The complexity of schizophrenia and how to understand it

An excellent, measured and thoughtful paper about the causes of schizophrenia appears in this week's Nature, a special issue on current knowledge about the disease.  Much recent research into this devastating disease has been gene-based, including of course genomewide association studies, but, as with all other complex traits, no simple genetic basis has been identified.  In this paper ("The environment and schizophrenia"), Jim van Os et al discuss reasons for this, and suggest ways to move the research forward.

GWAS have identified hundreds of genes for schizophrenia, or more, but currently only accounting for a small percent of the variation in disease presence or test-scores.  Depending on some assumptions and on what data one considers, estimates are that hundreds or even thousands of genes (including regulatory and other functional regions) contribute.  There are few that seem to make strong individual contributions, and one region that has been found to do that is in the HLA part of the immune system, a strange kind of finding.  Even with optimistic assumptions, predictive power will vary from sample to sample and population to population.  These will not, as currently designed, assess epigenetic changes, due to DNA modification.  And then there's the little trivial thing called the 'environment.'

Briefly, in this new paper van Os et al. argue that schizophrenia, and other 'psychotic syndromes', are the result of the interaction of the developing brain with environmental triggers during developmental sensitive periods in those with what is presumably a genetic susceptibility to disruptions in normal functioning of the brain.  We condense a long argument into one inadequate sentence here, but even so please note that it's a paean to complexity, flexibility as a response to the environment during development, and that genetic susceptibility is only one part of the picture.  

These researchers believe, based on a body of prior evidence, that the development of normal neuronal connections in the brain requires interaction with a variable environment, as they portray in the figure to the left.   Based on epidemiological data for associations of psychosis with environmental risk factors, they define risk as the stressors of urban environments, belonging to a minority group, developmental trauma, and/or cannabis use.  However, these factors are extremely common, while what they call the 'psychotic syndrome' is not.  This is where the genetic susceptibility comes in.

This suggests that beneath the relatively small marginal risks linking the environment to psychotic syndrome at the population level, vulnerable subgroups exist that are more sensitive to a particular environmental risk factor at a much larger effect size. Thus, the validity of observed associations with urban environment, developmental trauma, cannabis use and minority group position hinges on evidence of vulnerable subgroups. Genetically sensitive studies indicate that differential sensitivity to the psychosis-inducing effects of environmental factors may be mediated by genetic factors. For example, in siblings of patients with a psychotic disorder, who are at increased genetic risk to develop psychotic disorder, the psychotomimetic effect of cannabis is much greater than in controls, as is the risk to develop psychotic disorder when growing up in an urban environment

It's one thing to state this, and another thing to suggest ways to test this complex interaction of risk factors.  They do just this, however, describing a number of animal studies that can now be done to look at the effect of environmental factors on the developing brain of susceptible and non-susceptible animals.  The authors recognize that this won't be easy -- sensitive periods during development, risk factors, at-risk animals, and evidence of psychosis all must be well-defined and observed.

And then any potentially disastrous effects of methodological shortcomings, such as bias or confounding -- including genetic confounding -- must be ruled out before results can be considered credible.  E.g., are at-risk adolescents self-medicating with cannabis, making it appear that cannabis is the trigger when it's something intrinsic instead?  Does genetic susceptibility predispose to the use of cannabis, again making it look as though cannabis is the risk factor when it's genes?  They in fact include a box devoted to issues related to weighing the evidence.

Whether van Os et al. are correct in the details of which factors are most important to account for, or in the timing of the sensitive periods for specific aspects of normal growth we certainly can't say, but even so this is a beautifully nuanced and well-reasoned argument for accepting complexity, with suggestions for how to move forward from there, all based on the mountains of data that have come before.  And, the authors don't over claim, or say it will be easy. 

Indeed, the existence of many 'sensitive stages' during development means any number of pathways could be affected at any time to lead to disease.  Schizophrenia, like any trait, of course has genetic underpinnings, but given the 4-dimensional complexity of the developmental pathways in the brain,  this means that there are many ways that things could go awry, which only increases the difficulty with which they can be found, or, if found, be useful for prediction.

The authors conclude:

The human brain has evolved as a highly context-sensitive system, enabling behavioural flexibility in the face of constantly changing environmental challenges. There is evidence that genetic liability for psychotic syndrome is mediated in part by differential sensitivity to environments of victimization, experience of social exclusion and substances affecting brain functioning, having an impact during development. Given the complexity of the phenotype and evidence of dynamic developmental trajectories, with environmentally sensitive periods, longitudinal research on gene–environment interplay driving variation in behavioural expression of liability, that subsequently may give rise to more severe and more ‘co-morbid’ expressions of psychopathology and need for care, is required to identify the causes and trajectories of the psychotic syndrome. Examination of differential sensitivity to the environment requires technology to assess directly situated phenotypes indexing dynamic, within-person environmental reactivity as substrate for molecular genetic studies; parallel multidisciplinary translational research, using novel paradigms, may help identify underlying mechanisms and point the way to possible interventions.

So, this is an unusually sober and realistic treatment of a complex disease.  Is there anything surprising here?  Only that Nature is giving a number of pages to a nuanced treatment of a subject that is so often treated simply.