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

doi:10.1073/pnas.0800441105

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

^aLaboratory of Genomic Diversity, Human Genetics Section, National Cancer Institute–Frederick, Frederick, MD 21702;
^bClinical Genetics Service, Department of Medicine,
^cGenome Core Laboratory,
^mBreast Medicine Service,
^gDepartment of Biostatistics and Epidemiology, and
^kCancer Biology and Genetics Program, Memorial Sloan–Kettering Cancer Center, New York, NY 10065;
^dCancer Risk and Prevention Program, Dana–Farber Cancer Institute, Boston, MA 02115;
^eThe Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel;
^fCentre for Research in Women's Health, Toronto, ON, Canada M5G 1N8;
^hCenter for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, Manhasset, NY 11030;
ⁱLaboratory of Genomic Diversity, Human Genetics Section, SAIC-Frederick, Inc., Frederick, MD 21702;
^jDivision of Gastroenterology, Department of Medicine, University of Chicago, Chicago, IL 60637;
^lDepartment of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853; and
ⁿAnderson Cancer Institute, Memorial Health University Medical Center, Savannah, GA 31404

Communicated by Arnold J. Levine, Institute for Advanced Study, Princeton, NJ, January 15, 2008 (received for review October 25, 2007)

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.

Footnotes

^oTo whom correspondence should be addressed at:
Clinical Genetics Service, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, NY 10065.
E-mail: offitk{at}mskcc.org
Author contributions: T.K. and S.S. contributed equally to this work; N.A.E., L.N., J. Boyd, and K.O. designed research; T.K., A.V., K.K., and K.O. performed research; B.G., T.K., S.S., J.L., A.V., J.G., E.F., S.N., A.B.O., P.G., A.O., A.G.C., M.D., and K.O. contributed new reagents/analytic tools; B.G., T.K., S.S., J.L., K.K., A.O., J. Bergeron, N.A.E., R.J.K., A.G.C., M.D., and K.O. analyzed data; and B.G. and K.O. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0800441105/DC1.
Freely available online through the PNAS open access option.