T2D prediction, glycemic genetic score.

<p>Forest plot of association between glycemic genetic score with incident T2D over a decade-long follow-up period, by ancestry. MESA (European and Asian ancestry) and the <i>G6PD</i> variant (rs1050828) in ARIC (European and African American) were not included in the discovery GWAS analysis. Effect estimates were combined in a fixed effects meta-analysis. Overall effect estimate: 1.05, 95% CI 1.04–1.06, <i>p</i> = 2.5 × 10⁻²⁹. ARIC, Atherosclerosis Risk in Communities Study; ES, Effect Size; FHS, Framingham Heart Study; GWAS, genome-wide association study; G6PD, glucose-6-phosphate dehydrogenase; I-Squared, Higgin's I-squared statistic, a measure of heterogeneity; MESA, Multiethnic Study of Atherosclerosis; SCHS, Singapore Chinese Health Study; T2D, type 2 diabetes.</p

Manhattan plot of HbA1c associated variants.

<p>Manhattan plot of the transethnic meta-analysis results in MANTRA. The dashed grey line indicates log₁₀BF = 6. Grey and green points denote known/novel loci, respectively. The lead HbA1c-associated variants identified through the ancestry-specific/transethnic analyses are circled in purple (the <i>G6PD</i> variant was not included in the MANTRA analysis, but the locus on the X-chromosome is indicated in the figure). Lines joining the plot & SNP number denote known loci (black), novel loci (green), and loci with a secondary distinct signal (red). MANTRA, Meta-Analysis of Transethnic Association.</p

Reclassification of individuals with discordant T2D status based on prevailing diagnostic thresholds for FG and HbA1c before and after accounting for the effect of erythrocytic variants.

<p>Reclassification of individuals with discordant T2D status based on prevailing diagnostic thresholds for FG and HbA1c before and after accounting for the effect of erythrocytic variants.</p

Mean HbA1c of individuals at the bottom 5% and top 5% of the distribution of ancestry-specific genetic scores and rs1050828 by genotype.

<p>The difference in measured HbA1c of individuals at the bottom 5% and top 5% of the distribution of an ancestry-specific additive GS composed of all 60 variants (GS-Total), and the equivalent calculation for an ancestry-specific GS composed of up to 20 erythrocytic variants (GS-E). Far right of the figure shows the mean HbA1c by genotype for chromosome X rs1050828. AA men, African American men; AA women, African American women; HbA1c, glycated hemoglobin; GS, genetic scores.</p

T2D prediction, erythrocytic genetic score.

<p>Forest plot of association between erythrocytic genetic score with incident T2D over a decade-long follow-up period, by ancestry. MESA (European and Asian ancestry) and the <i>G6PD</i> variant (rs1050828) in ARIC (European and African American) were not included in the discovery GWAS analysis. Effect estimates were combined in a fixed effects meta-analysis. Overall effect estimate: 1.00, 95% CI 0.99–1.01, <i>p</i> = 0.60. ARIC, Atherosclerosis Risk in Communities Study; ES, Effect Size, FHS, Framingham Heart Study; GWAS, genome-wide association study; G6PD, glucose-6-phosphate dehydrogenase; I-Squared, Higgin's I-squared statistic, a measure of heterogeneity; MESA, Multiethnic Study of Atherosclerosis; SCHS, Singapore Chinese Health Study; T2D, type 2 diabetes.</p

Table of HbA1c associated variants.

<p>Table with results and classification of the 60 HbA1c-associated variants. SNP number corresponds to number in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002383#pmed.1002383.g001" target="_blank">Fig 1</a>.</p

T2D prediction, erythrocytic genetic score adjusted for HbA1c as a binary variable.

<p>Forest plot of association between erythrocytic genetic score with incident T2D over a decade-long follow-up period adjusted for HbA1c as a binary variable (≥5.7% versus <5.7%), by ancestry. HbA1c at baseline was not available in SCHS and was excluded from the meta-analysis. MESA (European and Asian ancestry) and the <i>G6PD</i> variant (rs1050828) in ARIC (European and African American) were not included in the discovery GWAS analysis. Effect estimates were combined in a fixed effects meta-analysis. Overall effect estimate: 0.95, 95% CI 0.94–0.96, <i>p</i> = 3.3 × 10⁻¹⁶. ARIC, Atherosclerosis Risk in Communities Study; ES, Effect Size; GWAS, genome-wide association study; FHS, Framingham Heart Study; G6PD, glucose-6-phosphate dehydrogenase; HbA1c, glycated hemoglobin; I-Squared, Higgin's I-squared statistic, a measure of heterogeneity; MESA, multiethnic study of atherosclerosis; SCHS, Singapore Chinese Health Study; T2D, type 2 diabetes.</p

Overview of design and findings.

<p>Among the 7 identified loci, we defined those close to (<1 cM) published hits <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003500#pgen.1003500-LangoAllen1" target="_blank">[25]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003500#pgen.1003500-Speliotes1" target="_blank">[29]</a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003500#pgen.1003500-Heid1" target="_blank">[31]</a> as <i>near published hit</i>s and <i>novel</i> otherwise. Novel loci with sex-combined discovery P-value<5.8×10⁻⁵, which is the P-value cut-off corresponding to 5% FDR, were declared as loci that <i>could have been discovered also with sex-combined analysis</i>, and otherwise that these <i>would have been missed without the sex-stratified analyses</i>. FDR = false discovery rate.</p

Seven SNPs show sex difference.

a<p>Trait and sex for which the SNP was selected;</p>b<p>Gene labels state the nearest gene or the gene as published previously; details on all genes near the association signal can be found in the <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003500#pgen.1003500.s002" target="_blank">Figure S2</a>;</p>c<p>One-sided P-Values.</p>d<p>larger sample size due to one additional study that did not have hip circumference, and therefore could not contribute to WHRadjBMI.</p>e<p>smaller sample size as this SNP was not on Metabochip.</p><p>Shown are the seven SNPs with significant (at 5% false discovery rate) sex difference in the follow-up data. These seven SNPs exhibit genome-wide significant association in women (joint discovery and follow-up <i>P_women</i><5×10−8) and only two of these show nominally significant association in men (joint <i>P_men</i><0.05). The three loci MAP3K1, HSD17B4, and PPARG are shown here for the first time for their anthropometric trait association as well as for sex-difference.</p

Seven identified SNPs compared to previously published loci.

a<p>The Effect allele refers to a positive effect direction in the discovery stage for the trait and gender, the SNP was selected for;</p>b<p>Gene near this SNP which was published previously from sex-combined analyses.</p><p>The seven SNPs with sex difference are considered to depict a known locus, if the index SNP is close to a published top SNP (<1 cM). These include four of the previously reported sexually dimorphic WHR loci (Heid et al., Nat Genet 2010).</p