Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33

Abstract

We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% CI 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis.

Fig. 1.

Principal components cluster analysis of phase 1 cases (triangles), controls (circles) of Ashkenazi origin, and a reference set of northern Europeans (squares).

Fig. 2.

Significant linkage disequilibrium in the region at 6q22.33 associating with breast cancer in AJs. (A) A 200-kb window. (B) A 500-kb window. A and B show triangle plots using the 101 AJ controls. Red filled triangles represent a D′ of 1. The intensity of the box color is proportional to the strength of the linkage-disequilibrium property for the marker pair; white regions represent regions of low or no linkage disequilibrium; gray represents missing values; pink represents regions of D′ < 1.