Further investigation of the association between rs7341475 and rs17746501 and schizophrenia

Genome-wide association studies (GWAS) with small sample size have had limited statistical power in identifying schizophrenia susceptibility genes. This is exemplified by the fact that one of the most convincing associations was detected only after meta-analyses of three different GWAS. Herewe used meta-analysis to study the association of two single-nucleotide polymorphisms (SNPs) (rs7341475 and rs17746501) previously indicated to be associated with schizophrenia by a GWAS of Ashkenazi Jews (AJ). In the initial report, rs7341475 was associated only in women, while rs17746501 was associated in both men and women. We collected genotyping results of samples published in four GWAS for the two SNPs, additional to results from AJ. We used the Mantel-Haenszel method to combine the data of the different samples. For both SNPs, the results of the meta-analysis of all samples, including the initial report, did not reach a genome-wide significance level. However, the association between rs7341475 and schizophrenia in women, after excluding the data from AJ, was significant (P = 9.0 × 10^-3), with a calculated odds ratio (OR) of 1.11, much smaller than the original result. Association between rs17746501 and schizophrenia was significant in four of the new samples, showing evidence for heterogeneity and very small effect when tested across all samples (P = 0.016, OR = 1.06). These findings suggest that the two SNPs might have a small effect on schizophrenia risk and suggest that meta-analyses of very large samples are needed to adequately study the contribution of common variants to schizophrenia susceptibility.