Investigating the molecular aetiology of Obsessive-compulsive disorder (OCD) and clinically-defined subsets of OCD

Abstract

Obsessive-compulsive disorder (OCD), a debilitating psychiatric disorder, affects 2-3% of the general population, and represents a global health problem. Evidence from family studies suggests that genetic factors play a role in mediating disease development. However, the pattern of inheritance is not consistent with monogenic disorders, but is “genetically complex”. Case-control association analysis, which facilitates dissection of the genetic aetiology of complex disorders, has yielded many inconsistent results in OCD studies, making identification of predisposing alleles difficult. These discrepant findings can largely be attributed to inappropriate statistical methodology and the lack of OCD phenotypic resolution. Although classified as a single clinical entity according to structured algorithms, OCD probably represents a final common outcome of multiple underlying aetiologies. Thus, numerous clinical subtypes of the disorder have been proposed; these “intermediate” phenotypes may be more closely related to a particular genetic substrate than the higher order construct of OCD. Furthermore, although genes encoding serotonergic (5-HT) and dopaminergic components are most commonly investigated, it is likely that the behavioural manifestations of OCD are mediated by a broader network of interconnected neurotransmitter and signalling pathways. Consequently, the aim of the present study was two-fold: to address the factors that may have confounded previous genetic case-control association studies and to investigate the genetic aetiology of OCD phenotypes while accounting for these factors. Case and control individuals were drawn from the reportedly genetically homogeneous Afrikaner population. However, as no empirical evidence existed to support the absence of genetic substructure, which would confound genetic association studies, a Bayesian modelbased clustering algorithm (Structure), that groups individuals on the basis of observed genotype data, was employed to assess population stratification in both case and control Afrikaner subjects. OCD patients were clinically stratified by gender, symptom severity, age at onset, the presence of selected co-morbid disorders and the presence of selected symptom dimensions, to facilitate the identification of susceptibility genes more closely related with these subtypes. Candidate genes included those coding for components of the 5-HT (5-HT receptors 1Dβ, 2A, 2C and 6), dopaminergic (dopamine receptors 1, 2, 3 and 4, dopamine transporter and catechol-O-methyltransferase [COMT]), glutamatergic (glutamate receptor subunit 2B [GRIN2B]) and neurodevelopmental pathways (brain-derived neurotrophic factor [BDNF] and homeobox 8 [HoxB8]), as well as previously uninvestigated genes (angiotensinconverting enzyme I, inositol-trisphosphate, phospholipase-C-gamma 1 and estrogen receptor alpha). The relationship between variants in these genes and OCD (or OCD subtypes) was investigated in a single locus and a haplotype context, while meta-analyses using published population-based case-control association data were also conducted. Significant associations noted between distinct COMT variants and OCD implicated COMT in the development of a genetically discrete, gender-dependant, early-onset, tic-related phenotype in males. Furthermore, investigations of variations in BDNF and GRIN2B point towards a genetically distinct, neurodevelopmental subtype of the disorder, mediated, in males at least, primarily by dysfunctions in BDNF. The striking gender dimorphism noted in these associations indicates the possibility of an epigenetic hormonal influence. Moreover, the significant association of polymorphisms within GRIN2B, in both a single locus and haplotype context, suggests the involvement of this gene in mediating a phenotypic subtype characterised by an early-onset, more severe form of the disorder. The present investigation forms part of ongoing research to elucidate genetic components involved in the aetiopathology of OCD and OCD-related subtypes. Such studies may pave the way towards more efficacious pharmacotherapeutic strategies, which will ease the suffering of individuals who are afflicted with this incapacitating condition.