Obsessive-compulsive disorder phenotypes: implications for genetic studies

Abstract

Obsessive-compulsive disorder (OCD) clinical presentation is remarkably diverse, and can vary both within and across patients over time. This variability in the phenotypic expression has led to the hypothesis that OCD is a heterogeneous disorder and that this heterogeneity obscures the findings of clinical, natural history and treatment response studies and complicates the search for vulnerability genes. A complete understanding of what comprises OCD and the underlying etiological mechanisms will require a dramatic change in how the disorder is conceptualized. In this review, several different approaches that may represent the first steps in this reconceptualization are discussed. These approaches include (1) narrowing the phenotype to identify categorically defined more homogeneous and mutually exclusive subtypes of OCD, (2) considering OC symptom dimensions as quantitative components of the more complex OCD phenotype and (3) broadening the phenotype to include other etiologically related conditions. A combined dimensional approach within distinctive subgroups is proposed as probably the most effective in helping to identify the heritable components of OCD. By identifying heritable components of OCD, it should be possible to find genes for these separate components. The review continues with the illustration of the possible role of some epigenetic risk and protective factors in the OCD presentation and the relevance of examining associated traits and/or endophenotypes to enhance our ability to understand the genetic basis of OCD. To conclude, we discuss the variability in treatment outcome and the significance of the development of specific pharmacological and/or behavioral based therapies tailored to each of these phenotypes. Molecular Psychiatry (2005) 10, 258-275.

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

“…These sub-phenotype definitions are based on an etiopathological hypothesis, which states that specific, and not necessarily overlapping, constellations of susceptibility genes, each of moderate effect size, will result in distinct phenotypes. Thus far, the overall success in genetic studies with specific OCD subtypes has been modest, which could be due to the overall small sample sizes in conjunction with the further loss of power that accompanies each stratification (Miguel et al, 2005).…”

Heritability of obsessive‐compulsive symptom dimensions

“…Our results seem also in line with Mathews et al [2004] who examined the structure of OC symptoms in a nonclinical population and concluded that this broad OC behavior phenotype, they call it ''obsessionality,'' is phenomenologically similar to OCD and is likely to comprise a continuum with OCD. This may implicate that, besides a traditional categorical model of OCD, an underlying quantitative OC behavior phenotype could be used to provide an alternative strategy for the detection of genetic susceptibility loci that contribute to OCS or OCD [Miguel et al, 2005]. Another approach would be the use of the contamination dimension, showing clear specific genetic influences explaining a substantial amount of its variance.…”

“…This is in contrast to the current concept adopted by the DSM-IV, which defines OCD as a unitary nosological entity [American Psychiatric Association, 1994]. This variability in phenotype may impact not only the findings of clinical, natural history and treatment response studies, but also complicate genetic studies and the search for vulnerability genes [Miguel et al, 2005]. One suggested approach to reconceptualize OCD or Obsessive-Compulsive Symptoms (OCS) is the use of OC symptom dimensions [Miguel et al, 2005].…”

“…This variability in phenotype may impact not only the findings of clinical, natural history and treatment response studies, but also complicate genetic studies and the search for vulnerability genes [Miguel et al, 2005]. One suggested approach to reconceptualize OCD or Obsessive-Compulsive Symptoms (OCS) is the use of OC symptom dimensions [Miguel et al, 2005]. OCD or OCS appears to encompass at least four consistent and temporally stable symptom dimensions [MataixCols et al, 2005].…”

“…OCD or OCS appears to encompass at least four consistent and temporally stable symptom dimensions [MataixCols et al, 2005]. By considering these OC symptom dimensions as quantitative components of a more complex OC phenotype, a dimensional approach could provide a more powerful approach for the detection of genes or environmental risk factors that contribute to OC behavior [Miguel et al, 2005]. However, before using symptom dimensions in linkage or association analyses, it is important to examine the extent to which these symptom dimensions are heritable.…”