Estimated coefficients , and their standard deviations calculated by bootstrap method in TILoR model for the WAFSS schizophrenia data set.

<p>Estimated coefficients , and their standard deviations calculated by bootstrap method in TILoR model for the WAFSS schizophrenia data set.</p

Boxplot of the estimates of the parameters in <i>g₁</i>, <b>, </b><i>g₂</i> and based on 100 simulations: .

<p>Boxplot of the estimates of the parameters in <i>g₁</i>, <b>, </b><i>g₂</i> and based on 100 simulations: .</p

WAFSS Study: Type I, Type II errors rates, predictive accuracy rates, and area under the curve (AUC) based on cross-validation estimate using GLM models, TILoR models, and random forest (RF) method.

<p>WAFSS Study: Type I, Type II errors rates, predictive accuracy rates, and area under the curve (AUC) based on cross-validation estimate using GLM models, TILoR models, and random forest (RF) method.</p

Boxplot of the absolute errors (AEs) of the estimates of the parameters in <i>g₁</i>, , <i>g₂</i> and based on 100 simulations: .

<p>Boxplot of the absolute errors (AEs) of the estimates of the parameters in <i>g₁</i>, , <i>g₂</i> and based on 100 simulations: .</p

WAFSS Study: The components of and whose absolute values are greater than 0.2.

<p>WAFSS Study: The components of and whose absolute values are greater than 0.2.</p

The ROC curves based on three methods/models (TILoR: Blue line; GLM: Red line; random forest: Green line) corresponding to folds 1–3.

<p>The ROC curves based on three methods/models (TILoR: Blue line; GLM: Red line; random forest: Green line) corresponding to folds 1–3.</p

Structure, neuropsychiatric morbidity and mutation segregation in families of schizophrenia probands with deleterious <i>GRM1</i> variants.

<p>Structure, neuropsychiatric morbidity and mutation segregation in families of schizophrenia probands with deleterious <i>GRM1</i> variants.</p

Functional analysis and relative plasma membrane expression of mGluR1 mutants in COS-7 cells.

<p>Cells transiently expressing mGluR1, wild-type (WT) or possessing the different mutations as indicated, were assayed for Quisqualate-induced inositol phosphate production using the IP-One assay (<b>a</b>) or plasma membrane expression using ELISA with anti-mGluR1 antibody on intact cells (<b>b</b>). With the IP-One assay, cells were stimulated with Quisqualate (10 µM) for 45 minutes and data were normalized to percentage of Quisqualate-induced IP₁ production in cells expressing mGluR1-WT (<b>a</b>). Similarly, the ELISA signals were normalized to percentage of plasma membrane expression of the mGluR1-WT (<b>b</b>). Data are Mean ± SEM of four independent experiments carried out in triplicate. *** P<0.001, ** P<0.01, * P<0.05, ns P>0.05.</p

Distribution of the coding mutations in the <i>GRM1</i> gene and the encoded mGluR1 protein.

<p>(<b>a</b>) All coding mutations relative to gene structure, with <i>GRM1</i> exons 1 to 8 shown in alternating shaded bars. Top panel: changes found in patients; bottom panel: changes found in controls. Colour coding: red - rare missense variants; blue - common missense variants (MAF>1%), black- synonymous variants. (<b>b</b>) Non-synonymous coding changes relative to the mGluR1 receptor protein domains (shown as grey bars). Colour coding: red circles – case-specific, green circles – control specific, red circles with green outline – detected in cases as well as controls. Mutation predicted by bioinformatics programs to have a deleterious effect on protein function are italicised and underlined.</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