Given the variability of recurrence risks observed in the family studies and the clinical heterogeneity that is evident in OCD, this result is not surprising. Nevertheless, it is noteworthy that the conclusions of the authors in all of these reports were that there are some genes of major buy AT13387 effect important for the manifestation of OCD. Given the variability in the estimates of recurrence risks in the reported studies, it is quite likely that OCD is an oligogenic disorder (ie, a number of genes are important for the expression of the disorder). In addition to advances in understanding

regarding familiality and genetic mechanisms that are likely to be Inhibitors,research,lifescience,medical involved in OCD, there have also been dramatic gains in our understanding of the phenotype of OCD. Perhaps most important for genetic research are new ways to assess the phenotype dimensionally, moving beyond traditional categorical diagnostic classifications. Over Inhibitors,research,lifescience,medical the last decade, results from a number of independent

studies have demonstrated that there are different clusters of symptoms that comprise the OCD phenotype73-77 and that they appear to be heritable.73,76 It follows then that there may be several genes that could influence Inhibitors,research,lifescience,medical the different components of OCD. Candidate gene studies Given current theoretical understanding of mechanisms that may be implicated in the emergence and maintenance of OCD symptoms and the treatment of the disorder, a number of investigators have pursued genetic studies of specific genes that are known to be involved in systems implicated in the pathogenesis of OCD. In particular, because of the efficacy of serotonin reuptake in treating OCD,78-79 a number of genes important in the serotonergic system have been examined. In addition, genes in the dopaminergic, Inhibitors,research,lifescience,medical glutamatergic, and opioid systems have also been studied to determine if they also contribute to the risk Inhibitors,research,lifescience,medical of OCD.80 Over 80 candidate gene studies have been published over the last decade (Table III) . As noted above, association studies have examined candidate genes that function

within the serotonergic and dopaminergic systems and more recently the glutamatergic system based on knowledge of the pathophysiology and pharmacology of OCD. However, with the exception of the glutamate transporter gene SLCL1A1,81-84 none have been consistently replicated. secondly While some of the more recent published studies have larger sample sizes, all have inadequate sample sizes to achieve genome -wide significance (ie, 5×10-8). Some recent studies have moved beyond simply documenting that individuals with OCD are more likely to have a specific allele or candidate gene that other nonaffected individuals (ie, association studies) and have begun to explore the function of some of the genes being studied. Preliminary results suggest that may be a promising approach.85 However, none of these studies have yet been replicated, so it is too early to reach any definite conclusions.