Histograms of numbers of genome-wide significant SNPs by tests across 290 traits.

We compare the signals identified by TFemale: Female-only analysis, TMale: Male-only analysis, TDiff: SNP-sex interaction-only test, T1,metaL: Traditional sex-combined meta-analysis, and T2,metaQ: Omnibus meta-analysis. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of 361,194 participants (194,174 females and 167,020 males). We excluded phenotypes with no signals in any of the five methods. (TIF)</p

Histograms of the number of associated traits across 1,113,865 SNPs associated with one or more traits, stratified by the five testing methods.

1,113,865 SNPs are associated with one or more traits identified by any of the five association testing methods: TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis). The histograms are based on , where I(⋅) is an indicator function, pj,t, m is the association p-value between SNP j and trait t by method m. The y-axis ticks are on the log10 scale for ease of visualization. (TIF)</p

19 bi-allelic SNPs exhibiting genome-wide significant effects on urate in opposite directions in females and males (including IRNT results).

We compared the p-values for the following methods: TFemale: Female-only analysis, TMale: Male-only analysis, TDiff: SNP-sex interaction-only test, T1,metaL: Traditional sex-combined meta-analysis, and T2,metaQ: Omnibus meta-analysis. The βFemale and βMale columns show the sex-specific effect size estimates from the stratified analysis, indicating the estimated effect of each copy of the minor allele. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of 361,194 participants (343,836 in urate GWAS, 184,755 females and 159,081 males). Columns notated with IRNT show result based on inverse normal transformed urate phenotype. (PDF)</p

Stacked Manhattan plots of genome-wide significant SNPs.

(A) 64,934 SNP-phenotype associations identified by T2,metaQ but missed by all other four methods across all the 290 traits, (B) 800,183 SNP-phenotype associations missed by T2,metaQ but identified by any other four methods across all the 290 traits, (C) 63,647 SNP-phenotype associations identified by T2,metaQ but missed by all other four methods after removing the testosterone, and (D) 797,585 SNP-phenotype associations missed by T2,metaQ but identified by any other four methods after removing the testosterone. The −log10 p-values (with further log10 transformation on y-axis to aid presentation) are shown for the five association methods, including TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis); see Table 1 for method details. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of up to 361,194 participants (194,174 females and 167,020 males). The red horizontal lines indicate the genome-wide significant threshold of 5 × 10−8 on the −log10 scale. (TIF)</p

Manhattan plots of the number of associated traits for each of the 1,113,865 SNPs associated with one or more traits, stratified by the five testing methods.

The 1,113,865 SNPs are associated with one or more traits identified by any of the five association testing methods: TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis). The plots are based on , where I(⋅) is an indicator function, pj,t, m is the association p-value between SNP j and trait t by method m. (TIF)</p

Pairwise scatter plots of the genome-wide significant (<i>p</i> < 5 × 10⁻⁸) associations detected by any of the five testing methods considered.

(A) includes 6,207,519 SNP-phenotype associations across all 290 traits analyzed, and (B) includes 6,175,594 SNP-phenotype associations after excluding testosterone. The five association methods include TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis); see Table 1 for method details. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of up to 361,194 participants (194,174 females and 167,020 males). Axes depict −log10 p-values for each pair of tests, and each hexagon’s color corresponds to the count of associations falling within the −log10 p-value range defined by that region. Dashed line indicates the main diagonal reference line. The −log10 p maximum was truncated at 200 to improve visualization.</p

Stacked Manhattan plots of genome-wide significant SNPs with either sex-stratified MAF ≤ 0.05, comparing <i>T</i>_{2,<i>metaQ</i>} vs all other four methods.

(A) SNPs identified by T2,metaQ but missed by all other four methods across all the 290 traits, (B) SNPs missed by T2,metaQ but identified by any other four methods across all the 290 traits, (C) SNPs identified by T2,metaQ but missed by all other four methods after removing the testosterone, and (D) SNPs missed by T2,metaQ but identified by any other four methods after removing the testosterone. The −log10 p-values (with further log10 transformation on y-axis to aid presentation) are shown for the five association methods, including TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis); see Table 1 for method details. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of up to 361,194 participants (194,174 females and 167,020 males). The red horizontal lines indicate the genome-wide significant threshold of 5 × 10−8 on the −log10 scale. (TIF)</p

Pairwise scatter plots of the number of associated traits across the 1,113,865 SNPs among the five testing methods.

The 1,113,865 SNPs are the SNPs associated with one or more traits identified by any of the five association testing methods: TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis). The plots are based on , where I(⋅) is an indicator function, pj,t, m is the association p-value between SNP j and trait t by method m. (TIF)</p

Stacked Manhattan plots (A) and pairwise scatter plots (B) of genetic association for testosterone level.

In (A) the −log10 p-values (with further log10 transformation on y-axis to aid presentation) are shown for the five association methods, including TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test), T1,metaL (the traditional sex-combined meta-analysis), and T2,metaQ (the omnibus meta-analysis); see Table 1 for method details. The sex-stratified GWAS summary statistics come from the Neale lab’s UK Biobank GWAS round 2, which included a cohort of up to 361,194 participants (312,102 in testosterone GWAS, 154,364 females and 157,738 males). The red horizontal lines indicate the genome-wide significant threshold of 5 × 10−8 on the −log10 scale. In (B), axes depict −log10 p-values for each pair of tests. For simplicity in computation and better visualization, we only included points that achieved genome-wide significance in at least one of the five tests. The −log10 p maximum was truncated at 200 to improve visualization. The dashed line indicates the reference main diagonal line. (TIF)</p

Histogram of the number of associated loci uniquely identified by <i>T</i>_{2,<i>metaQ</i>} but missed by any of the other four methods across phenotypes.

In total, 164 out of the 290 tested phenotypes have one or more associated loci identified by T2,metaQ (the omnibus meta-analysis), but missed by all four of TFemale (Female-only analysis), TMale (Male-only analysis), TDiff (SNP-sex interaction-only test) and T1,metaL (the traditional sex-combined meta-analysis). (TIF)</p