Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).

To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).

This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10^–29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P_het) = 1.3 × 10^–143], but no evidence of ethnic differences in per allele OR (P_het = 0.43). rs865686 was associated with estrogen receptor–positive (ER⁺) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10^–22) but less strongly, if at all, with ER-negative (ER^–) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; P_het = 1.16 × 10^–6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER⁺ tumors.

This study is the first to show that rs865686 is a susceptibility marker for ER⁺ breast cancer.

The findings further support the view that genetic susceptibility varies according to tumor subtype.