35×10-7, OR=0.68). An effect on splicing was demonstrated for the SNP rs950169 which is in PD184352 mouse linkage disequilibrium with rs2135551. The genetic association of rs2135551 was replicated in an independent cohort of patients but was not replicated in three other sample sets. Need et al also analyzed whether association of other current candidate genes for schizophrenia was present in their study. They observed gene-wide association
of polymorphisms in Fasciculation and elongation protein zeta-1 (FEZ1) and Notch homolog Inhibitors,research,lifescience,medical 4 (NOTCH4). By the middle of 2009, three GWAS of impressive scale were conducted by three large consortia for schizophrenia genetics. Each effort examined several thousand cases and controls, and they were published in the same issue of Nature. The study from the International Schizophrenia Consortium (ISC) analyzed 3322 schizophrenia cases and 3587 controls.96 The most significant association was observed for rs5761163 in the first intron of myosin XVIIIB (MYO18B; 22q11.2-q12.1; Inhibitors,research,lifescience,medical P=3.4×10-7). The second strongest association was with SNPs spanning the major histocompatibility complex (MHC, 6p22.1) and the most significant SNP was rs3130375. Following imputation, rs3130297, located in the MHC region 7.1 kilobases (kb) upstream from the Notch homolog 4 gene Inhibitors,research,lifescience,medical (NOTCH4) showed genome -wide significance (P=4.79×10-8). A trend for association of this SNP was observed in the
Molecular Genetics of Schizophrenia (MGS) sample (P=0.086)99 but not in the SGENE sample (P=0.14).41 In the combined sample from the three studies, including both
imputed and genotyped SNPs in the MHC region, rs13194053 was genome -wide significant. Inhibitors,research,lifescience,medical The study also provided evidence that a large number of common variants have an important role to play in schizophrenia Inhibitors,research,lifescience,medical susceptibility, as a group explaining about one third of the total variation in risk for the disease (34% [CI=32%-36%]).96 In the second GWAS, performed by the SGENE consortium, Stefansson et al41 did not observe any genomewide significant SNPs in their sample of 2663 schizophrenia cases and 13 498 controls. They analyzed the top 1500 SNPs in the ISC (2602 cases and 2885 controls) and the MGS samples (2681 cases and 2653 controls). The top 25 markers (P<1x10-5) in the combined sample were followed up in four independent samples (total of 4999 cases and 15 555 controls). They observed genome -wide Calpain significant association of SNPs in the MHC region (6p21. 3-22.1, HIST1H2BJ, PRSS16, and NOTCH4), as well as with the marker rs12807809 located 3.4kb upstream of the neurogranin gene (NRGN, 11q24.2), and an intron four SNP in transcription factor 4 (TCF4, 18q21.2). The odds ratios for associated SNPs in the MHC region varied from 1.15 (HIST1H2BJ, rs6913660, P=1.1×10-9), to 1.19 (NOTCH4, rs3131296, P=2.3×10-10) to 1.24 (PGDB1, rs13211507, P=8.3×10-7).
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