Comprehensive evaluation of positional candidates in the IL-18 pathway reveals suggestive associations with schizophrenia and herpes virus seropositivity

Interactions between genetic variation and environmental factors have been invoked in schizophrenia genesis, but pathways linking them are uncertain. We used a pathway-oriented approach to evaluate six genes mediating IL18 function (IL-18, IL18BP, IL18R1, IL18RAP, IL12B, and IL12A). The first five are also localized to regions previously linked with schizophrenia. Fifty-four representative tag SNPs were selected from comprehensive sequence data and genotyped in 478 patients with schizophrenia/schizoaffective disorder (DSM IV criteria) and 501 unscreened control individuals. Exposure to three herpes viruses previously suggested as risk factors for schizophrenia was estimated simultaneously among the cases. Five SNPs in four genes were associated with schizophrenia, most prominently rs2272127 at IL18RAP (P = 0.0007, odds ratio for C allele 1.49, 95% CI: 1.18-1.87; P = 0.03 following correction for multiple comparisons). Exploratory analysis revealed that rs2272127 was also associated with herpes simplex virus 1 (HSV1) seropositivity in cases (P = 0.04, OR for G allele 1.58, 95% CI: 1.04-2.39). Similar patterns were observed at another correlated SNP (rs11465702, P = 0.005 and 0.006, respectively for associations with schizophrenia and HSV1 seropositivity). We suggest plausible, testable hypotheses linking IL-18 signaling and HSV1 in schizophrenia pathogenesis.