Additional file 3: of Recently evolved human-specific methylated regions are enriched in schizophrenia signals

Annotation of enriched DMRs with genes, promoters, CpG islands and enhancers. This file contains detailed annotation of those human-lineage specific DMRs that are enriched for association with schizophrenia markers (except those in the MHC region). Compared to Additional file 2, these DMRs represent those that are enriched and whether they are present in any genes, promoters, enhancers or CpG islands. (XLSX 26 kb

Additional file 2: of Recently evolved human-specific methylated regions are enriched in schizophrenia signals

Annotation of all DMRs with schizophrenia-associated SNPs. This file contains annotation of all the human-lineage specific DMRs that are associated with schizophrenia markers. Details of the various markers present within each DMR is provided, along with the marker with most significant p-value. (XLSX 263 kb

Additional file 1: of Recently evolved human-specific methylated regions are enriched in schizophrenia signals

Additional Method, Figures and Tables (DOCX 475 kb

Schematic representation of the overall method.

<p>A1–A5: GWAS were performed for nine cognitive traits selected from the battery phenotyped in the healthy Norwegian NCNG sample (A1). Using the LDsnpR algorithm <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081052#pone.0081052-Christoforou1" target="_blank">[51]</a>, SNPs were assigned to gene bins (A2–3) and the gene bins were scored using the minimum <i>p</i>-value corrected for the number of SNPs in the bin with an adjusted Sidak <i>p</i>-value. The gene scores were ranked (smallest Sidak <i>p</i>-value to biggest – A4). These GWAS-based ranked lists of genes were used to generate the candidate gene sets, which comprised the top 25, 50, 100, 250, 500, 750, 1000, 1250, 1500, 1750 and 2000 genes associated with each of the cognitive traits (A5). Thus, the candidate gene sets were overlapping, and there was an incremental increase in the number of genes per set. B1–B4: The GWAS data for the psychiatric disorders (B1) were subjected to the same pipeline for assigning SNPs to gene bins (B2–3), scoring (see manuscript), and ranking the genes by their score (smallest Sidak <i>p</i>-value to the biggest – B4).</p

Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with <i>GUCY2C</i>-linked familial diarrhea

Objective: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. Methods: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. Results: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. Conclusions: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.</p

Description of the samples.

<p> BPD, bipolar disorder; SCZ, schizophrenia; NCNG, Norwegian Cognitive NeuroGenetics; TOP, Norwegian Thematically Organized Psychosis; WTCCC, British Wellcome Trust Case Control Consortium; Danish, Danish sub-sample of the Scandinavian Collaboration on Psychiatric Etiology; PGC, Psychiatric Genomics Consortium.</p><p> indicates the cases and controls in the single-centre samples that are also included in the PGC multi-centre sample.</p

A convergent pattern of genetically mediated relationships among cortical surface areas.

A) Genetic correlations (rg) of VETSA derived by an AE twin model. B) Genetic correlations (rg) of C5C derived by genotype-based GCTA-bivariate model. C) Gene expression or transcriptomic similarities of Allen Human Brain Atlas cohort based on Jaccard coefficient that are scaled to [-1,+1] such that they can be displayed on the same color scale with the correlation coefficients. Subsequent analyses were performed on the original similarity coefficients shown in S4 Table. D) Hierarchical clustering of the genetic correlations between cortical regions averaged over standardized twin rg (A), genotype rg (B), and gene expression similarity (C).</p

Testing gene sets associated with normal neurocognitive variation for enrichment of association with bipolar disorder.

<p><i>q</i>-value, obtained from 3 GSEA runs with 1,000 permutations each). The maximum standard deviation from the average <i>q</i>-value was 0.07. Sets that passed the enrichment threshold (<i>p</i>-value≤0.05, FDR <i>q</i>-value≤0.25) were tested for validation using random mimic sets (see Table S4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081052#pone.0081052.s001" target="_blank">File S1</a>). For each GWAS dataset, the 5 most enriched candidate sets are shown. For the German dataset, the 14 most enriched sets are presented to show the overlap with the other datasets. The rank position (R) of the gene set within the total number of gene sets tested is determined by the average false discovery rate (</p><p>% of the random sets (i.e. validated sets).^a indicates sets that were more enriched than 98</p><p>^b indicates sets that did not pass the enrichment threshold but were among the 5 most enriched in the corresponding sample.</p><p>“n.e.”. Visuospatial attention.1 – Visuospatial attention task with valid cue to the location of the visual target; Visuospatial attention.3 – Visuospatial attention task with neutral cue to the location of the visual target. The number after each gene set name represents the number of genes within that set (e.g. the Colour-word interference −25 set contains the top 25 genes within the colour-word interference ranking list of genes). Sets that did not pass the enrichment threshold and ranked outside the top 5 are indicated by </p><p><i>p-</i>value of zero (0.0) indicates an actual <i>p</i>-value of less than 1/number-of-permutations. A reported </p

Testing gene sets associated with normal neurocognitive variation for enrichment of association with schizophrenia.

<p><i>q</i>-value, obtained from 3 GSEA runs with 1,000 permutations each). The maximum standard deviation from the average <i>q</i>-value was 0.06. Sets that passed the enrichment threshold (<i>p</i>-value≤0.05, FDR <i>q</i>-value≤0.25) were tested for validation using random mimic sets (see Table S4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0081052#pone.0081052.s001" target="_blank">File S1</a>). For each GWAS dataset the 5 most enriched candidate sets are shown. The rank position (R) of the gene set within the total number of gene sets tested was determined by the average false discovery rate (</p><p>% of the random sets (i.e. validated sets).^a indicates sets that were more enriched than 98</p><p>^b indicates sets that did not pass the enrichment threshold but were among the 5 most enriched in the corresponding sample.</p><p>“n.e.”. Visuospatial attention.1 – Visuospatial attention task with valid cue to the location of the visual target; Visuospatial attention.3 – Visuospatial attention task with neutral cue to the location of the visual target. The number after each gene set name represents the number of genes within that set (e.g. the Colour-word interference −25 set contains the top 25 genes within the colour-word interference ranking list of genes). Sets that did not pass the enrichment threshold and ranked outside the top 5 are indicated by </p

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

<p>The occipital cortex enriched genes (n = 11) were analysed for allelic association to nine test measures from the NCNG GWAS. For trait abbreviations see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031687#pone-0031687-t004" target="_blank">Table 4</a>. 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>, and 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