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

The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis

<div><p>Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-values_binomial≤0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.</p></div

Descriptive statistics for the age at menarche (AAM, n = 44,367) and natural menopause (ANM, n = 17,100) analytic samples.

<p>Descriptive statistics for the age at menarche (AAM, n = 44,367) and natural menopause (ANM, n = 17,100) analytic samples.</p

Generalization of five previously described age at menarche and natural menopause loci to multiple race/ethnic groups or trans-ethnically.

<p>Generalization of five previously described age at menarche and natural menopause loci to multiple race/ethnic groups or trans-ethnically.</p

Regional plots of the novel array-wide significant age at menarche (Panel A: <i>CUX2</i>) and natural menopause loci (Panels B,C: <i>FRMD5</i>, <i>GPRC5B</i>) using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women, and showing independence from previously published cardiometabolic SNP associations (shown in gray if missing).

<p>Regional plots of the novel array-wide significant age at menarche (Panel A: <i>CUX2</i>) and natural menopause loci (Panels B,C: <i>FRMD5</i>, <i>GPRC5B</i>) using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women, and showing independence from previously published cardiometabolic SNP associations (shown in gray if missing).</p

Regional plots for age at menarche Bonferroni-significant loci at <i>SEC16B</i> (Panel A), <i>BDNF</i> (Panel B) and <i>FTO</i> (Panel C), showing previously published body mass index (BMI) primary and secondary SNP associations, using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women.

<p>Regional plots for age at menarche Bonferroni-significant loci at <i>SEC16B</i> (Panel A), <i>BDNF</i> (Panel B) and <i>FTO</i> (Panel C), showing previously published body mass index (BMI) primary and secondary SNP associations, using a modified random-effects trans-ethnic meta-analysis of more than 31,000 women.</p

Three loci with trans-ethnic array-wide significant modified random-effects associations^* at novel age at menarche or natural menopause loci.

<p>Three loci with trans-ethnic array-wide significant modified random-effects associations^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0200486#t004fn001" target="_blank">*</a>} at novel age at menarche or natural menopause loci.</p