The current status of association studies in obsessive-compulsive disorder.

During the last 2 decades, a large number of association studies have been dedicated to disentangling the genetic components that may be involved in the etiology of OCD. The preliminary and frequently in consistent nature of the data represented in the majority of OCD psychiatric genetic-association studies may seem discouraging. Failure to replicate, and thus to confirm, previously identified susceptibility loci could result from a number of reasons, including the potential for population admixture, the clinical heterogeneity of OCD, small sample sizes (and subsequent lack of power),publication bias, epistasis, or failure to account for multiple testing. Various methods of accounting for these confounders do exist and should be implemented in any genetic-association study that is to be regarded as robust and replicable. Discrepancy between results, however, might be ascribed to the underlying genetic differences between the populations in the respective studies (ie, the investigated variant may be in linkage disequilibrium with the causal variant in one population but not in another). Such discrepancies are difficult to reconcile in single-locus association studies; haplotype analyses(in which a number of variants, usually single-nucleotide polymorphisms occurring on the same gene, are analyzed as a unit) may be able to resolve these uncertainties. Investigating epistatic interactions between variants in other genes that might be involved in the same physiologic pathways would be an alternative means of deciphering the reason for discrepant genetic association results.A valid means of increasing the power (by reducing background noise)would be to stratify the patient sample according to clinically defined sub-types, such as obsession and compulsion subtypes, age at onset of the disorder, and severity of the disorder. Although many of the OCD genetics studies have incorporated investigations of these subtypes [65,66,68,77,84-86,89,107,118,132,133,145,148,149], the number of subjects decreases after stratification, thereby limiting the power of the studies. It may therefore be useful to employ other quantitative approaches in the design of the investigation: the possibility should be considered that OCD symptoms can be broken down into multiple dimensions that are continuous with the normal population [150]. This division would represent an important route to disentangling the complex inheritance of OCD. The results obtained from genetic investigations should be incorporated with clinical and epidemiologic parameters to elucidate correctly the cause of OCD. Future studies should also be extended to incorporate the screening of more polymorphisms, because high-resolution mapping within specific chromosomes will improve knowledge regarding the impact of genetic diversity within the genes or linked chromosomal regions in OCD. The advantages ofa gene-based over a single-nucleotide polymorphism based approach are becoming ever more apparent [151]. Therefore, a more complete assessment of candidate genes, possibly using haplotype blocks that span larger regions,is proposed. In addition, increasing the amount of information on human genome sequences and polymorphisms will make it possible to characterize the amount of sequence variation expressed in the brain and to delineate the potential effects that these variations may have on the development of OCD. Knowledge of new functional variants will emerge as researchers gain an understanding of the potential for genetic variants in the coding and regulatory regions to impact gene expression.