Select characteristics of study populations.

a<p>Corresponding mean E2 concentrations in pg/ml are 8.0, 23.7, and 5.5 and mean T concentrations in ng/dl are 23.7, 24.5, and 23.7 for NHS non-PMH users, NHS PMH users, and SIBS participants, respectively.</p

Summary of regions associated with log SHBG, log estradiol, and log testosterone levels at P<10⁻⁵ from GWAS meta-analyses. of non-PMH users.

a<p>From NCI genome build 35. ^bMajor/minor allele. ^cMinor allele frequency.</p>d<p>Combined effect sizes and P values are calculated using a fixed-effects meta-analysis (METAL software).</p

Summary of genes in the Clathrin-mediated vesicle pathways used for pathway-based analysis of multi-study bladder cancer GWAS.

1<p>Number of SNPs genotyped in the gene region (20 kb 5′ upstream and 10 kb 3′ downstream from the gene's coding region).</p>2<p>The SNP representing the gene in the pathway analysis after the removal of SNPs with heterogeneous effects.</p>3<p>The rank of the SNP among all SNPs in the gene's region based on their p-values.</p>4<p>Minor allele frequency among controls.</p>5<p>Per allele odds ratios +95% confidence intervals from logistic regression models adjusting for age, sex, study center, DNA source, and smoking.</p>6<p>1 d.f. trend test.</p

Summary of genes in the NAD metabolism pathways used for pathway-based analysis of multi-study bladder cancer GWAS.

1<p>Number of SNPs genotyped in the gene region (20 kb 5′ upstream and 10 kb 3′ downstream from the gene's coding region).</p>2<p>The SNP representing the gene in the pathway analysis after the removal of SNPs with heterogeneous effects.</p>3<p>The rank of the SNP among all SNPs in the gene's region based on their p-values.</p>4<p>Minor allele frequency among controls.</p>5<p>Per allele odds ratios +95% confidence intervals from logistic regression models adjusting for age, sex, study center, DNA source , and smoking.</p>6<p>1 d.f. trend test.</p

Summary of genes in the aromatic amine metabolism pathway used for pathway-based analysis of multi-study bladder cancer GWAS.

1<p>Number of SNPs genotyped in the gene region (20 kb 5′ upstream and 10 kb 3′ downstream from the gene's coding region).</p>2<p>The SNP representing the gene in the pathway analysis after the removal of SNPs with heterogeneous effects.</p>3<p>The rank of the SNP among all SNPs in the gene's region based on their p-values.</p>4<p>Minor allele frequency among controls.</p>5<p>Per allele odds ratios +95% confidence intervals from logistic regression models adjusting for age, sex, study center, DNA source , and smoking.</p>6<p>1 d.f. trend test.</p

Pathways enriched with bladder cancer susceptibility loci at a <i>P</i>≤0.01 level using GSEA and ARTP.

<p>Results of the top ranked pathways (<i>P</i><0.01) using GSEA and ARTP. In parenthesis are results prior of removal SNPs displaying heterogeneous signals.</p>1<p>The number of genes in the pathway.</p>2<p>The number of genes underlying the enrichment signal in the pathway.</p>3<p><i>P</i>-value of the enrichment score based on 10,000 permutations.</p>4<p>False-discovery rate calculated based on the normalized statistics of the permutation data to account for the variable sizes of genes and pathways.</p

Summary of genes in the Mitotic Metaphase/Anaphase Transition pathway used for pathway-based analysis of multi-study bladder cancer GWAS.

1<p>Number of SNPs genotyped in the gene region (20 kb 5′ upstream and 10 kb 3′ downstream from the gene's coding region).</p>2<p>The SNP representing the gene in the pathway analysis after the removal of SNPs with heterogeneous effects.</p>3<p>The rank of the SNP among all SNPs in the gene's region based on their p-values.</p>4<p>Minor allele frequency among controls.</p>5<p>Per allele odds ratios +95% confidence intervals from logistic regression models adjusting for age, sex, study center, DNA source , and smoking.</p>6<p>1 d.f. trend test.</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

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