An important issue in psychiatric disorders in general and ADHD in particular is phenotypic heterogeneity. First, psychiatric diagnosis must rely on clinical symptoms that, without external validators, cannot be expected to reflect biologically relevant concepts that are closely linked to genes (Kuntsi et al. 2006; Thapar et al. 2006). Although the instruments used to define psychiatric GWAS phenotypes are generally chosen for high reliability, they have no proven biological validity and will therefore (at best) result in a more ‘noisy’ phenotype definition than most biological tests (Craddock et al. 2008). More importantly, however, the classical nosological approaches identify phenotypically distinct diseases, such as ADHD, substance abuse, affective disorder and schizophrenia, though these exhibit considerable overlap in symptomatology, clinical course, and long-term outcome. ADHD is hardly ever the only disorder a patient suffers from, comorbidity is the rule rather than the exception. For example, reported frequencies of depression and substance use disorders were also high in the GWAS sample used by Lesch et al. (2008). These factors severely hamper the power of genetic association studies and might explain why psychiatric genetics has had an extremely modest track record in pinpointing and characterizing susceptibility loci, even using the GWAS approaches.
