Resolving the heterogeneity of psychiatric disorders: Clinical and statistical approaches

Despite some progress, the overwhelming majority of susceptibility genes that likely play an important role in psychiatric disorders remain undiscovered. This may be due to the fact that the etiologies of psychiatric disorders are complex and involve multiple genes of small effect acting independently and interactively. We review promising new strategies that utilize clinical information to facilitate the search for these susceptibility genes. We discuss family studies methods that can be used to assess whether a clinical feature reflects the underlying genetic heterogeneity of psychiatric disorders. We then review approaches for incorporating clinical covariates into linkage and association analyses for gene mapping. Finally, we discuss some considerations for assessing the significance of findings that emerge from the exploration of clinical data. The strategy of using clinical information to resolve the genetic heterogeneity of complex disorders has been successfully used in the past. We believe the wider application of this strategy in the study of psychiatric disorders may yield considerable benefits in the future.