The ability of ASE and GTE analysis to detect significantly associated rSNPs at different MAF.

<p>Fractions of rSNPs are shown for different minor allele frequencies (MAF) with significant association signals according to a Bonferroni-corrected p-value of 0.05. Each data point underlying the curves represents the fraction of significant associations within a 1% MAF bin. Sliding 5% MAF window averages are plotted for different sample sizes analyzed by ASE and GTE. Both methods detect a lower fraction of low frequency rSNPs, compared to the fraction of all the SNPs at the same frequency (black line). The ASE method detects a higher fraction of the SNPs (solid lines) with a MAF <15% than GTE (dashed lines) regardless of sample size except for the largest GTE sample set.</p

Overlap of significantly associated rSNPs identified by ASE and GTE.

<p>The percentage of overlapping rSNPs detected by allele-specific expression (ASE) and genotype expression (GTE) analysis is plotted for varying numbers of samples. The top 9536 SNPs from the GTE analysis are compared with the top 38203 SNPs from the ASE analysis, which corresponds to a Bonferroni threshold of p = 0.05 for a GTE sample size of 395 and an ASE sample size of 188. The p-value cut-offs were adapted so that the same SNP top-list sizes were obtained at all sample sizes for both GTE (p-value of 1.17E-7, 1.06E-4, 1.93E-3, 6.12E-3 for n = 395, n = 188, n = 95, and n = 50 respectively) and ASE (p-value of 8.06E-8, 9.35E-5, 4.90E-3 for n = 188, n = 95, and n = 50 respectively). The vertical axes show the percentage of SNPs in the top-lists detected by both GTE and ASE analysis and the horizontal axes show the number of samples analyzed using GTE and ASE, respectively. The percentage overlap is calculated by dividing the number of overlaps with the number of top SNPs in the GTE analysis. In (A), each line shows the effect on the number of overlapping SNPs detected by ASE analysis of a specific sample size when the sample size in GTE analysis was increased. In (B), each line shows the effect on the number of overlapping rSNPs detected by GTE analysis of a specific sample size when the samples size in ASE analysis is increased.</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

Consistently higher effect sizes for women for all seven loci.

<p>Shown are beta-estimates and 95% confidence intervals for the seven identified SNPs (also stating the phenotype for which the SNP was selected for).</p

Genome-wide scan for sex-specific genome-wide association highlights numerous loci.

<p>(a) Manhattan plot showing the men-specific (upward, up to 60,586 men) and women-specific (downward, up to 73,137 women) association P-values from the discovery with the 619 selected loci colored by the phenotype for which the locus was selected; (b) QQ-plot showing the sex-specific association P-values as observed against those expected under the null overall phenotypes (black) and for each phenotypes separately (colored).</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

Genome-wide sex-difference scan fails to pinpoint loci.

<p>(a) Manhattan plot showing sex-difference P-values, (b) QQ plot for sex-difference P-values overall phenotypes (black) and for each phenotype separately (colored).</p