Top hits for the set of 27 cardiovascular-related traits.

<p>For each locus, the <i>p</i>-value of the most significant hit is given as calculated in EMMA. Scores are highlighted in bold letters when they were obtained at SNPs with fully documented allelic information. When this information was incomplete, the corrected score was imputed manually (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041032#s4" target="_blank">Material and Method</a>s). Corr. Effect size: effect size at the surrogate SNP used for imputation; *: loci 4 and 6 share identical SDPs on separate chromosomes; ^#: the SDP of locus 7 is compatible with that of suggestive locus 32 for the same trait (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041032#pone.0041032.s014" target="_blank">Table S3</a>); bpm: beats per min; nf: not found.</p

Replication studies.

<p>For each trait listed, the suggestive hits mapped by EMMA were tested using the indicated replication dataset (RD) of the MPD. RD ID: MPD ID number of the trait considered for the replication test; RD strains in EMMA: number of strains of the RD used in EMMA; strains in common: number of strains in common between this study and the RD.</p

Synoptic maps of the top loci associated with the effects of <i>iso</i> and <i>ate</i>.

<p>The genetic maps of eight loci are presented and annotated as described in the legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041032#pone-0041032-g001" target="_blank">Figure 1</a>. CHF: congestive heart failure; AF: atrial fibrillation; LQTS: long QT syndrome.</p

Top hits for the set of approximated drug effects.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041032#pone-0041032-t001" target="_blank">Table 1</a> for the details of the abbreviations.</p

Metabomatching.

<p>Each subfigure compares the <i>CoLaus</i> pseudo-spectrum (bottom half) with the NMR spectrum (top half) of the most likely candidate for the associated metabolite. (A) rs37369 vs. 3-aminoisobutyrate. (B) rs2147896 in <i>PYROXD2</i> vs. trimethylamine (C) rs8101881 in <i>SLC7A9</i> vs. lysine (D) rs281408 in <i>FUT2</i> vs. fucose.</p

Allelic heterogeneity at the <i>AGXT2</i> locus.

<p>Abbreviations: <i>P_C, P_T</i> – P-values, <i>x_C, x_T</i> – multivariate effect sizes, <i>R²</i> – explained variance of full model, <i>R²_diff</i> – additional explained variance of full model compared to best single SNP association, <i>model P</i> – probability of observing same or equal <i>R²_diff</i> increase with the same stepwise model selection for 2,500 permuted phenotypes.</p

Local Manhattan plots.

<p>The Manhattan plots show combined −log(P-values) in the neighborhood of the most strongly associated SNP for (A) the <i>FUT2</i> with fucose association, and (B) the <i>SLC7A9</i> with lysine association.</p

Genome- and metabolome-wide analysis results, first stage.

<p>(A) Manhattan plot for feature 1.2025. (B) Genome- and metabolome-wide P-value heat map, showing associations with <i>P_C</i><5×10⁻⁸ in <i>CoLaus</i>. (C) Pseudo-spectrum for SNP rs37369, obtained by plotting the association P-values between rs37369 and all metabolic features.</p

Locus-metabolite associations.

<p>For every locus, the association results are listed for the strongest association, after meta-analysis, of a SNP in the locus with a feature (bold) of the metabolite. Abbreviations: Chr – chromosome, Position – chromosomal position in NCBI build 36, <i>x_C</i> – effect size in <i>CoLaus</i>, <i>x_T</i> – effect size in <i>TasteSensomics</i>, <i>x_m</i> – effect size after meta-analysis, <i>P_m</i> – P-value after meta-analysis.</p

Genotype-Metabotype-Phenotype associations.

<p>The two novel gene-metabolite associations of this study implicate SNPs that had previously been associated with disease-related phenotypes by the indicated publications: (A) Fucose–Crohn's disease–<i>FUT2</i> (rs492602), (B) Lysine–eGFR–<i>SLC7A9</i> (rs8101881). A link between the metabolite and the phenotype has been established for (A) based on a mouse model and for (B) by a direct correlation with the indicated significance and effect size. Abbreviations: OR refers to the odds ratio, <i>x</i> to the linear regression effect size, <i>P</i> to the corresponding P-value, and the <i>m</i>-index indicates values obtained in the combined <i>CoLaus</i> and <i>TasteSensomics</i> sample.</p