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

• DOI: 10.1073/pnas.0800441105
• Publication Date: 2008-03-08T02:09:34Z
• Authors: Bert Gold; Tomas Kirchhoff; Stefan Stefanov; James Lautenberger; Agnes Viale; Judy Garber; Eitan Friedman; Steven Narod; Adam B. Olshen; Peter Gregersen; Kristi Kosarin; Adam Olsh; Julie Bergeron; Nathan A. Ellis; Robert J. Klein; Andrew G. Clark; Larry Norton; Michael Dean; Jeff Boyd; Kenneth Offit
• Keywords: Minor allele frequency; Genome-wide Association Study; Genetic Association; Candidate gene

We performed a three-phase genome-wide association study (GWAS) using cases and controls from 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 299 cancer-free chi(2) Cochran-Armitage trend tests. second genotyped 343 123 regions most significantly stage 1, including 4 FGFR2 region, 950 consecutive 979 age-matched controls. replicated major associations third independent set 243 187 obtained significant P value 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). addition, found risk locus chromosome 6q22.33 2.9 10(-8), OR 1.41, CI 1.25-1.59 rs2180341). Using several each implicated locus, were able verify impute haplotypes. The haplotype conferred protection disease, whereas minor Candidate genes include ECHDC1, which encodes protein involved mitochondrial fatty acid oxidation, also RNF146, ubiquitin ligase, both known pathways pathogenesis.