The inheritance of intermediate phenotypes for schizophrenia

Purpose of review While schizophrenia is substantially heritable, the mode of inheritance is complex, involving numerous genes of small effect and a non-trivial environmental component. The 'endophenotype' approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes in the context of complexly inherited traits. Here we review recent studies applying this method to measures of brain structure, physiology, and function in samples of schizophrenia patients and their non-ill first-degree relatives (siblings and co-twins). Recent findings The results suggest that there are multiple heritable dimensions of central nervous system pathology in schizophrenia, including disturbances in the structure and functioning of frontal lobe systems involved in working memory and executive processes, temporal lobe systems involved in episodic memory, auditory perception, and language processing, and cortical and sub-cortical systems, mediating smooth pursuit eye movements and sensorimotoi gating. A number of genetic loci that are suspected to play e role in predisposing to schizophrenia, including the DISC1 COMT, neuregulin, dysbindin, and alpha-7 nicotinic receptor genes, appear to affect quantitative variation on one or more of these indicators. Summary Future work is encouraged to address whether each of these neural system dysfunctions are under the influence of a partially distinct set of genes, to elucidate the manner it which multiple genes may coalesce in determining schizophrenia-promoting dysfunction in each neurobehavioral domain, and to clarify the degree of overlap in these quantitative trait loci-endophenotype relationships with other forms of psychosis, particularly bipolar disorder.