تاثیر ناهمگونی بالینی در اسکیزوفرنی در تجزیه و تحلیل ژنومی

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.

Schizophrenia (SZ) is a severe psychiatric disorder characterized by abnormalities in a patient's thoughts, perceptions, and behaviors, manifesting as hallucinations, delusions, and/or disorganized speech with significant social or occupational dysfunction (Andreasen, 1995). The substantial clinical heterogeneity associated with SZ, which Bleuler perhaps more appropriately labeled the “Group of Schizophrenias” (Bleuler, 1911), has likely combined with the inherent genetic heterogeneity to plague many attempts at identifying casual genetic variants (Karayiorgou and Gogos, 1997, Owen et al., 2007, Schork et al., 2007 and Sanders et al., 2008). Although genome-wide association studies (GWAS) of increasingly large samples have finally begun to overcome this heterogeneity to provide valuable insight into the role of common genetic variants in SZ risk (O'Donovan et al., 2008 and Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, 2011; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014 and Shi et al., 2009), investigations of smaller samples may suffer unnecessary power losses if the clinical heterogeneity is not appropriately accommodated. Here we demonstrate the importance of using specific diagnostic criteria to identify the core features of psychiatric disorders in genetic studies. We further show why screening the control population for disorders genetically related to the disorder of interest may be critical to the success of the study. For this purpose, we use data from the subset of the Molecular Genetics of Schizophrenia (MGS) that was genotyped as part of the Genetic Association Information Network (GAIN). Finally, we emphasize that one must use caution when acquiring data from publicly available sources and always verify that no identical subjects exist within or between samples prior to conducting any type of genetic analysis to avoid the potential confounding of results.