A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

Abstract

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

Figure 1. Summary of genome-wide association study results by chromosome

Association with breast cancer was determined for 528,173 SNPs among 1,145 cases of postmenopausal breast cancer, and 1,142 controls. The x axis represents position on each chromosome from pter (left) to qter (right) ; the y axis shows the P value on a logarithmic scale. Only P values <10⁻² are displayed.

Figure 2. Association Analysis of SNPs Across the FGFR2 gene

Upper Panel. P-values for association testing drawn from the genome wide association scan covering the FGFR2 gene and 100 Kb 5’ upstream. The presented analysis is based on the two degrees of freedom test corrected for age and the three first principal components of population stratification (see Supplemental materials and Methods). Lower Panel. Estimates of the squared correlation coefficient, r², were calculated for each pairwise comparison of SNPs. Log₁₀ r² was color coded according to the scale shown on the left. The 4 black diamonds indicate the 4 SNPs most strongly associated with breast cancer risk.