title: 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.
authors.affiliation: Laboratory of Genomic Diversity, Human Genetics Section, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Stefan
authors.initials: S
authors.lastname: Stefanov
authors.forename: James
authors.initials: J
authors.lastname: Lautenberger
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Judy
authors.initials: J
authors.lastname: Garber
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Steven
authors.initials: S
authors.lastname: Narod
authors.forename: Adam B
authors.initials: AB
authors.lastname: Olshen
authors.forename: Peter
authors.initials: P
authors.lastname: Gregersen
authors.forename: Kristi
authors.initials: K
authors.lastname: Kosarin
authors.forename: Adam
authors.initials: A
authors.lastname: Olsh
authors.forename: Julie
authors.initials: J
authors.lastname: Bergeron
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Klein
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Clark
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D015331:Cohort Studies; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007599:Judaism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors