Co-author Dana C. Crawford is a PLOS ONE Editorial Board member. This membership does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Conceived and designed the experiments: KLS CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Performed the experiments: KLS CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Analyzed the data: KLS JM CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR LAH SB DCC. Contributed reagents/materials/analysis tools: KLS JM CLC NF LFR AY IC MDR CAH LW CW TCM CSC KB AP AR SB DCC. Wrote the paper: KLS JM CLC NF LFR LAH SB DCC.
Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (n = 161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women’s Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/
Age at menarche (AM) and age at natural menopause (ANM) are components of the reproductive lifespan in women. Timing of these reproductive milestones is associated with various diseases and cancers such as type 2 diabetes, cardiovascular disease, endometrial and breast cancers, as well as with fertility issues
Both cross-sectional and longitudinal studies have shown an overall decline in age of menarche in US girls from the 1960s to the 1990s
Similar to the timing of age at menarche, the age at which natural menopause occurs is affected by multiple factors
Genetic and environmental factors that determine AM and ANM have been considered in numerous studies, but many of these studies have conflicting or unreplicated results
In this study, we used data from the Metabochip genotyping array to characterize previously identified variants associated with menarche and menopause in African Americans in a combined cohort of African-American women from the Women’s Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies
Women participants from two cohorts of the PAGE Study
Age at menarche was defined as the age when menstrual periods started in years, with extreme values pooled in groups of 9 years or less and 17 years or older. Age at natural menopause was defined as the age at which cessation of regular menstrual periods due to the body’s natural aging process occurred. In ARIC, women were asked, “Was your menopause natural or the result of surgery or radiation?” Only women who indicated natural menopause were included. Women in WHI who underwent hysterectomy, oophorectomy, or hormone replacement therapy before the onset of natural menopause were excluded. In both studies, women reporting age at natural menopause <40 years were excluded; women reporting age at natural menopause >60 years were censored at age 60. All women included in the present study were post-menopausal.
Genotyping was performed on the Metabochip, a custom Illumina iSelect genotyping chip designed to genotype SNPs associated with metabolic traits and cardiovascular disease
All participants self-reported African American ancestry. To adjust for potential population stratification, we used the principal components method implemented in Eigenstrat
Linear regression was performed assuming an additive genetic model to test for associations between individual SNPs and the outcomes of age at menarche in years. We examined two models for menarche: 1) a minimally adjusted model that accounted only for study sites and principal components, and 2) a fully adjusted model that included study site, year of birth, principal components, and body mass index at ascertainment, with the understanding that BMI at ascertainment may be a poor proxy for BMI at age of menarche. Age at menarche was self-reported many years later at time of examination, which has been shown to be fairly accurate
The overall goal of the study was to test for SNPs associated with AM and/or ANM using the Metabochip in African Americans from the WHI and ARIC studies. We looked to generalize to our population of African American women genes, gene regions (400 kb upstream and downstream of a gene of interest), and SNPs described in previous GWAS and candidate gene studies associated with AM and ANM. We tested all SNPs in the regions regardless of linkage disequilibrium (LD) with the index SNP, although we only considered a test of association generalized if the tested SNPs were identical to the index SNP or in strong LD with the index variant in HapMap CEU samples. For each candidate gene, we plotted results of single SNP tests of association using LocusZoom and examined regions 400 kb upstream and downstream of the gene/gene region of interest. Tests of association were considered significant for generalization at a liberal threshold of p<0.05. For previously reported variants not genotyped in our study, we identified SNPs in LD with our directly genotyped SNPs
In addition to generalization, we sought to discover novel SNP-trait associations using the entire Metabochip. Significance in this discovery phase was defined as p<3.1×10−07, after Bonferroni correction (0.05/161,098). Because this threshold is highly conservative given the correlation among the SNPs on the Metabochip, we also defined an arbitrary suggestive significance level as p<1×10−4 in the discovery phase.
