Nature has a really interesting article on the sheer difficulty (impossibility?) of finding the genetic underpinnings of mental illness:
Finding genes involved in psychiatric conditions is proving to be particularly intractable because it is still unclear whether the various diagnoses are actually separate diseases with distinct underlying genetics or whether, as the DISC1 [a gene implicated in shcizophrenia] story suggests, they will dissolve under the genetic spotlight into one biological continuum. Indeed, some researchers suggest that it would be better to abandon conventional clinical definitions and focus instead on 'intermediate phenotypes', quantifiable characteristics such as brain structure, wiring and function that are midway between the risk genes involved and the psychopathology displayed.In the past two years, researchers have pulled out a host of genes involved in other multifactorial diseases, such as diabetes and obesity, by use of genome-wide association studies. These use powerful new genomic tools to scan for variations in the DNA sequence called single nucleotide polymorphisms (SNPs) that tend to occur in individuals with a particular condition. They allow scientists to see which gene variants pop up more frequently in people who have a disorder.
Finding small genetic signals is a question of statistics: a weak association between a gene and a disease may stray into significance only when a study has hundreds or thousands of participants. But instead of helping to firm up which genes might be candidates, the largest population studies completed so far in psychiatric genetics seem to be eliminating them. A study this year led by Patrick Sullivan, a geneticist at the University of North Carolina at Chapel Hill, involved nearly 750 patients with schizophrenia and a similar number of controls, and analysed almost half a million SNPs. But not one gene met the rigorous statistical requirements needed to show it was a risk factor3 -- not even DISC1.
Vaughan is exactly right: one of the real stumbling blocks of such studies is that they are forced to find subtle connections across very different levels of description. The genome is a biological text, a long alphabet full of quantifiable variation. The diagnosis of mental illness, on the other hand, is a squishy and subjective process. (This isn't a criticism: there's simply no other way.) As a result, doctors are forced to render a verdict based on phenomenological reports, even though the same condition will often manifest itself quite differently in different people. And then, of course, there's the influence of society and culture. If geneticists had been around during Freud's time, they would have been looking for the SNP's underlying hysteria, searching for the confluence of genes that triggered such a bizarre set of symptoms. As Foucault famously pointed out, the definition of madness has always been mercurial, precisely because it has traditionally been defined against something else. Madness, in other words, is not necessarily a consistent set of symptoms caused by a particular genetic mishap: it's just the opposite of "reason," whatever that is.
Brain & Behavior
Comments (7)
Thanks for highlighting this article. In pathogen/pest related genetics we have the "gene for gene" hypothesis which at its most general has a combination of resistance genes (host) and virulence genes (pathogen). Why raise this point - its a strong reminder that genes and illness will be "2-way traffic" and that the current hunt in the human arena is focussed on the susceptible expression (eg can I develop a diagnostic and a treatment - the latter preferably tablet form). The environmental (eg lifestyle etc) impacts may be more important in discovering the "resistant response in an apparently susceptible genotype" but horrendously complex to unravel.
Plant and animal breeders have been traversing this ground experimentally with classical genetics for a long time and know the joys of interactions. The opening note of the Nature article is a salutory reminder of the value of the human cytogenetics work and the need for the molecular "adventure" to travel with the classical genetics and statistics.
Posted by: Jim Fortune | July 10, 2008 6:55 PM