Structural cerebral variations as useful endophenotypes in schizophrenia: do they help construct "extended endophenotypes"?

Endophenotypes represent intermediate phenotypes on the putative causal pathway from the genotype to the phenotype. They offer a potentially valuable strategy to examine the molecular etiopathology of complex behavioral phenotypes such as schizophrenia. Neurocognitive and neurophysiological impairments that suggest functional impairments associated with schizophrenia have been proposed as endophenotypes. However, few studies have examined the structural variations in the brain that might underlie the functional impairments as useful endophenotypes for schizophrenia. Over the past three decades, there has been an impressive body of literature supporting brain structural alterations in schizophrenia. We critically reviewed the extant literature on the neuroanatomical variations in schizophrenia in this paper to evaluate their candidacy as endophenotypes and how useful they are in furthering the understanding of etiology and pathophysiology of schizophrenia. Brain morphometric measures meet many of the criteria set by different investigators, such as being robustly associated with schizophrenia, heritable, quantifiable, and present in unaffected family members more frequently than in the general population. We conclude that the brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Some caveats for the utility of endophenotypes are discussed. A proposal to combine more than one endophenotype ("extended endophenotype") is suggested. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.