Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Deep targeted sequencing of 12 breast cancer susceptibility regions in 4611 women across four different ethnicities

“…Earlier breast cancer fine-mapping studies [30, 56, 63–65] identified multiple candidates for causal variants, but it remains a challenge to determine the evidence required to confidently declare a variant causal. In contrast to previous studies, this is the first study, to our knowledge, to use sequence data rather than genotyped and imputed data, greatly improving genomic coverage.…”

Accuracy of Gene Scores when Pruning Markers by Linkage Disequilibrium

“…Many fine-mapping studies have identified independent effects within regions of LD [20,21] , with the proportion of such regions being reported as high as onethird [22] . Given the limited power to detect multiple independent effects, the true proportion may be higher.…”

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

“…One additional variant, rs11571833 at chromosome 13q13, was not genotyped and could not be imputed in all 3 studies; this variant had a minor allele frequency of 0.006 in the 1000 Genomes AFR population. These 74 risk variants include stronger markers than the index SNP found in GWAS as well as independent signals discovered through subsequent fine-mapping studies (Supplemental Table S1) (1, 3, 4, 8, 10, 11). …”