Association study between Apolipoprotein L and schizophrenia by exhaustive and rule-based combination analysis for identification of multilocus interactions

Several single marker association and haplotypic analyses have been performed to identify susceptible genes for various common diseases, but these approaches using candidate genes did not provide accurate and consistent evidence in each analysis. This inconsistency is partly due to the fact that the common diseases are caused by complex interactions among various genetic factors. Therefore, in this study, to evaluate exhaustive genotype or allele combinations, we applied the binomial and random permutation test (BRP) proposed by Tomita et al. [IPSJ Digital Courier, 2, 691–709 (2006)] for the association analysis between an Apolipoprotein L gene cluster and schizophrenia. Using the seven selected representative single nucleotide polymorphisms (SNPs) based on the results of linkage disequilibrium evaluation, we analyzed 845 schizophrenic patients and 707 healthy controls, and investigated the validation of risk and protective factors with two randomly divided data sets. A comparative study of a method for analyzing the interactions was performed by conventional methods. Even if all the tested methods were used for analysis, the risk factor with a high significance was not commonly selected from both independent data sets. However, the significant interactions for the protective factor against disease development were commonly obtained from both data sets by BRP analysis. In conclusion, although it is considered that the causality of schizophrenia is too complex to identify a susceptible interaction using a small sample size, it was suggested that the healthy controls tend to have the same combination of certain alleles or genotypes for protection from disease development when BRP as a new exhaustive combination analytical method was used.