Susceptibility genes for schizophrenia and their functional relationships

Zhilin Luan

    Research output: ThesisThesis fully internal (DIV)

    682 Downloads (Pure)

    Abstract

    As a highly heterogeneous disorder, the genetic risk for schizophrenia probably results from joint effects of many loci with small contributions. In this thesis, a combined genetic and functional approach was applied to examine the involvement of several candidate genes in schizophrenia. These genes were selected based on a genome-wide association study (GWAS) in a Chinese Han population and two major hypotheses on the pathogenesis of schizophrenia.

    Numerous single-nucleotide polymorphisms (SNP) for these gene loci were genotyped. The distributions of allelic and genotype frequencies between cases and controls were examined, and we found that several SNP markers and haplotypes of STON2, MSI2, NAT2 and SOX11 were significantly associated with schizophrenia, indicating their contribution to the risk of schizophrenia. For the SOX11 gene, we further focused on its role in neurodevelopment. Mouse neural stem cell and primary neuron models were applied to investigate Sox11 function in neurodevelopment. The spatiotemporal expression profile of the Sox11 gene was examined by realtime PCR and in situ hybridization. By introducing Sox11 shRNA constructs into the developing mouse cortex, the neuron migration pattern was evaluated. Our results showed a high expression of Sox11 in neurogenic brain regions and Sox11 impacted the early stage of neurodevelopment by inhibiting neural stem cell proliferation and inducing neuronal differentiation. Additionally Sox11 functions as a neuron maturation inhibitor by blocking neuron development, axon growth and neuron migration.

    Our genetic studies showed significant association of the relevant genes with schizophrenia, and functional examination of schizophrenia-associated SOX11 gene revealed its essential involvement in multiple phases of early-stage neurodevelopment.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Boddeke, Erik, Supervisor
    • Copray, Joseph, Co-supervisor
    • Schoevers, R.R., Assessment committee, External person
    • Kremer, Berry, Assessment committee
    • van der Zee, Eddy, Assessment committee
    Award date13-Mar-2017
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-90-367-9649-1
    Electronic ISBNs978-90-367-9648-4
    Publication statusPublished - 2017

    Cite this