Tuesday, July 14, 2009

The mind boggles

Schizophrenia is one of those important human traits that has eluded understanding despite heavy research investment. It is elusively variable and hence challenging to diagnose as a single entity or to decide how to split it up into causally distinct subsets. It seems highly familial in terms of its increased risk among family members, and hence seems clearly to have a genetic component. But the specific genes have been elusive--they must be there in the genome, but where are they?

A recent paper in Nature ("Common polygenic variation contributes to risk of schizophrenia and bipolar disorder", The International Schizophrenia Consortium, published online 1 July 2009) looked at large amounts of data on schizophrenia from several study populations. The authors did an extensive amount of genotyping and then various kinds of analysis (they looked, for example, at about a million variable sites (SNPs) in the genome, to identify regions where a particular variant marker was found more often in some 3322 cases than 3587 controls--pretty large studies for this kind of trait.

No really strong signal, that is that explained a high fraction of the disorder, was found. But through a series of analytic approaches, including computer simulations to test a range of possible genetic causal models to see which fit best, the authors (and this is one of those papers with a huge list of authors) concluded that many thousands of genes (classically they'd be known as 'polygenes') contribute to the trait. Most of the contributing variants are rare, but more importantly, they have individually very small effects.

Regardless of the details of the study, which could include all sorts of artifacts or be affected by the methods and assumptions of the authors, the study seems convincing that schizophrenia is like many other traits of a polygenic nature. The authors confirmed current ideas that bipolar disorder may involve many of the same genes, as well.

There are good evolutionary and biological reasons why this makes sense. In a nutshell, it's because so many processes are involved in brain development and function, each of them subject to mutational variation, that there are many ways to end up with the same trait. Natural selection only prunes those who can't reproduce as successfully, but the effect is distributed across these many parts of the genome, and hence acts only very weakly against any one of them. The result is an accumulation of variation that, at each individual region is essentially undetectably abnormal. The frequency of the individual variants changes over generations (and over geographic space in our species) mainly by chance (genetic drift).

The individual components have to work together--the 'cooperation' that is at the core of life as we outline in our book The Mermaid's Tale, but there is plenty of tolerance for variation, what we refer to as functional 'slippage'. It all makes sense biologically, evolutionarily, and causally.

In addition to its consistency with evolutionary expectations, this flies in the face of current predominant thinking about the prospects for what is being called 'personalized medicine', that is, medicine based on each individual person's genotype. If genotypes are poorly predictive, as in this case they seem to be, then they are of no real use to a clinician. In fact, as with so many similar studies, the total identified effect was small: based on various assumptions, the polygenic component identified by this geomewide search accounted for only 3 to 20% of the total disease risk, which itself is only 1%! Schizophrenia is an important problem (1% of the population is a lot of people), but clearly the predictive power of these gene-sets is modest, and this assumes that environmental effects will retain their current overall nature and impact (many of the genes probably have effects that vary depending on environment).

Many researchers will try to develop synthesizing methods to make individual sense of polygenotypes, so that treatment might be varied accordingly. How well they succeed only time will tell. But this is another case in which extensive study of a trait based on modern high-intensity technology has documented the nature of complex traits.

No comments: