Thesis (PhD (Psychiatry))-- Stellenbosch University, 2006. / 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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/1256 |
| Date | 03 1900 |
| Creators | Hemmings, S.M.J. |
| Contributors | Stein, Dan J., Moolman-Smook, Johanna C., Corfield, Valerie A., Stellenbosch University . Faculty of Medicine & Health Sciences. Dept. of Psychiatry. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | Unknown |
| Type | Thesis |
| Format | 5728224 bytes, application/pdf |
| Rights | Stellenbosch University |
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