ANM Discovery–SNPs associated with age at natural menopause (ANM) in African American women from the PAGE Study.

<p>Tests of association at p≤1E-04 from single SNP linear regressions adjusted for study site and principal components in 1,860 African American women from the PAGE Study are shown. For each significant test of association, the chromosome, rs number, nearest gene, location, coded allele, beta, standard error (SE), and p-value are given. Genes listed are nearest genes to the SNP as measured from the transcription start site for upstream SNPs or the transcription stop site for downstream SNPs. Abbreviations: CAF, coded allele frequency.</p

Regional Association Plots for Age at Natural Menopause in African American women in the PAGE Study.

<p>Locus Zoom plots for selected gene regions in age at natural menopause analysis. Vertical axis is the –log₁₀ of the p-value, the horizontal axis is the chromosomal position. Each dot represents a SNP tested for association with age at natural menopause in 1,860 African American women from the PAGE Study. Linkage disequilibrium between the most significant SNP, listed at the top of each plot, and the other SNPs in the plot is shown by the r² legend in each plot. (A) Locus Zoom plot for the <i>APOE</i> region, with rs78916952 the most significant SNP in the region. (B) Locus Zoom plot for the <i>MCM8</i> region; rs237688 is the most significant SNP in the plot region. (C) <i>FSHB</i> region Locus Zoom plot; rs605765 is the most significant SNP in the plot region. (D) Locus Zoom plot of the <i>BRSK1</i> region with rs11672111 as the most significant SNP in the plot region.</p

Comparison of GWAS-identified ANM variants in African American women in PAGE Study.

<p>Comparison of previously reported SNPs associated with ANM in European and Chinese descent women to 1,860 African American women from the PAGE Study. Data presented are for the previously identified SNP. If the previously identified SNP was not directly genotyped in present study, data are shown for the best proxy SNP based on linkage disequilibrium calculated from the International HapMap Project CEU data.</p

Regional Association Plots for Age at Menarche in African American women in the PAGE Study.

<p>Locus Zoom plots for selected gene regions in age at menarche analysis. Vertical axis is –log₁₀ of the p-value, the horizontal axis is the chromosomal position. Each dot represents a SNP tested for association with age at natural menopause in 1,860 African American women from the PAGE Study. Approximate linkage disequilibrium between the most significant SNP, listed at the top of each plot, and the other SNPs in the plot is shown by the r² legend in each plot. (A) Locus Zoom plot for the <i>CYP19A1</i> region, with rs10519297 the most significant SNP in the region. (B) Locus Zoom plot for the <i>FTO</i> region; rs2689243 was the most significant SNP in the plot region. (C) <i>LIN28B</i> region Locus Zoom plot; rs408949 was the most significant SNP in the plot region. (D) Locus Zoom plot of the <i>CYP1B1</i> region; rs13391045 was the most significant SNP in the plot region.</p

Pleiotropy of Cancer Susceptibility Variants on the Risk of Non-Hodgkin Lymphoma: The PAGE Consortium

<div><p>Background</p><p>Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).</p><p>Objective</p><p>We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.</p><p>Methods</p><p>As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.</p><p>Results</p><p>The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, <i>p</i> = 0.013; DLBCL OR = 1.23, <i>p</i> = 0.013; NHL OR = 1.22, <i>p</i> = 5.9×E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in <i>TERT</i>: OR per C allele = 0.89, <i>p</i> = 3.7×E-03; rs4975616 in <i>TERT</i>: OR per A allele = 0.90, <i>p</i> = 0.01; rs3131379 in <i>MSH5</i>: OR per T allele = 1.16, <i>p</i> = 0.03), prostate (rs7679673 in <i>TET2</i>: OR per C allele = 0.89, <i>p</i> = 5.7×E-03; rs10993994 in <i>MSMB</i>: OR per T allele = 1.09, <i>p</i> = 0.04), and breast (rs3817198 in <i>LSP1</i>: OR per C allele = 1.12, <i>p</i> = 0.01) cancers, but none of these associations remained significant after multiple test correction.</p><p>Conclusion</p><p>This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.</p></div

Pleiotropic association of selected cancer susceptibility variants with the risk of overall non-Hodgkin lymphoma (NHL).

<p>* ORs and 95% CIs in individual studies were estimated in unconditional logistic regression models that were adjusted for age, sex (in BioVU and MEC) and ethnicity (ancestry informative markers). Summary ORs and 95% CIs were estimated in a meta-analysis of fixed-effects models.</p>†<p>The Bonferroni corrected <i>p-value</i> for 53 SNPs/tests is 4.4E-04.</p><p>Abbreviations: <i>p</i>-het. (<i>P</i>-values for heterogeneity across studies measured in Cochran's Q statistic); BioVU (the biorepository of the Vanderbilt University), MEC (the Multiethnic Cohort Study), WHI (the Women's Health Initiative).</p

Forest plots for the association between a published follicular lymphoma risk variant (rs6457327) and the risk of follicular lymphoma or overall non-Hodgkin lymphoma (NHL) in the Multiethnic Cohort (MEC) and the Women's Health Initiative (WHI) in the PAGE consortium.

<p>(a) follicular lymphoma, (b) overall NHL, and (c) overall NHL among whites only.</p

Associations between a risk score (RS) for 53 GWAS-identified cancer risk variants and the overall and subtype-specific risks of NHL.

<p>* ORs and 95% CIs in individual studies were estimated per risk allele in unconditional logistic regression models that were adjusted for age, sex (in BioVU and MEC) and ethnicity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in a meta-analysis of fixed effects models.</p><p>Abbreviations: <i>p-het</i>. (<i>p-values</i> for heterogeneity across studies measured in Cochran's Q statistic); BioVU (the biorepository of Vanderbilt University), MEC (the Multiethnic Cohort Study), WHI (the Women's Health Initiative).</p

Characteristics of non-Hodgkin lymphoma (NHL) cases and controls in the PAGE studies.

<p>* Any prior cancer cases were excluded from the NHL cases and controls for the current analysis, based on self-report (BioVU, MEC, WHI), the SEER registry linkage (BioVU, MEC), and medical record reviews (BioVU, WHI).</p><p>Abbreviations: BioVU (the biorepository of the Vanderbilt University), MEC (the Multiethnic Cohort Study), WHI (the Women's Health Initiative); CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma), DLBCL (diffuse large B-cell lymphoma), FL (follicular lymphoma), SEER (Surveillance, Epidemiology and End Results).</p

Examples of loci without evidence of association in AA_mchip or fine mapping EA signal.

<p>(a) At rs16996148 (CILP2/LDL) we are reasonably well powered, and no significant associations were observed in AA, suggesting that either the associated variant, or the synthetic allele that tags it is EA-restricted. Similar null results at (b) rs5219 (KCNJ11/T2D) and (c) rs17145738 (MLXIPL/logTG) were underpowered to draw strong conclusions. (d) At rs780094 (GCKR/logTG) and (e) rs599839 (PSRC1/LDL) the index tagSNP from EA showed significantly diluted signal in AA (purple dot). However, in each region a tagged SNP showed an effect size consistent with the EA index tagSNP, and after adjustment for this variant no residual evidence for association was observed at any additional variants in the region. (f) At rs2954029 (TRIB1/logTG) a similar effect was observed, save for the fact that the strongest AA association was imperfectly tagged in EA (r² = 0.33).</p