The impact of clinical heterogeneity in schizophrenia on genomic analyses

Though clinically useful, the diagnostic systems currently employed are not well equipped to capture the substantial clinical heterogeneity observed for most psychiatric disorders, as exemplified by the complex psychotic disorder(s) that Bleuler aptly labeled the "Group of Schizophrenias". The clinical heterogeneity associated with schizophrenia has likely frustrated decades of attempts to illuminate the underlying genetic architecture, although recent genome-wide association studies have begun to provide valuable insight into the role of common genetic risk variants. Here we demonstrate the importance of using diagnostic information to identify a core form of the disorder and to eliminate potential comorbidities in genetic studies. We also demonstrate why applying a diagnostic screening procedure to the control dataset to remove individuals with potentially related disorders is critical. Additionally, subjects may participate in multiple studies at different institutions or may have genotype data released by more than one research group. It is thus good practice to verify that no identical subjects exist within or between samples prior to conducting any type of genetic analysis to avoid potential confounding of results. While the availability of genomic data for large collections of subjects has facilitated many investigations that would otherwise not have been possible, we clearly show why one must use caution when acquiring data from publicly available sources. Although the broad vs. narrow debate in terms of phenotype definition in genetic analyses will remain, it is likely that both approaches will yield different results and that both will have utility in resolving the genetic architecture of schizophrenia.