A total of 4,159 and 1,860 African American female participants met the study definitions for AM and ANM, respectively, and both PAGE studies were represented roughly equally (
Age at Menarche (AM) | Age at Natural Menopause (ANM) | ||||
Study Population | Study Population | ||||
ARIC | WHI | ARIC | WHI | ||
|
2078 | 2081 | 994 | 866 | |
|
12.89 (1.76) | 12.56 (1.64) | 47.97 (3.83) | 50.84 (4.50) | |
|
53.36 (5.73) | 61.01 (6.87) | 53.07 (5.75) | 61.30 (6.78) | |
|
30.86 (6.63) | 31.34 (6.83) | 31.29 (6.94) | 30.95 (6.76) | |
|
181.05 (39.68) | 182.87 (41.26) | 183.78 (40.80) | 181.05 (40.63) | |
|
64.24 (2.43) | 64.00 (2.63) | 64.31 (2.38) | 64.05 (2.75) | |
|
|
– | 26 (1.24) | – | 12 (1.39) |
|
504 (24.07) | 414 (19.82) | 221 (22.23) | 183 (21.13) | |
|
1083 (51.72) | 981 (46.96) | 522 (52.52) | 414 (47.81) | |
|
507 (24.21) | 668 (31.98) | 251 (25.25) | 257 (29.68) |
Data presented as means (sd) unless otherwise noted. Abbreviations: Atherosclerosis Risk in Communities (ARIC) and Women’s Health Initiative (WHI).
To generalize previously-associated genetic variants in our African American population, we examined regions/genes previously associated with AM from either published candidate gene studies or GWAS:
Overall, 11/21 (52%) SNPs previously identified for AM from earlier studies and 15/42 (36%) from the Elks
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
Locus | Gene/Region | Prior GWAS in European descent women | African American women from the PAGE Study | ||||||||||
SNP | Chr | Coded Allele | Beta | P-value | Ref. | Best Proxy SNP from present study | r2 in HapMap CEU/YRI | Coded Allele | Model 1 | Model 2 | |||
Beta (SE) | P-value | Beta (SE) | P-value | ||||||||||
rs314277 | 6 |
|
A | 0.16 | 2.7E-13 |
|
rs314277 | – | A | 0.03(0.04) | 0.34 | 0.03(0.04) | 0.36 |
rs369065 | 6 |
|
C | 0.11 | 2.4E-11 |
|
rs7759938 | 1.00/0.34 | A | −0.02(0.04) | 0.61 | −0.02(0.04) | 0.55 |
rs7759938 | 6 |
|
C | 0.09 | 7.0E-09 |
|
rs7759938 | – | A | −0.02(0.04) | 0.61 | −0.02(0.04) | 0.55 |
rs314276 | 6 |
|
C | −0.22 | 1.5E-08 |
|
rs314274 | 1.00/0.73 | A | 0.05(0.04) | 0.22 | 0.05(0.04) | 0.24 |
rs314280 | 6 |
|
T | 0.09 | 2.3E-08 | rs7759938 | 0.64/0.28 | A | −0.02(0.04) | 0.61 | −0.02(0.04) | 0.55 | |
rs4946651 | 6 |
|
A | 0.09 | 3.1E-08 |
|
rs4946651 | – | A | 0.03(0.04) | 0.55 | 0.03(0.04) | 0.55 |
rs314262 | 6 |
|
C | 0.08 | 9.7E-08 |
|
