We agree with Gurling et al1 that the central question in psychosis is the relationship between genetic susceptibility and brain change but have concerns about their claim to have established that “The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.” Uncertainty in the identification of any gene relevant to psychosis on the one hand and the nonspecificity of morphological change in the brain on the other maximize the scope for multiple testing. In each case, Gurling et al have assumed heterogeneity on the basis of a post hoc criterion and have thereby increased the risk of attaching significance to a random association that will be difficult to disprove even with very large samples.
Crow TJ, DeLisi L. Gene–Brain Structure Relationships: Arbitrary Assumptions of Heterogeneity Generate Unfalsifiable Claims. Arch Gen Psychiatry. 2007;64(9):1097-1098. doi:10.1001/archpsyc.64.9.1097