LocusZoom plots of sleep duration associations in the <i>VRK2</i> locus.

<p>Both plots show the same locus but each highlights a different lead variant: rs1380703 (left) and rs17190618 (right). Variants with association <i>P</i>-values > 0.01 were omitted for clarity. The two leads variants represent separate signals.</p

Genetic variants associated with chronotype (as either a continuous or binary trait) at <i>P</i><5x10^-8 in the UK Biobank study.

<p>Variants highlighted in bold were not identified by the 23andMe study, those in italic did not reach genome-wide significance on meta-analysis and those not highlighted replicate previously reported loci from 23andMe. Genes listed are candidate or nearest genes within 250Kb of the lead SNP. Odds ratios correspond to risk of morningness over eveningness. Beta, OR and frequency refers to A1. Replication data is based on continuous data and as the replication beta is in different units to the discovery GWAS beta, a P-value meta-analysis was performed.</p

LocusZoom plot of chronotype associations in the <i>PER2</i> locus.

<p>Variants are coloured by their LD r² with lead variant rs75804782 and those with association <i>P</i>-values > 0.01 were omitted for clarity.</p

LocusZoom plot of chronotype associations in the <i>RGS16</i> locus.

<p>The plot displays -log₁₀ <i>P</i>-value on the y-axis and physical position on the x-axis. Points identify individual variants whose colour indicates their LD r² with lead variant rs516134. The blue line indicates pre-calculated recombination rates (in cM/Mb) at each position. Variants with association <i>P</i>-values > 0.01 were omitted for clarity.</p

Manhattan and quantile-quantile (QQ) plots for chronotype.

<p>Summary information plots for inverse-normalised (self-report) Sleep Duration vs. ~16.8 million imputed genetic variants in 127,573 White British individuals in the UK Biobank study. The Manhattan plot (top) shows association test (-log₁₀ <i>P</i>-value on the y-axis against physical autosomal location on the x-axis with the standard genome-wide significance cutoff of <i>P</i> = 5x10^-8 shown by the horizontal black line. Variants tested had imputation R²>0.4, a Hardy-Weinberg Equilibrium (HWE) <i>P</i>-value > 1x10^-6 and minor allele frequency (MAF) > 0.1%. The Sleep Duration QQ plot (bottom) identifies some inflation (λ_GC = 1.097) but, as with Chronotype, this is consistent with expected inflation from a highly polygenic trait in such a large sample size [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006125#pgen.1006125.ref015" target="_blank">15</a>].</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

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

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