Clustering of Genetic Correlations

<p>The 98 quantative traits are classified into clusters inferred from genetic correlations between any two traits, with an “average” distance measure used in the clustering algorithm. Classes of traits are color-coded as personality (red), serum composition (blue), cardiovascular (black), and anthropometric (green). Overlap of the apparent genetic contribution to variance is indicated on the ordinate, with larger overlaps towards the bottom. Eighteen values exceed 50% overlap (see text).</p

Top association signals for IL-6, ESR, MCP-1, and hsCRP in the ImmunoChip and MetaboChip data-sets.

<p>The table summarizes top association signals for IL-6, ESR, MCP-1 and hsCRP phenotypes in the ImmunoChip and MetaboChip data-sets (Step 3). For each marker, frequency and effect estimates are given with respect to the minor allele. We also reported the r² with the SNP detected in the GWAS scan (Step 1). Novel signals are indicated in bold.</p>a<p>The effect size is measured in standard deviation units, being estimated as the β coefficient of the regression model when using the normalized trait (e.g. an effect size of 1.0 implies each additional copy of the allele being evaluated increases trait values by 1.0 standard deviations).</p>b<p>I =  ImmunoChip, M =  MetaboChip.</p>c<p>The table reports the pvalue on the primary analysis. On the conditional analysis, the pvalue for the independent SNPs were: rs12378220, 9.43×10⁻⁰⁸; rs3093077, 9.02×10⁻¹¹; rs2259816, 7.58×10⁻¹⁰.</p>d<p>Independent signals.</p

Manhattan plot and QQ plot of association findings.

<p>The figure summarizes the association results obtained on the ImmunoChip and MetaboChip markers (Step 3). The blue dotted line marks the Bonferroni threshold significance levels (1.7×10⁻⁷), and SNPs in loci exceeding this threshold are highlighted in green. The bottom panel represents the QQ plot, where the red line corresponds to all test statistics, and the blue line to results after excluding statistics at top markers (highlighted in green in the Manhattan Plot). The gray area corresponds to the 90% confidence region from a null distribution of P values (generated from 100 simulations).</p

Zoom views of the association results in the loci associated with IL-6 and ESR.

<p>Each panel shows the association curve around the strongest SNP, which is highlighted with a purple dot. The SNPs are coloured according to their linkage disequilibrium (r²) with the top variant in the 1000 Genomes European data set, with symbols that reflect genomic annotation as indicated in the legend. Arrows highlight independent signals, if any, described in the manuscript; while light blue lines indicate the recombination rate, according to the right-hand Y axis. Genomic positions are as in build 37. Gene transcripts are annotated in the lower box. Plots were drawn using the standalone LocusZoom version <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002480#pgen.1002480-Pruim1" target="_blank">[65]</a>.</p

Zoom views of the association results in the loci associated with MCP-1 and hsCRP.

<p>Each panel shows the association curve around the strongest SNP, which is highlighted with a purple dot. The SNPs are coloured according to their linkage disequilibrium (r²) with the top variant in the 1000 Genomes European data set, with symbols that reflect genomic annotation as indicated in the legend. Arrows highlight independent signals, if any, described in the manuscript; while light blue lines indicate the recombination rate, according to the right-hand Y axis. Genomic positions are as in build 37. Gene transcripts are annotated in the lower box. Plots were drawn using the standalone LocusZoom version <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002480#pgen.1002480-Pruim1" target="_blank">[65]</a>.</p

Top genome-wide association results for IL-6, ESR, MCP-1, and hsCRP.

<p>The table summarizes top genome-wide association signals for IL-6, ESR, MCP-1 and hsCRP phenotypes in the HapMap based GWAS (Step 1), as well as results in the replication independent cohort (Step 2) and in the combined data-sets. For each marker, frequency and effect estimates are given with respect to the minor allele. Imputation quality scores (RSQ) are reported for imputed SNPs. Novel signals are indicated in bold.</p>a<p>The effect size is measured in standard deviation units, being estimated as the β coefficient of the regression model when using the normalized trait (e.g. an effect size of 1.0 implies each additional copy of the allele being evaluated increases trait values by 1.0 standard deviations).</p>b<p>Independent signals.</p

Independent SNPs associated with TSH and FT4 serum levels.

<p>The table shows the association results for SNPs that reached genome-wide level (p<5×10⁻⁰⁸) in the main meta-analysis. SNPs at <i>LPCAT2/CAPNS2</i> and <i>NETO1/FBXO15</i> reached the GW threshold in the gender-specific meta analysis (see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003266#pgen-1003266-t003" target="_blank">Table 3</a>), and here the p-value in the main meta-analysis is reported. For each SNP, the best candidate gene is showed, as well as its genomic position in build 36, the effect allele (A1) and the other allele (A2), its combined frequency across studies and its standard error, the effect size and its standard error, the p-value for association, the number of samples analyzed, and the p-values for heterogeneity of effects across the cohorts meta-analyzed. Effect sizes are standardized, so they represent the estimated phenotypic change, per each copy of the effect allele, in standard deviation units.</p

Regional association plots showing genome-wide significant loci for serum TSH.

<p>In the upper panel, the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003266#pgen.1003266-Pruim1" target="_blank">[61]</a>. Genes and the position of exons, as well as the direction of transcription, are noted in the lower box. The scale bar on the Y-axis changes according to the strength of the association.</p

Regional association plots showing genome-wide significant loci for serum TSH.

<p>In each panel (A–F), the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003266#pgen.1003266-Pruim1" target="_blank">[61]</a>. Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.</p

Regional association plots showing genome-wide significant loci for serum FT4.

<p>In each panel (A–F), the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003266#pgen.1003266-Pruim1" target="_blank">[61]</a>. Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.</p