The contribution of epidemiology to defining the most appropriate approach to genetic research on schizophrenia.

Psychosis is thought to have a strong genetic component, but many efforts to discover the underlying putative schizophrenia genes have yielded disappointing results. In fact, no strong associations emerged in the first genome-wide association studies in psychiatry and weakly observed associations were not related to the candidate genes identified in previous studies. These partially successful findings may be explained by the fact that genetic research in psychiatry suffers from confounding issues related to phenotype definition, the considerable degree of phenotypic variability and diagnostic uncertainty, absence of specific neuropathological features and environmental influences. To make progress it is first necessary to deconstruct psychosis based on symptomatology, and then to correlate particular phenotypes with genetic variants. Moreover, it is time to conduct studies that define persistent aspects of the schizophrenic profile that are more likely to represent an underlying biological pathogenesis, as opposed to fluctuating symptoms that are possibly environmentally mediated. In fact, progress in understanding the etiology of schizophrenia will depend upon the availability of good measures of genetic liability as well as relevant environmental exposures during critical periods of an individual's life. If environmental and/or genetic factors are not precisely measured, it is impossible to study their independent effects or interactions