Temporal trends in GWAS publications and results availability.

<p>Top panel: Cumulative chronological release of 643 GWAS papers at their earliest release dates. Middle panel: Distribution of GWAS papers among five categories of reported maximum results availability from 2002 to 2006, and in 6-month intervals from January 1, 2007 to July 1, 2010. Bottom panel: Distribution of 643 GWAS papers among five categories of reported maximum results availability by open access or controlled access application in the period before October 1, 2008 (left) and from October 1, 2008 to July 1, 2010 (right).</p

Top five genes whose eSNPs show strongest association with CAD in GWAS (termed “GWAS signal genes”) and key driver genes for selected CAD-associated supersets.

<p>^*Genes within superset whose eSNPs (i.e. putative functional SNPs that affect gene expression) show best association with CAD in the GWAS meta-analysis.</p>#<p>The key driver genes were ascertained by combining key driver analyses of all available Bayesian networks, and taking into account both the consistency across datasets and the KDA statistics.</p

Key driver genes of six CAD-associated supersets, and their adjacent regulatory partners.

<p>Key driver genes were denoted as larger nodes in the network. Genes were colored based on their membership in the six CAD-associated supersets. A) ‘Lipid II’ superset in red. B) ‘Lipid I’ superset in yellow. C) ‘Unknow II’ superset in lime. D) ‘Immunity’ superset in green. E) ‘Antigen’ superset in blue. F) ‘Unknown I’ superset in magenta. Only edges that were present in at least two Bayesian networks constructed from independent studies were included.</p

Schematic overview of the study design.

<p>A) The SNP set enrichment analysis (SSEA) comprised four steps. First, gene sets from knowledge-driven pathways and data-driven co-expression modules were collected. Second, the gene sets were converted to expression SNP (eSNP) sets according to genetics of gene expression or eQTL studies. Third, P-values from CAD GWAS were extracted for each eSNP. Fourth, the GWAS P-values within eSNP sets were compared against random expectation to derive pathways and network modules enriched for CAD genetic signals. B) Overlapping CAD-associated gene sets were merged and trimmed into non-overlapping supersets. C) Integration of Bayesian gene-gene network models with CAD-associated supersets to determine key driver genes based on network topology.</p

Knowledge-based grouping of canonical pathways that were significantly enriched for CAD genetic loci.

<p>The enrichment score was defined as the mean of negative log-transformed Kolmogorov-Smirnov and Fisher P-values for over-representation of high-ranking GWAS SNPs among the eSNPs that affect the expression of the pathway member genes. The number in parentheses in the first column indicates the number of CAD-associated pathways (detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004502#pgen.1004502.s004" target="_blank">Table S1</a>).</p><p>*FDR<20% in Stage 1 and 2 respectively, and FDR<5% in combined Stage 1 & 2.</p

CAD enrichment scores for selected non-overlapping supersets after the merging of CAD-associated canonical pathways and co-expression modules.

<p>The enrichment score was defined as the mean of negative log-transformed Kolmogorov-Smirnov and Fisher P-values for over-representation of high-ranking GWAS SNPs among the eSNPs that affect the expression of the superset member genes.</p><p>*P<0.05 in either Fisher's exact test or Kolmogorov-Smirnov test after Bonferroni correction for the 3,539 original gene sets.</p

Gene set enrichment analysis for BP associated gene expression changes.

<p>*<b>NES</b>: normalized enrichment score;</p><p><b>GO-BP</b>: Gene ontology- biological process;</p><p><b>KEGG</b>: Kyoto encyclopedia of genes and genomes.</p><p>Gene set enrichment analysis for BP associated gene expression changes.</p

GWAS eQTLs for the top differentially expressed BP signature genes.

<p>* rs653178, intronic to <i>ATXN2</i> and in tight linkage disequilibrium with rs3184504 (r² = 1), was also associated with BP in ICBP GWAS and all the 6 genes;</p><p>⁺ A proxy SNP rs4698412 at LD r² = 1 associated with the same trait;</p><p>$ A proxy SNP rs4389526 at LD r² = 1 associated with the same trait;</p><p>^§ indicated eQTL were identified from[<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005035#pgen.1005035.ref012" target="_blank">12</a>].</p><p>^& highlighted p values indicated passing transcriptome-wide significance at Bonferroni corrected <i>p</i><0</p><p>GWAS eQTLs for the top differentially expressed BP signature genes.</p

Global view of BP eQTLs effects on differentially expressed BP signature genes.

<p>A) 2-Dimensional plot of in whole blood eQTLs vs. transcript position genome wide. eQTL-transcript pairs at FDR<0.1 are shown in black dots; those that fall along the diagonal are cis eQTLs and all others are trans eQTLS. eQTL-transcript pair SNPs that are associated with BP in GWAS [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005035#pgen.1005035.ref003" target="_blank">3</a>] are highlighted with blue triangles. eQTL-transcript pair genes that are BP signature genes from analysis of differential gene expression in relation to BP are depicted by red circles. B) Regional association plots for rs3184504 proxy QTLs that showing association with BP in ICBP GWAS [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005035#pgen.1005035.ref003" target="_blank">3</a>]. −log10(p) indicated the −log10 transformed DBP association <i>p</i> values in ICBP GWAS [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005035#pgen.1005035.ref003" target="_blank">3</a>]. Color coding indicates the strength (measured by r²) of LD of each SNP with the top SNP (rs3184504). Five master <i>trans-</i>eQTLs (also BP GWAS SNPs) for BP signature genes are labeled in the figure. This figure was drawn by LocusZoom [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005035#pgen.1005035.ref032" target="_blank">32</a>].</p

Differentially expressed genes associated with BP and hypertension at Bonferroni correction <i>p</i><0.05 in meta-analysis of the six cohorts.

<p>*<b>Meta</b>: meta-analysis of all six cohorts.</p><p>Differentially expressed genes associated with BP and hypertension at Bonferroni correction <i>p</i><0.05 in meta-analysis of the six cohorts.</p