Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium

Abstract

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.

Figure 1.

Overview of the study design.

Figure 2.

ORs per risk allele of SNP rs10822013 and 95% CIs for breast cancer by study site, ethnicity and study stage. The size of the box is proportional to the number of cases and controls in each study. The heterogeneity test for results among all studies was not statistically significant (P= 0.4817).

Figure 3.

A regional plot of the −log P-values for SNPs at 10q21.2. Results (−log P) are shown for directly genotyped (blue diamonds) and imputed (white circles) SNPs for a 1 Mb region centered on SNP rs10822013. SNP rs10822013 is shown in red diamonds for Stage-I data and yellow diamonds for all four stages combined. Gene locations are from the March 2006 UCSC Genome Browser assembly.

Figure 4.

Electrophoretic mobility shift assays of SNP rs10822013. Nuclear protein extracts from MCF7 (top panel) and HEK293 (bottom panel) cells were incubated with biotin-labeled probes corresponding to the reference allele (lanes 1–5) or risk allele (lanes 6–10) of rs10822013 in the absence or presence of competitors. Lanes 1 and 6, no nuclear extracts; lanes 2 and 7, unlabeled competitor in 200-fold molar excess; lanes 3 and 8 (5 mm MgCl₂); lanes 4 and 9 (2.5 mm MgCl₂); and lanes 5 and 10 (1.25 mm MgCl₂), no competitor. I, free biotin-labeled probes; II, specific DNA–protein complex bands.