Genome-wide association study in East Asians identifies two novel breast cancer susceptibility loci

Abstract

Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10^{- 8} This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10 ^{- 8} The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.

Figure 1.

Forest plots for risk variants in the two newly identified breast cancer risk loci by study site and stage. Per-allele OR estimates and fixed-effect summary OR estimates are presented. The size of the square box is proportional to the number of cases and controls in each study site.

Figure 2.

Regional plots of association results for the two newly identified risk loci for breast cancer. (A) rs12118297. (B) rs16992204. Each plot shows the -log10 P-values (y-axis) for each SNP in a given genomic region on the x-axis based on NCBI Build 37. The marker SNPs are shown in purple circles and Refseq genes are shown beneath each plot. The top SNPs (rs12118297 and rs16992204) with purple circles are from the meta-analyses of all studies conducted among East Asians, and data shown for all other SNPs are from Stage I only. Pairwise LD with adjacent SNPs as measured by r2 values (according to the 1000 Genomes Project Phase 3 Asian data) is indicated by the color of each circle. (a) rs12118297. (b) rs16992204. Combined P-values for SNPs rs12118297 and rs16992204 were 4.48 x 10^− 8 and 4.63 x 10^− 8, respectively.