Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

Abstract

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

Figure 1. Manhattan plot of GWAS for breast cancer in 1,497 Latina cases and 3,213 controls.

On the x axis are genomic positions by chromosome. On the y axis are the negative log₁₀ P values for the association between the genetic variants and breast cancer risk. LMO4, LIM domain only 4; MARCH4, membrane-associated ring finger (C3HC4) 4, E3 ubiquitin protein ligase; PDZD2, PDZ domain containing 2; ESR1, oestrogen receptor 1; PSMA1, proteasome (prosome, macropain) subunit, alpha type, 1; TOX3, TOX high-mobility group box family member 3; RALY, RALY heterogeneous nuclear ribonucleoprotein.

Figure 2. Quantile–quantile plot for GWAS of breast cancer in Latinas.

The gray line represents a perfect match between the expected distribution of –log10 P under the uniform and those observed in the present analysis.

Figure 3. A regional plot of the −log10 P values for SNPs at 6q25.1.

The SNP with the highest −log10 P value is coloured purple and identified by its rs no. on top of the graph. The two SNPs that were replicated in multiple independent samples are circle-shaped, updated −log10 P values after meta-analysis are X-shaped, and previously reported risk SNPs are triangle-shaped. All other SNPs are represented by crosses and the colours reflect the level of correlation with the SNP with highest −log10 P value. The LD is estimated using data from 1,000 Genomes Project Amerindian populations. In addition, shown are the SNP Build 37 coordinates in megabases (Mb), recombination rates in centimorgans (cM) per megabase (Mb) and the name and location of genes in the UCSC Genome Browser (below).

Figure 4. Box plot of percent mammographic breast density by genotypes for SNP rs140068132 at 6q25 in 1,113 women (304 cases and 809 controls) from the Mexican study.

The boxes represent the median (black middle line) limited by the 25th (Q1) and 75th (Q3) percentiles. The whiskers are the upper and lower adjacent values, which are the most extreme values within Q3+1.5(Q3−Q1) and Q1−1.5(Q3−Q1), respectively. The black dots represent outliers. N defines the number of individuals within each genotype category.

Figure 5. Replication of previously reported associations in Latinas.

Scatter plot of odds ratios previously published (x axis) and in Latinas (y axis). Red dots represent SNPs that were associated at ≤0.05 level of significance in Latinas.