Genome-wide association study of age at menarche in African-American women
Genome-wide association study of age at menarche in African-American women
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DOI：
10.1093/hmg/ddt181
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发表时间：
2013-08-15
影响因子：
3.5
通讯作者：
Haiman, Christopher A.
中科院分区：
文献类型：
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作者：
Demerath, Ellen W.;Liu, Ching-Ti;Haiman, Christopher A.
非洲裔美国人(AA)女性的月经初潮平均比欧洲血统(EA)女性早，而较早的月经初潮是肥胖和2型糖尿病等慢性疾病的风险因素。识别与月经初潮年龄相关的常见遗传变异在指出慢性病风险的遗传途径方面具有潜在价值，但AA女性缺乏全面的月经初潮年龄全基因组研究。在这项研究中，我们使用加性遗传线性回归模型检验了15项研究中18 089名再生障碍性贫血妇女的月经初潮年龄与常见单核苷酸多态(SNPs)的全基因组相关性，并对出生年份和人口分层进行了调整，随后进行了逆方差加权荟萃分析(阶段1)。然后，在2850名女性的独立样本中对顶级荟萃分析结果进行测试(阶段2)。首先，虽然在第一阶段没有SNP超过预先指定的P5 10(8)显著阈值，但在Flr2和PIK3R1附近的变异中发现了暗示关联，条件分析发现了RORA中或附近的两个独立的SNP(rs339978和rs980000)，加强了对在EA女性中发现的这一暗示基因座的支持。其次，对42个先前在EA女性中发现的月经初潮基因座进行的SNPs调查显示，其中25(60)个SNPs包含与AA女性月经初潮显著相关的变异。这些发现提供了迄今为止已发现的月经初潮基因跨种族泛化的第一个证据，并表明了一些新的生物学联系与再生障碍性贫血女性的月经初潮时间有关。
African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P 5 10(8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.