rs7759938 | 0.60/0.29 | A | −0.02(0.04) | 0.61 | −0.02(0.04) | 0.55 |
rs7861820 | 9 | 9q31 | C | −0.09 | 3.4E-09 |
|
rs7861820 | – | A | −0.10(0.06) | 0.10 | −0.09(0.06) | 0.12 |
rs12684013 | 9 | 9q31 | T | −0.10 | 3.6E-08 |
|
rs4452860 | 0.81/0.01 | A | −0.03(0.04) | 0.43 | −0.03(0.04) | 0.42 |
rs4452860 | 9 | 9q31 | G | −0.09 | 7.9E-08 |
|
rs4452860 | – | A | −0.03(0.04) | 0.43 | −0.03(0.04) | 0.42 |
rs7028916 | 9 | 9q31 | A | −0.09 | 9.7E-08 |
|
rs4452860 | 0.98/0.85 | A | −0.03(0.04) | 0.43 | −0.03(0.04) | 0.42 |
rs2090409 | 9 | 9q31 | A | −0.10 | 1.7E-09 |
|
rs4452860 | 0.83/0.82 | A | −0.03(0.04) | 0.43 | −0.03(0.04) | 0.42 |
rs555621 | 11 |
|
C | 0.06 | 0.001 |
|
rs1856142 | 0.43/0.71 | A | 0.03(0.04) | 0.44 | 0.03(0.04) | 0.36 |
rs1782507 | 11 |
|
T | −0.07 | 0.006 |
|
rs605765 | 0.83/0.87 | A | −0.06(0.04) | 0.14 | −0.06(0.04) | 0.13 |
rs4953616 | 2 |
|
T | −0.07 | 0.006 |
|
rs1589749 | 0.17/0.05 | A | 0.002(0.07) | 0.97 | −0.01(0.07) | 0.87 |
rs7579411 | 2 |
|
T | 0.06 | 0.01 |
|
rs1589749 | 0.17/0.05 | A | 0.002(0.07) | 0.97 | −0.01(0.07) | 0.87 |
rs4374421 | 2 |
|
C | 0.06 | 0.02 |
|
rs17326321 | 0.19/0.69 | A | −0.01(0.06) | 0.86 | −0.01(0.06) | 0.84 |
rs2470144 | 15 |
|
G | – | 5.9E-06 |
|
rs12148492 | 0.23/0.01 | A | −0.01(0.07) | 0.91 | −0.02(0.07) | 0.73 |
rs2445761 | 15 |
|
G | – | 1.2E-06 |
|
rs4774585 | 0.28/0.02 | A | 0.04(0.05) | 0.47 | 0.03(0.05) | 0.58 |
rs9525641 | 13 |
|
T | – | 0.04 |
|
rs931273 | 0.05/0.03 | A | 0.11(0.09) | 0.24 | 0.11(0.09) | 0.21 |
rs3826620 | 18 |
|
A | – | 0.02 |
|
rs8092336 | 0.16/0.22 | A | 0.16(0.17) | 0.33 | 0.17(0.17) | 0.29 |
rs6214 | 12 |
|
G | – | 0.02 |
|
rs6214 | – | A | −0.01(0.04) | 0.71 | −0.02(0.04) | 0.61 |
Comparison of previously reported SNPs associated with AM in European descent women to 4,159 African American women from the PAGE Study in a minimally adjusted model for AM (Model 1) and a model adjusted for study site, year of birth, principal components, and body mass index (Model 2). Data presented are for the previously identified SNP. If the previously identified SNP was not directly genotyped in present study, data shown are for the best proxy SNP based on linkage disequilibrium from the International HapMap Project CEU panel.
We also examined SNPs associated with AM that were reported in a recent meta-analysis performed by Elks
As with AM, to generalize results to our African American population, we examined previously identified 400 kb regions around genes associated with ANM from published candidate gene studies and GWAS:
