Molecular genetic strategies to identify Obsessive-compulsive disorder (OCD) and schizophrenia candidate genes in a South African sub-population group

[摘要] ENGLISH ABSTRACT: Obsessive-compulsive disorder is a severe, debilitating psychiatric disorder for which theunderlying molecular aetiology still remains unclear. Evidence from family studies havesuggested that OCD may be caused by a complex interplay of environmental and geneticfactors.In order to identify the genetic factors that mediate OCD susceptibility, several geneticassociation studies have been undertaken, which have yielded inconsistent findings. Moreover,the majority of these studies have focused on a small number of candidate genes that encodecomponents of the serotonin and dopamine neurotransmitter pathways. However, based on thecomplexity of clinical manifestations observed in OCD, it is likely that its pathogenesis ismediated by a broader complex of interrelated neurotransmitter systems and signal transductionpathways; consequently there is a need to identify and assess novel candidate genes.One method of identifying such novel OCD candidate genes is by utilising knowledge of diseaseswith phenomenological overlap with OCD, which lend themselves to better genetic dissectionthrough linkage analysis and animal studies. Genetic loci for such disorders, identified thoughlinkage analysis, could potentially harbour novel OCD candidate genes, while genes implicatedthrough animal models may lead to the identification of additional susceptibility genes throughdelineation of pathways by, for instance, interactome analysis. One such disorder isschizophrenia, which manifests overlap in both symptoms and brain circuits with OCD. Inschizophrenia, in addition to several case-control association studies having been performed,linkage data, studies of chromosomal aberrations and animal models have led to the identificationof many chromosomal regions that may contain genes involved in its aetiology and thus may alsocontain OCD candidate genes.In the present investigation, this approach was employed using previously reported schizophreniasusceptibility loci to identify novel OCD candidate genes. All genes residing in each of these lociwere catalogued and individually analysed using a battery of bioinformatic techniques in order toassess their potential candidature for OCD susceptibility. These analyses yielded 13 credibleOCD candidate genes.Additional candidates were sought using information regarding a well-defined schizophreniaanimal model, the heterozygous reeler mouse, that exhibits neurodevelopmental, neuroanatomicaland behavioural abnormalities, similar to those displayed by patients with schizophrenia. Thephenotype of these mice is caused by a mutation in Reln, which encodes reelin, a largeextracellular matrix protein that plays a pivotal role in the ordered migration of neurons duringthe development of laminar brain structures. The fact that both reelin protein and mRNA levelshave been shown to be reduced in post-mortem brain sections of schizophrenic patients, coupledwith the observed behaviour and neurochemical similarities between the heterozygous reelermouse and schizophrenic patients suggests that reelin may be involved in the pathogenesis ofschizophrenia and hence also OCD. Furthermore, genes encoding proteins that interact with reelinmay thus also be considered plausible candidate genes for both schizophrenia and OCD. For thisreason, novel reelin-interacting proteins were sought using the N-terminal reeler-domain ofreelin, a domain only found in proteins involved in neuronal migration, as 'bait in a yeast twohybridscreen of a foetal brain cDNA library. Putative reelin ligands were subsequently reevaluatedusing co-immunopreciptitation and mammalian two-hybrid analysis to corroborate theyeast two-hybrid findings. Results of these analyses showed that WDR47, a WD40-repeat domainprotein, interacts with reelin via its reeler-domain; therefore, the gene encoding this ligandprotein, as well as RELN itself, was also considered a credible OCD candidate gene.Each of the candidate genes identified using the afore-mentioned strategies were assessed fortheir potential role in the aetiology of OCD by case-control association studies of a cohort ofAfrikaner OCD patients and control individuals. Statistically significant associations weredetected for two genes, DLX6 and SYN3, with the disorder. These associations are exciting asthey may point to novel mechanisms involved in OCD development.The identification of WDR47 as a novel reelin-interacting protein has significant implications forour understanding of reelin-dependant signalling. Using this protein as the starting point, furthernovel components of the reelin signalling pathway may be unravelled, an investigation whichmay lead to the identification of novel roles for reelin in neurodevelopment. Such novelcomponents may, of course, also be considered OCD and schizophrenia candidate genes, whichmay, in turn, augment the existing knowledge of the pathophysiologies of OCD, schizophreniaand other neurodevelopmental disorders. Taken together, the current study yielded exciting results that warrants follow-up investigation infuture. The identification of DLX6 and SYN3 as novel OCD susceptibility genes as well as theidentification of WDR47 as a reelin-interacting protein may provide investigators with alternativeavenues of research into potential pathological mechanisms involved both in OCD andschizophrenia, which may ultimately lead to alternative pharmacotherapy.

[发布机构] Stellenbosch University