The two main hormonal events of a woman's life, menarche and menopause, have a paramount impact on the duration of exposure to estrogen. Reproductive aging phenotypes, including age at menarche (AM) and age at natural menopause (ANM) have been consistently associated with breast cancer risk. Despite an estimated strong genetic component, genome-wide association studies (GWAS) for AM and ANM found that common variants identified to date account for only 7.4% for SNPs related to AM and 2.5-4.1% for ANM. As most previous GWAS on AM and ANM were conducted in women of European ancestry (EA), studies examining genetic components of reproductive aging in African-American (AA) women are needed. We hypothesize that although the index GWAS variants discovered in EA women may differ from those in AA women, rare and low-frequency causal variants may reside in the same genetic regions.
A candidate analysis of previously identified GWAS variants and genes in association with AM, ANM was conducted in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. All SNPs within a 500kb window of previously discovered GWAS SNPs for AM and ANM were extracted from the Illumina Human Exome Beadchip v1.1, leading to 1,505 candidate SNPs from 125 genes for AM and 1,198 candidate SNPs from 35 genes for ANM in a total of 7,886 AA subjects. Single SNP association tests were run in PLINK using linear regressions for the continuous trend test for AM/ANM and logistic regression for the extreme AM phenotype (<11 v. >=≥15 years). The SKAT-O test for the gene-based analyses was performed using the SKAT R package to aggregate variants with an MAF upper bound of 5%.
The top variants related to AM were two SNPs, rs314277 (β=0.11, MAF= 0.45, p=6.24E-05) and rs4742314 (β= -0.11, MAF= 0.39, p=6.44E-05), located in LIN28B and KDM4C respectively. rs974828 (RORA, MAF= 0.23, OR=0.71, p=0.0003) and rs314277 (p=0.0007) were found to be the top variants in association with the extreme AM phenotype. For ANM, rs16991615, located in MCM8, was the most significant variant associated with increased ANM ((β=2.06, MAF= 0.01, p=0.0005). rs314277 (LIN28B) has been previously associated with AM, and rs16991615 (MCM8) had also been related to ANM in previous GWAS in EAs. In gene-based analysis for AM, SLC38A3 (p=0.0007) and WDR6 (p= 0.003) were
nominally significant; and EPS8L1 (p= 0.005) and RBM6 (p= 0.01) were associated with the AM phenotype. For ANM, RBMS2 (p= 0.006) was nominally significant in gene-based analysis.
This is to date the largest study in AA women for reproductive life events to interrogate rare and low-frequency variants, which are beyond the spectrum of common variants in previous GWAS. Although the overall replication success rate is low, our analyses identified several rare and low-frequency variants in regions from previous GWAS. Our data contributed to the literature on genetic variation for reproductive aging in AA women.
Citation Format: Marie V. Coignet, Qianqian Zhu, David G. Cox, Kathryn Lunetta, Elisa V. Bandera, Christopher Haiman, Andrew Olshan, Julie Palmer, Christine Ambrosone, Song Yao. Single variant and gene-based replication analysis of reproductive aging in African American women in the AMBER Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 226.