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
Locus | Gene/region | Prior GWAS in European descent women | African American women from the PAGE Study | ||||||||
SNP | Chr | CodedAllele | Beta | P-value | Ref. | Best Proxy SNPfrom presentstudy | r2 in HapMapCEU/YRI | CodedAllele | Beta (SE) | P-value | |
rs16991615 | 20 |
|
A | 1.07 | 1.21E-21 | rs16991615 | – | A | −0.17(0.15) | 0.25 | |
rs236114 | 20 |
|
A | 0.50 | 9.71E-11 |
|
rs236114 | – | A | 0.02(0.06) | 0.69 |
rs1172822 | 19 |
|
T | −0.49 | 1.8E-19 | rs4806660 | 0.98/0.64 | A | 0.002(0.03) | 0.97 | |
rs2384687 | 19 |
|
C | −0.47 | 2.4E-18 |
|
rs11668309 | 0.85/0.43 | A | 0.02(0.04) | 0.59 |
rs897798 | 19 |
|
G | −0.40 | 1.1E-14 |
|
rs8113016 | 0.72/0.02 | A | 0.12(0.05) | 0.03 |
rs1065778 | 15 |
|
A | – | 0.05 |
|
rs10519297 | 0.90/0.32 | A | −0.01(0.05) | 0.84 |
rs2255192 | 15 |
|
A | – | 0.04 |
|
rs10459592 | 0.32/0.02 | A | −0.02(0.04) | 0.52 |
rs621686 | 11 |
|
A | 0.32 | 0.007 |
|
rs1856142 | 0.27/0.32 | A | 0.04(0.03) | 0.29 |
rs7951733 | 11 |
|
A | −0.32 | 0.02 |
|
rs7951733 | – | A | 0.11(0.13) | 0.37 |
rs769450 | 19 |
|
A | – | 0.007 |
|
rs769450 | – | A | −0.07(0.03) | 0.03 |
rs7412 | 19 |
|
– | – | 0.001 |
|
rs7412 | – | A | −0.03(0.05) | 0.55 |
rs1019731 | 12 |
|
C | −0.28 | 0.005 |
|
rs1019731 | – | A | −0.03(0.11) | 0.82 |
rs9457827 | 17 |
|
T | 0.37 | 0.04 |
|
rs9457827 | – | A | 0.04(0.04) | 0.28 |
rs4135280 | 3 |
|
T | 0.54 | 0.005 |
|
rs4135280 | – | A | −0.14(0.18) | 0.42 |
rs1256044 | 14 |
|
G | – | 0.03 |
|
rs1268656 | 0.08/0.004 | A | −0.01(0.06) | 0.88 |
rs1256059 | 14 |
|
A | – | 0.05 |
|
rs1268656 | 0.08/0.004 | A | −0.01(0.06) | 0.88 |
rs1056836 | 2 |
|
G | – | 0.04 |
|
rs10495874 | 0.04/0.03 | A | −0.03(0.05) | 0.60 |
rs346578 | 13 |
|
A | – | 0.007 |
|
rs6561072 | 0.07/0.07 | A | 0.04(0.04) | 0.22 |
rs9525641 | 13 |
|
T | – | 0.01 |
|
rs931273 | 0.05/0.03 | A | −0.02(0.08) | 0.81 |
rs8086340 | 18 |
|
G | – | 0.02 |
|
rs8094440 | 0.10/0.01 | A | 0.03(0.03) | 0.38 |
rs2002555 | 12 |
|
G | 0.30 | 0.02 |
|
rs7131938 | 0.59/0.54 | A | 0.01(0.04) | 0.84 |
rs2384687 | 19 |
|
C | 0.38 | 1.39E-10 |
|
rs11668309 | 0.85/0.43 | A | 0.02(0.04) | 0.59 |
rs897798 | 19 |
|
G | 0.31 | 3.91E-08 |
|
rs8113016 | 0.72/0.02 | A | 0.12(0.05) | 0.03 |
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.
