One of the difficult aspects of understanding mental illness, is separating the real causes of the illness from what might be secondary or tertiary consequences of having the illness. If you think about a car whose engine is not running normally, there may be many observable things going wrong (pinging sound, stalling, smoke, vibration, overheating, loss of power, etc.) – but, what is the real cause of the problem? What should be done to fix the car? – a faulty sparkplug or timing belt perhaps? Such is often the problem in medicine, where a fundamental problem can lead to a complex, hard-to-disentangle, etiology of symptoms. Ideally, you would fix the core problem and then expect the secondary and tertiary consequences to normalize.

This inherent difficulty, particularly in mental illness, is one of the reasons that genetic research is of such interest. Presumably, the genetic risk factors are deeper and more fundamentally involved in the root causes of the illness – and hence – are preferable targets for treatment. The recent paper, “Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability” [Arch Gen Psychiatry. 2009;66(5):467-477] seeks to ascertain whether one aspect of schizophrenia – a widespread and well-documented thinning of the neocortex – is due to genetic risk (hence something that is closer to a primary cause) or – rather – if cortical thinning is not due to genetics, and so more of a secondary consequence of things that go wrong earlier in the development of the illness.

To explore this idea, the team of Goldman et al., did something novel. Rather than examine the differences in cortical thickness between patients and control subjects, the team evaluated the cortical thickness of 59 patients and 72 unaffected siblings as well as 196 unrelated, matched control participants. If the cortical thickness of the siblings (who share 50% of their genetic variation) was more similar to the patients, then it would suggest that the cortical thinning of the patients was under genetic control and hence – perhaps – a biological trait that is more of a primary cause. On the other hand, if the cortical thickness of the siblings (who share 0% of their genetic variation) was more similar to that of the healthy control participants, then it would suggest that cortical thinning was – perhaps more of a secondary consequence of some earlier deficit.

The high-resolution structural neuroimaging allowed the team to carefully assess cortical thickness – which is normally between a mere 2 and 4 millimeters – across different areas of the cortex. The team reports that, for the most part, the cortical thickness measures of the siblings were more similar to the unrelated controls – thus suggesting that cortical thickness may not be a direct component of the genetic risk architecture for schizophrenia. Still, the paper discusses several candidate mechanisms which could lead to cortical thinning in the illness – some of which might be assessed in the future using other imaging modalities in the context of their patient/sibling/control experimental design.