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


Authors: Gold, B.; Kirchhoff, T.; Stefanov, S.; Lautenberger, J.; Viale, A.; Garber, J.; Friedman, E.; Narod, S.; Olshen, A. B.; Gregersen, P.; Kosarin, K.; Olsh, A.; Bergeron, J.; Ellis, N. A.; Klein, R. J.; Clark, A. G.; Norton, L.; Dean, M.; Boyd, J.; Offit, K.
Article 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 χ2 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 × 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 × 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. © 2008 by The National Academy of Sciences of the USA.
Keywords: adult; controlled study; aged; aged, 80 and over; middle aged; gene mutation; major clinical study; single nucleotide polymorphism; genetics; polymorphism, single nucleotide; cancer risk; genetic predisposition to disease; cohort studies; breast cancer; cohort analysis; gene locus; genetic association; genotype; gene frequency; haplotypes; risk factors; breast neoplasms; risk factor; haplotype; confidence interval; statistical significance; oligonucleotide array sequence analysis; breast tumor; genomics; chromosomes, human, pair 6; genome; dna microarray; high risk population; genetic predisposition; religion; fatty acid; chromosome 6; fibroblast growth factor receptor 2; genome, human; chromosome 6q; family; disease; predisposition; brca1 associated ring domain protein 1; fatty acid oxidation; mapping; snp; judaism
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 105
Issue: 11
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2008-03-18
Start Page: 4340
End Page: 4345
Language: English
DOI: 10.1073/pnas.0800441105
PUBMED: 18326623
PROVIDER: scopus
PMCID: PMC2393811
DOI/URL:
Notes: --- - "Cited By (since 1996): 112" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Kenneth Offit
    519 Offit
  2. Larry Norton
    581 Norton
  3. Adam B Olshen
    107 Olshen
  4. Agnes Viale
    205 Viale
  5. Robert J. Klein
    60 Klein
  6. Kristi Kosarin
    11 Kosarin