Overall, 14/23 (40%) SNPs previously identified for ANM via GWAS and 6/20 SNPs from the Stolk
Three of the twenty SNPs recently identified by Stolk
We tested all SNPs genotyped on the Metabochip for an association with AM adjusted for study site and principal components (Model 1) and adjusted for study site, year of birth, principal components, and body mass index (Model 2) (
CHR | SNP | GENE | GENE REGION | CODED ALLELE | ||||
CAF | BETA | SE | P VALUE | |||||
19 | rs189596789 |
|
upstream | A | 0.006 | 1.09 | 0.20 | 4.98E-08 |
11 | rs79972789 |
|
intronic | C | 0.997 | −1.76 | 0.34 | 1.90E-07 |
5 | rs181686584 |
|
intronic | A | 0.002 | 2.35 | 0.46 | 2.85E-07 |
6 | rs114158228 |
|
intronic | A | 9E-04 | 3.60 | 0.73 | 7.12E-07 |
21 | rs117876865 |
|
downstream | A | 9E-04 | 3.58 | 0.73 | 8.55E-07 |
10 | rs11195485 |
|
downstream | A | 0.002 | 2.89 | 0.59 | 9.63E-07 |
11 | rs11224401 |
|
intronic | A | 0.997 | 2.20 | 0.45 | 1.13E-06 |
1 | rs78937547 |
|
downstream | A | 0.992 | −1.97 | 0.41 | 1.89E-06 |
17 | rs75394140 |
|
downstream | A | 0.002 | −0.93 | 0.21 | 6.48E-06 |
11 | rs76988592 |
|
downstream | A | 0.702 | −0.93 | 0.21 | 7.24E-06 |
3 | rs114451007 |
|
intronic | A | 0.253 | 1.70 | 0.38 | 9.30E-06 |
12 | rs10846771 |
|
downstream | A | 0.997 | −0.16 | 0.04 | 9.43E-06 |
11 | rs12804247 |
|
upstream | A | 0.655 | 0.17 | 0.04 | 1.45E-05 |
1 | rs76571116 |
|
downstream | A | 3E-04 | −1.54 | 0.36 | 1.57E-05 |
17 | rs17634167 |
|
cds-synon. | A | 6E-04 | −0.34 | 0.08 | 1.62E-05 |
7 | rs117382431 |
|
downstream | A | 0.999 | 4.38 | 1.03 | 2.17E-05 |
6 | rs76294174 |
|
intronic | C | 3E-04 | 4.38 | 1.03 | 2.17E-05 |
6 | rs74918542 |
|
intronic | A | 0.999 | −4.38 | 1.03 | 2.17E-05 |
1 | rs76078015 |
|
intronic | A | 9E-04 | 4.38 | 1.03 | 2.17E-05 |
18 | rs117454233 |
|
downstream | A | 0.999 | −4.38 | 1.03 | 2.17E-05 |
3 | rs73025249 |
|
intronic | A | 9E-04 | 4.38 | 1.03 | 2.17E-05 |
3 | rs182857216 |
|
intronic | A | 0.999 | −4.38 | 1.03 | 2.17E-05 |
3 | rs73027210 |
|
intronic | A | 9E-04 | 4.38 | 1.03 | 2.17E-05 |
9 | rs75220302 |
|
downstream | A | 0.999 | −4.38 | 1.03 | 2.18E-05 |
9 | rs74599268 |
|
upstream | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs3731245 |
|
intronic | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs76774391 |
|
upstream | C | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
2 | rs117258126 |
|
downstream | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs3808846 |
|
5′ flanking | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs77706751 |
|
upstream | A | 6E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs3808845 |
|
5′ flanking | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs76810097 |
|
upstream | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs36228836 |
|
5′ flanking | A | 3E-04 | 4.38 | 1.03 | 2.18E-05 |
9 | rs75039118 |
|
intronic | A | 0.999 | −4.38 | 1.03 | 2.19E-05 |
18 | rs75914913 |
|
downstream | A | 3E-04 | 4.38 | 1.03 | 2.19E-05 |
11 | rs190060931 |
|
downstream | A | 0.999 | −4.38 | 1.03 | 2.21E-05 |
2 | rs186397905 |
|
downstream | C | 3E-04 | 4.38 | 1.03 | 2.21E-05 |
16 | rs9934222 |
|
cds-synon. | A | 0.163 | −0.19 | 0.04 | 2.28E-05 |
15 | rs72751410 |
|
intronic | A | 0.998 | −1.51 | 0.36 | 2.30E-05 |
15 | rs72747452 |
|
intronic | A | 0.002 | 1.51 | 0.36 | 2.30E-05 |
11 | rs180751580 |
|
