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Meta-Analysis
, 50 (10), 666-73

Large-scale Genotyping Identifies a New Locus at 22q13.2 Associated With Female Breast Size

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Meta-Analysis

Large-scale Genotyping Identifies a New Locus at 22q13.2 Associated With Female Breast Size

Jingmei Li et al. J Med Genet.

Abstract

Background: Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7169 women of European descent across three independent sample collections with digital or screen film mammograms.

Methods: The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211 155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm(2)) on a mammogram.

Results: We confirm genome-wide significant associations at 8p11.23 (rs10086016, p=1.3×10(-14)) and report a new locus at 22q13 (rs5995871, p=3.2×10(-8)). The latter region contains the MKL1 gene, which has been shown to impact endogenous oestrogen receptor α transcriptional activity and is recruited on oestradiol sensitive genes. We also replicated previous genome-wide association study findings for breast size at four other loci.

Conclusions: A new locus at 22q13 may be associated with female breast size.

Keywords: Cancer: breast; Complex traits; Epidemiology; Genetic epidemiology; Genome-wide.

Conflict of interest statement

Conflict Of Interest: None.

Figures

Figure 1
Figure 1
Manhattan plot combining association results from 4,492,143 SNPs from the genome-wide meta-analysis based on mammograms collected as of May 15th 2012. SNPs genotyped on the iCOGS genotyping array were imputed using the IMPUTE (v2.0) software based on the 1000 Genomes Project (Phase I integrated variant set release (v3), 19 Apr 2012) using multi-population reference panels. Sample-specific association results were computed with SNPTEST (v2.3), meta-analyses were performed in METAL (Mar 25 2011 release). Meta-analysis results are plotted as -log10 P-values (y-axis) against physical chromosomal location (x-axis). Black triangles indicate genotyped SNPs P<1.0 × 10−5. The plot was generated in R using “qqman”.
Figure 2
Figure 2
Quantile-quantile (QQ) plot for the combined association results (λGC = 1.02)
Figure 3
Figure 3
Regional plots of the genome-wide meta-analysis association results and recombination rates for the 8p11.23 and 22q13.2 regions (a–b). Association results of both genotyped (squares) and imputed (circles) SNPs in the combined samples and recombination rates within the loci at 8p11.23 (a) and 22q13.2 (b). For each plot, −log10 P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The top genotyped SNP in each combined analysis is shown as a purple square and is labeled by its rsID. Color intensity of each symbol reflects the extent of LD with the top genotyped SNP. Genetic recombination rates, estimated using 1000 Genomes EUR samples (Nov 2010), are shown with a light blue line. Physical positions are based on NCBI Build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to each region of association.
Figure 3
Figure 3
Regional plots of the genome-wide meta-analysis association results and recombination rates for the 8p11.23 and 22q13.2 regions (a–b). Association results of both genotyped (squares) and imputed (circles) SNPs in the combined samples and recombination rates within the loci at 8p11.23 (a) and 22q13.2 (b). For each plot, −log10 P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The top genotyped SNP in each combined analysis is shown as a purple square and is labeled by its rsID. Color intensity of each symbol reflects the extent of LD with the top genotyped SNP. Genetic recombination rates, estimated using 1000 Genomes EUR samples (Nov 2010), are shown with a light blue line. Physical positions are based on NCBI Build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to each region of association.

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