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

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls. We identified a set of four SNPs in intron 2 of FGFR2, a tyrosine kinase receptor previously shown to be amplified and/or over-expressed in some breast cancers, as highly associated with breast cancer and we confirmed this association in 1,776 cases and 2,072 controls from three additional studies. In both association testing and ancestral recombination graph analysis, FGFR2 haplotypes were associated with risk of breast cancer. Across the four studies the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP, rs1219648 = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other chromosomal loci most strongly associated with breast cancer in the initial GWAS were not associated with risk in the three replication studies. Our summary results from the GWAS are freely available online in a form that should speed the identification of additional loci conferring risk.