missense | C | 0.999 | −4.36 | 1.03 | 2.30E-05 |
3 | rs186437034 |
|
intronic | A | 0.999 | −2.46 | 0.58 | 2.45E-05 |
7 | rs78912482 |
|
upstream | A | 0.012 | 0.64 | 0.15 | 3.04E-05 |
1 | rs116071515 |
|
intronic | A | 0.002 | 1.88 | 0.45 | 3.06E-05 |
6 | rs1997770 |
|
downstream | A | 0.970 | −0.41 | 0.10 | 3.55E-05 |
7 | rs118135044 |
|
upstream | A | 4E-04 | 4.22 | 1.02 | 3.73E-05 |
11 | rs74402657 |
|
intronic | C | 4E-04 | 2.93 | 0.72 | 3.96E-05 |
1 | rs117217277 |
|
downstream | A | 0.999 | −2.97 | 0.72 | 3.97E-05 |
1 | rs116881786 |
|
downstream | A | 0.999 | −2.97 | 0.72 | 3.97E-05 |
1 | rs76471454 |
|
downstream | A | 6E-04 | 2.97 | 0.72 | 3.97E-05 |
1 | rs79775735 |
|
downstream | A | 6E-04 | 2.97 | 0.72 | 3.97E-05 |
1 | rs79468804 |
|
downstream | A | 6E-04 | 2.97 | 0.72 | 3.97E-05 |
1 | rs74703854 |
|
downstream | A | 0.999 | −2.97 | 0.72 | 3.97E-05 |
1 | rs116923068 |
|
downstream | C | 0.999 | −2.97 | 0.72 | 3.97E-05 |
1 | rs117674205 |
|
downstream | C | 0.999 | −2.97 | 0.72 | 3.97E-05 |
1 | rs117260315 |
|
downstream | A | 6E-04 | 2.97 | 0.72 | 3.97E-05 |
1 | rs76020919 |
|
downstream | A | 6E-04 | 2.97 | 0.72 | 3.97E-05 |
11 | rs2306034 |
|
UTR-3′ | A | 4E-04 | 2.94 | 0.72 | 3.99E-05 |
2 | rs189110944 |
|
downstream | A | 4E-04 | 4.17 | 1.02 | 4.72E-05 |
5 | rs1976311 |
|
upstream | C | 0.996 | −1.02 | 0.25 | 4.98E-05 |
7 | rs13245084 |
|
intronic | A | 4E-04 | 4.14 | 1.02 | 5.07E-05 |
6 | rs115178932 |
|
intronic | A | 4E-04 | 4.14 | 1.02 | 5.07E-05 |
1 | rs77353590 |
|
downstream | A | 0.009 | 0.74 | 0.18 | 5.42E-05 |
2 | rs111826230 |
|
upstream | A | 0.984 | −0.58 | 0.14 | 5.47E-05 |
11 | rs193030163 |
|
upstream | C | 0.999 | −4.11 | 1.02 | 5.57E-05 |
11 | rs114702513 |
|
intronic | A | 0.996 | −1.23 | 0.31 | 5.60E-05 |
6 | rs117124693 |
|
intronic | A | 0.999 | −4.11 | 1.02 | 5.62E-05 |
6 | rs181947983 |
|
upstream | A | 4E-04 | 4.11 | 1.02 | 5.62E-05 |
15 | rs183951867 |
|
upstream | A | 9E-04 | 4.11 | 1.02 | 5.62E-05 |
9 | rs191930498 |
|
upstream | C | 4E-04 | 4.10 | 1.02 | 5.83E-05 |
17 | rs192656758 |
|
downstream | A | 4E-04 | 4.10 | 1.02 | 5.86E-05 |
7 | rs740259 |
|
5′ flanking | A | 4E-04 | 4.09 | 1.02 | 5.97E-05 |
1 | rs114389068 |
|
cds-synon. | A | 0.005 | 0.93 | 0.23 | 6.07E-05 |
11 | rs185476610 |
|
intronic | A | 0.999 | −4.08 | 1.02 | 6.24E-05 |
16 | rs246192 |
|
intronic | C | 0.256 | 0.15 | 0.04 | 6.25E-05 |
7 | rs192457106 |
|
intronic | A | 0.999 | −4.08 | 1.02 | 6.35E-05 |
7 | rs73702566 |
|
intronic | A | 0.999 | −4.08 | 1.02 | 6.35E-05 |
6 | rs187190790 |
|
upstream | A | 0.999 | −4.08 | 1.02 | 6.38E-05 |
7 | rs74984879 |
|
upstream | C | 0.999 | −2.04 | 0.51 | 6.40E-05 |
11 | rs184056970 |
|
intronic | A | 4E-04 | 4.07 | 1.02 | 6.53E-05 |
3 | rs76909367 |
|
intronic | A | 4E-04 | 4.06 | 1.02 | 6.89E-05 |
10 | rs11187795 |
|
intronic | A | 4E-04 | 4.06 | 1.02 | 6.93E-05 |
6 | rs186129489 |
|
intronic | A | 4E-04 | 4.05 | 1.02 | 7.12E-05 |
2 | rs73923981 |
|
intronic | A | 9E-04 | 4.05 | 1.02 | 7.32E-05 |
15 | rs180807356 |
|
upstream | A | 0.999 | −4.04 | 1.02 | 7.52E-05 |
5 | rs10062135 |
|
intronic | A | 0.009 | 0.73 | 0.19 | 7.85E-05 |
12 | rs17568045 |
|
intronic | A | 0.993 | −0.86 | 0.22 | 8.11E-05 |
1 | rs116411856 |
|
upstream | A | 0.003 | 1.32 | 0.34 | 8.16E-05 |
1 | rs78696400 |
|
downstream | A | 0.985 | −0.58 | 0.15 | 8.96E-05 |
