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

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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.

Section snippets

Subjects, psychiatric assessment, and SNP data

In this study, 96 healthy controls were recruited for the evaluation of linkage disequilibrium (LD). All subjects were unrelated to each other and were ethnically Japanese. In this study, the subjects with schizophrenia have been referred to as case subjects and the healthy controls were referred to as control subjects.

The psychiatric assessment of each subject was performed, as described in our previous paper (29). After describing the study, a written informed consent was obtained from each

Interaction analysis of complex genetic diseases using BRP

First, the association between the isolated SNPs and schizophrenia was assessed from the P value calculated using the χ2 test with respect to the genotypic and allelic data. As shown in Table 1, there was no association between the isolated SNPs and schizophrenia in the genotypic and allelic analyses. Therefore, we focused on the analysis of SNP combinations. To validate risk or protective factor candidates (RFCs or PFCs), the BRP analysis (24) was performed by dividing the original data to two

Discussion

Schizophrenia is a neurodevelopmental disorder and one of the common diseases with an estimated heritability of 80%. Chromosome 22q11–q13 (OMIM: #600850 SCZD4) is one of the most probable schizophrenia susceptibility regions because the microdeletions of the 22q11 chromosome are reported to be associated with schizophrenia (31); furthermore, the two independent meta-analyses of linkage studies reveal the suggested linkage in this region (32, 33).

The APOL proteins belong to a group of

Acknowledgments

We are grateful to Ms. M. Miyata and Ms. S. Nakaguchi for technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation).

We also acknowledge the Hori Information Science Foundation for financial support.

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    The first two authors contributed equally to this work.

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