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

Hemmings, S.M.J. (2006-03)

Thesis (PhD (Psychiatry))-- Stellenbosch University, 2006.

Thesis

ENGLISH 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.

AFRIKAANSE OPSOMMING: Obsessiewe-kompulsiewe steuring (OKS) is 'n aftakelende psigiatriese siektetoestand wat 2- 3% van die algemene bevolking affekteer en 'n globale gesondheidsprobleem verteenwoordig. Familiestudies dui daarop dat genetiese faktore 'n rol in die ontwikkeling van hierdie siekte speel. Die patroon van oorerwing is egter nie verenigbaar met dié van monogeniese siektes nie, maar is geneties "kompleks". Geval-kontrole assosiasie-ontleding, wat die disseksie van die genetiese etiologie van komplekse siektes fasiliteer, het teenstrydige resultate in OKS gelewer en dit bemoeilik die identifikasie van predisponerende allele. Die teenstrydige bevindings kan grootliks aan ontoepaslike statistiese metodiek en die gebrek aan fenotipiese differensiasie in OKS toegeskryf word. Alhoewel dit volgens gestruktureer algoritmes as 'n enkele kliniese entiteit geklassifiseer word, verteenwoordig OKS waarskynlik die eindresultaat van veelvoudige onderliggende oorsake. Baie kliniese subtipes van die toestand is al voorgestel en dié "intermediêre' fenotipes mag nader verwant aan 'n spesifieke genetiese substraat as die hoër orde konsep van OKS wees. Verder, alhoewel die gene wat die serotonergiese (5-HT) en dopaminergiese komponente kodeer meestalondersoek word, is dit waarskynlik dat die gedragsmanifestasies van OKS deur 'n breër netwerk van intergekonnekteerde neuro-oordragstof- en seinoordragpaaie meegebring word Gevolglik was die doel van die huidige studie tweevoudig: om faktore wat vorige genetiese geval-kontrole assossiasie-studies verwar het aan te spreek en om die genetiese etiologie van OKS-fenotipes te ondersoek met in ag neming van hierdie faktore. Geval- en kontrole-individue is gekies uit die Afrikaner-bevolking wat as geneties homogeen beskryf kan word. Daar was geen empiriese bewyse vir die afwesigheid van 'n genetiese substruktuur (wat genetiese assossiasie-studies sou verwar),nie. Daarom is 'n Bayesiese model-gebaseerde groeperings-algoritme (Structure), wat individue op grond van waargenome genotipiese data groepeer, gebruik om die populasie-stratifikasie is beide gevalen kontrole- Afrikaner-individue te bepaal. OKS-pasiënte is klinies gestratifiseer volgens geslag, ernstigheid van simptome, ouderdom by aanvang van simptome, die teenwoordigheid van geselekteerde komorbiede siektetoestande en die teenwoordigheid van geselekteerde simptoomdimensies of -groepe, om die identifikasie van moontlike vatbaarheidsgene wat nader verwant is aan die verskillende subtipes te fasiliteer/vergemaklik. Kandidaatgene het ingesluit: dié wat kodeer vir komponente van die 5-HT-(5-HT reseptore IDB, 2A, 2C and 6), dopaminergiese (dopamienreseptore 1, 2, 3 and 4, dopamien-transporter and katesjol-O-metieltransferase [COMTJ), glutamatergiese (glutamaat-reseptor subeenheid 2B [GRIN2B]) and neuro-ontwikkelingspaaie (brein-gederiveerde neurotrofiese faktor [BDNF] en homeobox 8 [HoxB8]), sowel as die gene wat nie voorheen ondersoek is nie (angiotensien-omsettingsensiem I, inositol-trisfosfaat, fosfolipase-C-gamma 1 en estrogeen-reseptor alpha). Die verhouding tussen variante in hierdie gene en OKS (of OKS-subtipes) is ondersoek in 'n enkel-lokus en haplotipe konteks, en meta-analises, wat gepubliseerde bevolkings-gebaseerde geval-kontrole ontledingsdata gebruik het, is ook gedoen. Beduidende assosiasies gevind tussen spesifieke COMT-variante en OKS in mans, het daarop gedui dat COMT in die ontwikkeling van geneties-diskrete, vroeë-aanvang, senutrekking ("tics") -verwante fenotipe in mans betrokke is. Verder het ondersoeke van variasies in BDNF en GRIN2B daarop gedui dat 'n geneties-afsonderlike, neuro-ontwikkelings-subtipe van.OKS wat, ten minste in mans, primêr deur wanfunksie van BDNF meegebring word. Die opvallende geslags verskil wat in hierdie assosiasies gesien word, dui op die moontlikheid van 'n epigenetiese hormonale invloed. Bowendien, die beduidende assosiasie van polimorfismes in GRIN2B in beide die enkel-lokus en haplotipe konteks, dui op die betrokkenheid van hierdie geen in die meebring van 'n fenotipiese subtipe wat deur 'n vroeë aanvang, en meer ernstige vorm van die siekte gekenmerk word. Die huidige ondersoek vorm deel van voortgesette navorsmg om die genetiese komponente wat betrokke is by die etiopatologie van OKS en OKS-subtipes, bloot te lê. Sodanige studies kan die weg baan na meer doeltreffende farmakoterapeutiese strategieë wat die lyding van indi vidue wat deur hierdie aftakelende toestand geraak word, kan verlig.

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