Genetic neuropathology of schizophrenia: new approaches to an old question and new uses for postmortem human brains.

Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.