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Meta-Analysis

Genome-wide Association Study of Age at Menarche in African-American Women

Ellen W Demerath et al. Hum Mol Genet. .
Free PMC article

Abstract

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.

Figures

Figure 1.
Figure 1.
Overview of analysis and results. Flow of analyses and brief summary of results from each analysis are presented for the genome-wide meta-analysis of age at menarche in AA women and for the targeted interrogation of 42 menarche loci previously reported in EA women.
Figure 2.
Figure 2.
Conditional analysis identifies two independent signals for age at menarche near RORA, both of which are different from the previously identified index SNP in EA women. SNPs are plotted using Locus Zoom by position on the chromosome against association with age at menarche (−log10 P). Estimated recombination rates are plotted in blue to reflect local LD structure using the 1KGP AFR reference panel, and the SNPs surrounding the top SNP from the Stage 1 meta-analysis (rs339978, purple diamond) are color coded to reflect their LD with this SNP. Both the first (represented by rs339978, P = 1 × 10−6) and the second signal (represented by rs980000, P = 2 × 10−6) were independent of the index SNP (rs3743266) previously reported for EA women (see Table 3).
Figure 3.
Figure 3.
Fine-mapping of the SEC16B locus in AA women reveals a stronger genetic marker for age at menarche than the index SNP identified in European American women. (A) SNP associations with age at menarche near SEC16B in AAs, using LD from the 1KGP EUR reference panel, in relation to the index SNP rs633715 identified in EA women (purple diamond). The SNP with the lowest P value in the AA meta-analysis (rs543874) is 0.5 Mb upstream from the index SNP and has significantly lower P value (4.9 × 10−4 versus 0.12). The two SNPs are in strong LD in EUR populations (red color indicates r2 > 0.8), showing that it would be considered the same signal in EA women. (B) SNP associations with age at menarche near SEC16B in AAs, using LD from the 1KGP AFR reference panel, in relation to the index SNP rs633715 identified in EA women (purple diamond). The SNP with the lowest P value in the AA meta-analysis (rs543874) was in relatively weak LD (light blue color indicates r2 between 0.2 and 0.4) with the index SNP in AFR, suggesting they lie on different haplotypes. (C) SNP associations with age at menarche near SEC16B in AAs, using LD from the 1KGP AFR reference panel, in relation to the putatively stronger marker SNP rs543874 (purple diamond). Strong LD in AFR populations between rs543874 and a cluster of SNPs surrounding it, but low LD with SNPs near the index SNP rs633715 is seen. This suggests rs543874 may better localize the causal variant giving rise to the association of menarche age with SNPs near SEC16B previously reported in EA women. Note: SNPs are plotted using Locus Zoom by position on the chromosome against association with age at menarche (−log10 P). Estimated recombination rates are plotted in blue to reflect local LD structure, and the SNPs surrounding the index SNP (or most significant SNP) in each case are color coded to reflect their LD with this SNP, marked as a purple diamond.

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