Association of genetic risk scores with symptom dimensions and case-control status across thresholds.

**<p>p<.001.</p>*<p>p<.01.</p

Object discrimination was measured by the relative time male mice spend exploring the novel (unknown) object.

<p>Significant longer exploration of the novel object compared to the 50% coincidence level indicates recognition of the novel object compared to the familiar one (group mean +/− SEM).</p

Representation of open field movement tracking pattern measured in individual male and female WT(+/+) and heterozygous KO(+/−) mice in three consecutive 5 minute trials.

<p>Representation of open field movement tracking pattern measured in individual male and female WT(+/+) and heterozygous KO(+/−) mice in three consecutive 5 minute trials.</p

Total distance moved in the open field arena in cm (A) and total time spend in the center of the open field in seconds (B) were measured in the open field test in male and female heterozygous KO(+/−) and WT(+/+) mice (mean +/− SEM).

<p>Alpha was set at 0.0167 after Bonferroni correction.</p

Habituation was described by the difference between trial 3 and trial 1, determined for the total distance moved in the open field (A) and the total time spend in the center of the open field test (B).

<p>Error bars are standard errors of the mean. P-values of less than 0.050 shows significant effects, while p-values between 0.050 and 0.100 indicate a trend.</p

Age-associated hypomethylated blocks enriched for hypermethylated CGIs.

<p><b>A)</b> Example of a large genomic region on chromosome-19 containing a significant age-associated hypomethylated block (indicated in green). y-axis gives the fit from the Bumphunter algorithm indicating the methylation change for an increase in 10 age-years, x-axis the genomic position. <b>B)</b> Selected age-hypomethylated blocks enriched for CGIs undergoing hypermethylation. Each plot shows the fit from the Bumphunter algorithm indicating the methylation change per 10 age-years (y-axis) as a function of opensea probe position (x-axis). In blue we indicate the positions of CGIs, and in red those that are significantly hypermethylated with age. Some of the genes associated with the age-hypermethylated CGIs are indicated in red.</p

Age-associated hypermethylation (hypomethylation) targets lowly (highly) expressed genes.

<p><b>A)</b> Boxplots of mRNA expression levels in cord blood and placenta samples, for three sets of genes: (i) genes undergoing age-associated hypomethylation in their CGI promoters (AgeHypoM), (ii) genes not undergoing any age-associated DNAm changes (NonAgeDMR), and (iii) genes undergoing age-associated hypermethylation in their CGI promoters (AgeHyperM). P-values shown between groupds are from a Wilcoxon-rank sum test comparing the respective neighboring gene classes. The number of genes in each class is indicated below plot. The P-value from a linear regression of expression against gene-class is also indicated in red. <b>B)</b> Left panel: As A) but for the whole blood samples of de Jong et al 2014, for individuals under the age of 30. Right panel: As left panel, but now for 49 whole blood samples from people over the age of 50. <b>C)</b> As B) but now for the expression data set of Beineke et al 2012.</p

Age-associated hypomethylated blocks exhibit preferential hypomethylation in cancer.

<p>Left boxplots show the average beta methylation levels over open-sea regions within an age-associated hypomethylated block on Chr-10 in normal tissue and age-matched cancers from the TCGA. (<b>A)</b> Endometrial Cancer (UCEC), <b>B)</b> Lung Adenoma Carcinoma (LUAD), <b>C)</b> Breast Cancer, <b>D)</b> Lung Squamous Cell Carcinoma (LSCC). P-values in boxplots are from a Wilcoxon rank sum test. Number of samples in each group is indicated. Right panel depicts the density distribution of the t-statistics of all age-hypomethylated blocks (magenta), as assessed between normal and age-matched cancer tissue. The cyan curve represents the corresponding statistics for a random set of non-age associated blocks, matched for number and length distribution of the observed age-hypomethylated blocks. P-value is from a Kolmogorov-Smirnov test.</p

Identification of pluripotent and lineage-specific TFs by integration of Illumina 450k DNAm with ENCODE data.

<p><b>A)</b> Probabilities that a randomly picked open-sea, shore/shelf and CpG-island region is a DMR between pluripotent and differentiated cells (defined as the top 5% of DMRs). <b>B)</b> Relative numbers of DMRs hypomethylated within hESCs and differentiated cell types and within each regional class. <b>C)</b> Enrichment heatmap of transcription factor binding sites (as assessed in H1-hESC) for 58 TFs, among the DMRs hypomethylated in hESCs (HypoESC) and DMRs hypomethylated in differentiated cells (HypoDIFF). <b>D)</b> Enrichment heatmap of transcription factor binding sites (HepG2 line) for the top ranked 58 TFs, among DMRs hypomethylated in hESCs (HypoESC) and DMRs hypomethylated in liver cells (HypoLIV). In C-D), TFs have been ranked according to the significance of enrichment among HypoESC DMRs. Color codes: white (<i>P</i> > 0.01), pink (<i>P</i> < 0.01), red (<i>P</i> < 1<i>e</i> − 5), brown (<i>P</i> < 1<i>e</i> − 10). ChIP-Seq binding profiles of the same TF but generated by different labs are distinguished by an abbreviation of the corresponding lab: SF (Stanford), HA (Hudson-Alpha).</p

Enrichment of TFBSs among age-DMRs.

<p><b>A)</b> Left top panel depicts the age of the individuals from which the blood samples were taken, sorted by increasing age. Heatmap depicts relative DNA methylation levels for the top 500 age-hypomethylated and top 500 age-hypermethylated DMRs (blue = relative high DNA methylation, yellow = relative low DNA methylation), with samples sorted by increasing age. Right panel depicts (with black lines) which DMRs overlap with transcription factor binding sites (TFBS) for a number of TFs which exhibited highly significant enrichment either for age-hypermethylated or age-hypomethylated DMRs (or both). Below the panels we give the odds ratios (OR) and Fisher-test P-values (P) of enrichment of the corresponding TFBSs among age-hypermethylated and age-hypomethylated regions of the top 5% of age-DMRs. <b>B)</b> Combinatorial enrichment analysis of TFBSs. TFs have been sorted according to the strength of association (P-value) of their binding profile with the association of a region’s DNA methylation with age, as assessed from a multivariate linear regression model. Color code for P-values: white (<i>P</i> > 0.01), pink (<i>P</i> < 0.01), red (<i>P</i> < 1<i>e</i> − 5), brown (<i>P</i> < 1<i>e</i> − 10). Below P-value bar we show the corresponding estimated t-statistic in the multivariate analysis (magenta = strongly significant (<i>P</i> < 0.001) positive values, cyan = strongly significant (<i>P</i> < 0.001) negative values).</p