15 | rs74979292 |
|
upstream | A | 0.002 | 1.49 | 0.38 | 9.29E-05 |
11 | rs144204188 |
|
intronic | A | 0.002 | 2.79 | 0.72 | 9.39E-05 |
1 | rs78411379 |
|
intronic | A | 0.999 | −2.27 | 0.58 | 9.62E-05 |
15 | rs190893945 |
|
intronic | A | 0.998 | −1.76 | 0.45 | 9.67E-05 |
9 | rs12555547 |
|
upstream | C | 0.998 | −2.30 | 0.59 | 9.69E-05 |
2 | rs10932320 |
|
intronic | A | 0.807 | −0.17 | 0.04 | 9.93E-05 |
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.
We tested all SNPs on the Metabochip for associations with ANM adjusted for study site and principal components. Three SNPs were significant after Bonferroni correction (p<3.1×10−07):
Two genes were suggestively associated with both ANM and AM at a nominal significance threshold.
Here we demonstrated the use of the Metabochip genotyping array to identify SNPs associated with AM and ANM in a sample of African American women. Previous GWAS studies for AM and ANM have been performed in primarily European descent populations; generalization to diverse populations has largely been lacking
In the discovery phase of our AM analysis, none of our results reached genome-wide significance. However, the ANM analysis yielded three associations that were significant after multiple testing corrections. Broadly, we demonstrate the ability to potentially uncover new variants associated with age at natural menopause in our African American cohort using the Metabochip.
Several studies have shown relationships between a woman’s reproductive milestones (AM, ANM, parity) and menstrual characteristics and risk for breast cancer, endometrial cancer, and ovarian cancer
Different pathways appear to be involved in the initiation and cessation of menses. Prior GWAS and linkage studies performed in European descent or Asian populations for AM and ANM show little concordance with specific genes (reviewed in
The Metabochip was designed to be a cost-effective method of genotyping approximately 200,000 metabolic and cardiovascular SNPs and SNPs in other useful regions of the genome, such as the HLA region and the X and Y chromosomes. Overall, median SNP density on the Metabochip is approximately one SNP per 370 bases
Metabochip performance in non-European populations was recently evaluated in a pilot study in African American PAGE participants
Although the Metabochip was designed for genotyping of cardiovascular and metabolic SNPs, this study demonstrates the feasibility of utilizing such a targeted chip to identify SNP associations with age at menarche and age at natural menopause. We identified potentially novel associations with AM/ANM at loci implicated in cardiovascular traits, obesity and cancer. This may result from pleiotropic loci or may suggest that the AM/ANM timing mechanisms influence underlying disease process. With numerous genes implicated in both metabolic and cardiovascular phenotypes and both AM and ANM, further studies will allow us to consider how specific genes may influence the reproductive lifespan in women.
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The data and materials included in this report result from collaboration between the following studies: ARIC and WHI. The authors thank the staff and participants of the ARIC study for their important contributions. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible.