Visual representation of connections of genes in the Tan schizophrenia module.

<p>This figure shows target genes of the probes in the Tan schizophrenia module with the strongest connections only (<i>r</i> >0.64). Blue-colored nodes represent brain-expressed genes. Square-shape nodes indicate <i>cis</i>-regulation. Node size is related to the number of connections of that particular gene; a highly connected gene (i.e. ‘hub gene’) is therefore larger than genes with fewer connections. Red text indicates genes previously implicated in schizophrenia. Image created using Cytoscape software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039498#pone.0039498-Smoot1" target="_blank">[69]</a>.</p

Module eigengene significance for co-expression modules.

<p>The modules that were found by WGCNA in the first dataset are listed together with the number of genes they contain (shown in the second column). Differences in cases and controls were tested using a linear model with FDR correction. Results for the medicated cases versus controls are presented in column three and four. The modules that were found to be differentially expressed were also tested for significance between cases and controls in the antipsychotic-free set, and results are presented in the fifth and sixth column. The last column indicates the percentage of module content that was also found to be expressed in brain (log₂>4). For all genes in the other modules, this was found to be 45%. For the Tan module, this was significantly higher (Fisher <i>p</i> = 4.3×10⁻⁴).</p

Description of datasets.

<p>For this study, three datasets were used; schizophrenia cases and controls, an antipsychotic-free set and a control dataset. Age and gender information is given for cases and controls separately. Gene expression data was generated in two batches (batch 1: Illumina H-8 and batch 2: Illumina H-12) and collected at different sites, information given in the fourth and fifth row). The batch effect resulting from the use of different arrays on different time points in the latter set was removed using the SampleNetwork R package <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039498#pone.0039498-Oldham3" target="_blank">[62]</a>. The number of expressed genes is given in the last row. *DK  =  Denmark and NL  =  The Netherlands.</p

Network construction identifies distinct modules of co-expressed genes.

<p>The network was constructed using gene expression data of 92 medicated schizophrenia cases and 78 controls (dataset 1). The dendrogram was produced by average linkage hierarchical clustering of genes using 1-topological overlap as dissimilarity measure (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039498#s4" target="_blank">methods</a> section). Modules of co-expressed genes were assigned colors corresponding to the branches indicated by the horizontal bar beneath the dendrogram.</p

Median concentrations of monoamine metabolites (in nmol/L) in cerebrospinal fluid with standard deviations (S.D.), per season (italics indicate totals).

<p>Median concentrations of monoamine metabolites (in nmol/L) in cerebrospinal fluid with standard deviations (S.D.), per season (italics indicate totals).</p

Median CSF 5-HAA Concentrations (in nmol/L) are plotted against Month of Birth.

<p>Bold line represents cosine, thin line represents LOESS and dashed lines represent 95% CIs of the cosine. Whiskers indicate 95% CIs of 5-HIAA concentrations.</p

Median CSF 5-HAA Concentrations (in nmol/L) are plotted against Month of CSF Sampling.

<p>Bold line represents cosine, thin line represents LOESS and dashed lines represent 95% CIs of the cosine. Whiskers indicate 95% CIs of 5-HIAA concentrations.</p

Amplitude of the best fitting models per metabolite with significance levels (in bold: Bonferroni-corrected significant results).

<p>T-statistic of the amplitudes, tmax (month during which levels peak), tmin (month during which levels are at their lowest), and best-fitting model based on deviance calculations. Feb = February; Nov = November; Sept = September; Dec = December.</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies