INTERACTION BETWEEN HERPESVIRUSES AND GENETIC VARIATION IN SCHIZOPHRENIA PATHOGENESIS: A CANDIDATE GENE APPROACH

摘要

Schizophrenia is a debilitating disorder characterized by disturbances in thought with lifetime prevalence of one percent. The public health burden of schizophrenia due to medical care, social disability, and co-morbid conditions is substantial. Genetic variation, viral infection, or interaction of the two could influence schizophrenia risk. An understanding of these disease pathways could lead to strategies for prevention and treatment of schizophrenia. We used a positional approach to identify schizophrenia candidate genes that could interact with cytomegalovirus and herpes simplex viruses (HSV). We focused on three groups of genes: TNF and MICB near D6S2672, which was associated with schizophrenia and CMV in our previous studies; IL1â, IL1RN, and IL10, immune related genes associated with schizophrenia in published articles; and IL-18, IL18BP, IL18RAP, IL12A, and IL12B, positional candidate genes in the IL-18 pathway. We used multiple case-control and family-based samples to test these hypotheses. We comprehensively sequenced TNF, and genotyped eight SNPs in a case-control sample. We detected no significant associations. We used a dual-luciferase expression assay to quantify TNF expression driven by common promoter haplotypes. Differences in TNF expression did not correlate with schizophrenia. To localize the D6S2672 association, we genotyped 26 SNPs spanning 100kb in a case-control sample. Based on suggestive associations, we selected five SNPs to assay among additional samples. A SNP in MICB was associated with schizophrenia in these samples. The opposite allele was associated with HSV1 in two non-schizophrenia groups. We used comprehensive sequencing data to select tag SNPs at IL1â, IL1RN, IL10, and IL-18 pathway genes. Tag SNPs were evaluated in a case-control sample. In IL1â, IL1RN, and IL10 significant associations were not detected. However, meta-analysis of rs16944 (IL1â -511) studies suggests modest, but significant, risk for schizophrenia in Caucasian samples. In IL-18 pathway genes, a IL18RAP SNP was associated with schizophrenia, the opposite allele was associated with HSV1. Identified associations with schizophrenia may be due to host gene-virus interaction. These genetic variants could clarify which patients are vulnerable to viral infection. Treatment or prevention may be feasible, if our results are confirmed. Further replicate studies are warranted, as are functional studies of associated polymorphisms.