Results of the sensitivity analyses: a comparison of different nominal p-values.

<p><i>Note</i>. Results for variations of the method for the 32 Mbp width region on chromosome 5, 128–160 bp. Nom 0.01: the analysis was performed using p = 0.01 as the cutoff for nominal SNP-wise significance. Nom 0.11: the analysis was performed using p = 0.1 as the cutoff for nominal SNP-wise significance. EIGENSTRAT: the analysis was performed on data corrected for population stratification using the EIGENSTRAT procedure.</p

“Manhattan plot of the top segment located at chromosome 5 (128–136

<p> <b>Mbp)”.</b> This figure shows at the y–axis the p-values of the SNPs located at chromosome 5 (128–136 Mbp). The chromosomes are shown at the x-axis. The red line indicates a p-value of 10-7, the blue line indicates a p-value of 10-5 and the green line indicates a p-value of .05.</p

Overview of disease associated genes located within the significantly associated region at chromosome 5 (128–136 Mbp).

<p>Note: The table shows genes that have previously reported to be associated with disease based on the UCSC Genome Bioinformatics site (NCBI36/hg18) (<a href="http://genome.ucsc.edu/" target="_blank">http://genome.ucsc.edu/</a>) and genes previously found to be associated with schizophrenia based on the Schizophrenia Research Forum (<a href="http://www.schizophreniaresearchforum.org" target="_blank">www.schizophreniaresearchforum.org</a>). The final column represents the phenotype and disease associations according to the UCSC Genome Bioinformatics site.</p><p>Set-based tests were performed in Plink to assess the association between SNPs within a particular gene and case-control status. This test uses permutation to determine the significance. The default values were used (r-squared = .5; p-value = .05; maximum number of SNPs within a gene = 5); more details can be found at <a href="http://pngu.mgh.harvard.edu/~purcell/plink" target="_blank">http://pngu.mgh.harvard.edu/~purcell/plink</a>.</p

Metasignificance of segments located in chromosome 5 (128–160 Mbp).

<p><i>Note</i>. Segment width refers to the width of regions over which tests of the number of nominally significant SNPs were tested. The replicable region indicates the location of the segment. The p-values provide the results of permutation based tests.</p

“Manhattan plot of the 22 autosomal chromosomes”.

<p>This figure shows at the y–axis the p-values of the SNPs in a GWA analysis. The chromosomes are shown at the x-axis. The red line indicates a p-value of 10-7, the blue line indicates a p-value of 10-5 and the green line indicates a p-value of .05.</p

CNVs in regions previously associated with SCZ.

<p>SCZ, schizophrenia; del, microdeletion; dup, microduplication; P, P-value; OR, odds ratio. Position according to NCBI built 36; all P-values and ORs were calculated using Fisher's exact test.</p><p>Two of the patients with a deletion in 1q21.1 and one patient with a deletion in 15q11.2 were already reported by Stefansson et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064035#pone.0064035-Stefansson1" target="_blank">[3]</a>, three patients with a deletion in Neurexin were included in Rujescu et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064035#pone.0064035-Rujescu1" target="_blank">[5]</a> and two patients with a deletion and one patient with a duplication in 16p13.11 were part of the study performed by Ingason et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064035#pone.0064035-Ingason1" target="_blank">[10]</a>.</p

Phenotypic information of patients with a CNV in regions previously associated with SCZ.

<p>Chr, chromosome; DEL, deletion; DUP, duplication; Diagnosis, DSM-IV diagnosis; f, female; m, male; AAO, age-at-onset; Family history SCZ, any fist degree relative with schizophrenia; ., missing data; Position according to NCBI built 36.</p

GSEA of differentially expressed cortical genes in psychiatric disorders and non-psychiatric phenotypes.

<p>GSEA was used to analyse the differentially expressed cortical genes, as gene sets, for enrichment of association signal in three different BP GWASs (a German sample, the Norwegian TOP sample and the British WTCCC BP sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Cichon1" target="_blank">[20]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Djurovic1" target="_blank">[41]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>), three SCZ GWASs (the Norwegian TOP sample, the German part of a combined German-Dutch SCZ GWAS and a Danish sample <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Rietschel1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Athanasiu1" target="_blank">[43]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Ingason1" target="_blank">[44]</a>) and six non-psychiatric phenotypes (from WTCCC; CD: Crohn's disease, CHD: coronary heart disease, HT: hypertension, RA: rheumatoid arthritis, T1D: type 1 diabetes and T2D: type 2 diabetes, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-WTCCC1" target="_blank">[42]</a>). The analysis was based on extraction of modified Sidak's minimum <i>P</i>-values <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Saccone1" target="_blank">[45]</a>, as implemented in LDsnpR. FDR q-value<0.1 was set as cut-off value for significant enrichment.</p>*<p>: One FMCx gene was not represented in the data set.</p>**<p>: Two FMCx genes were not represented in the data set.</p

Gene-based analysis of frontomedial cortex enriched genes for association to cognitive abilities.

<p>The frontomedial cortex enriched genes (n = 29) were analysed for allelic association to nine test measures from the NCNG GWAS: <b>FSIQ</b>: estimated Full-Scale Intelligence Quotient, <b>Vocabulary</b>: Wechsler Abbreviated Scale of Intelligence, Vocabulary, <b>Reasoning</b>: Wechsler Abbreviated Scale of Intelligence, Matrix Reasoning, <b>CVLT-L</b>: California Verbal Learning Test, Learning measure, <b>CVLT-DR</b>: California Verbal Learning Test, Delayed free Recall, <b>Stroop3</b>: the third condition from the D-KEFS Color-Word Interference Test, <b>CDT</b>: Cued Discrimination Task, <b>Valid, Invalid and Neutral</b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Wechsler1" target="_blank">[37]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Espeseth1" target="_blank">[40]</a>. The modified Sidak's minimum <i>P</i>-value for each candidate gene was extracted <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone.0031687-Saccone1" target="_blank">[45]</a>. Only modified Sidak's <i>P</i>-values<0.05 are reported. “-”: non-significant <i>P</i>-value (i.e. <i>P</i>-values>0.05), HGNC: HUGO Gene Nomenclature Committee, SNPs: number of SNPs assigned to each gene by LDsnpR.</p

Schematic overview of the method.

<p>SNP markers from GWAS data were assigned to single genes in a process termed “gene binning”, by implementing a novel LD-based tool (LDsnpR, Christoforou <i>et al.</i> under revision). Modified Sidak's <i>P</i>-values were extracted for each gene (“gene bin”) in the GWAS data sets. Single gene-based analysis of the differentially expressed cortical genes was performed by extracting the modified Sidak's <i>P</i>-values for the candidate genes from the NCNG GWAS. Gene set-based analysis of the differentially expressed cortical genes was performed by extraction of the modified Sidak's <i>P</i>-values, followed by GSEA of GWAS data on cognition, psychiatric disorders and non-psychiatric phenotypes. GSEA: Gene set enrichment analysis, GWAS: Genome-wide association study.</p