The Investigation of the HLA System and Wheat Gluten in Determining Risk of Schizophrenia
Genome-wide association (GWA) studies confirmed that the HLA genes were strongly associated with schizophrenia but the HLA variants identified by GWA studies had a lower frequency in patients with schizophrenia than control subjects. The HLA molecules have function of presenting peptide antigens to T lymphocytes in order to initiate an immune response. Environmental factors such as infection and dietary proteins have been found to be associated with schizophrenia. This PhD program has thus focused on the following objectives: (1) identification of genetic variants for schizophrenia in the HLA region and (2) investigation of circulating antibodies to linear peptide antigens derived from wheat gluten in schizophrenia. The major findings from this work are as follows: 1. The HLA-DQ2.5 variants were strongly associated with schizophrenia; this finding is consistent with that from GWA study. 2. The NOTCH4 association was replicated in our study samples, in which a CNV in exon 19 of the gene may be associated with risk of schizophrenia. 3. There was no HLA-II variant identified to be associated with a high risk of schizophrenia but a CNV present in the HLA-DQ/DR region might confer risk of the disease. 4. The levels of circulating antibodies to linear peptide antigens derived from wheat gluten were significantly lower in schizophrenia patients than controls. This finding is inconsistent with previous studies that showed elevated levels of circulating antibodies in schizophrenia across subpopulations. In conclusion, it is likely that not one but many HLA variants lead to risk of schizophrenia development. From this research it is likely that anti-gluten antibodies are not an environmental trigger for this disease. Further investigation is needed to clarify the role of the HLA region in bridging the gap between genetic make-up and environmental factors in developing schizophrenia.
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