper did much to stoke the expectation that the days of more precise diagnosing might be on the horizon. The reader could be forgiven for thinking from the paper that Tsuang's team had indeed found definitive diagnostic markers of the separate disease states, but Tsuang says this is not yet the case. And Harrison says the apparent implications of the paper were overstated.

Nevertheless Tsuang and others, in particular Harrison, remain enthusiastic about the field of genetics and psychiatry, whether as a way of determining a genetic and biological underpinning for brain pathology and thus new research targets or as a means of improved diagnostics. By contrast with the enthusiasts for the field of psychiatry and genetics Murray is cautious, Hardy is deeply sceptical, going so far as to say that as a field, psychiatry and genetics is in serious trouble. All make the important assertion that cures and new therapies are some distance in the future. But in Murray's view the next few years will determine whether the investment made by funding bodies in the field of psychiatry and genetics will pay off. Perhaps, too, the forthcoming spring meeting of UK government funding bodies will help to disentangle the arguments.