Human Molecular Genetics Advance Access originally published online on December 3, 2007
Human Molecular Genetics 2008 17(6):825-834; doi:10.1093/hmg/ddm354
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Comprehensive association testing of common genetic variation in DNA repair pathway genes in relationship with breast cancer risk in multiple populations
1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA 2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 3 Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, USA 4 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA 5 Cancer Research UK, Department of Oncology, Strangeways Research Laboratory, University of Cambridge, UK 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA 7 Epidemiology Department, Harvard School of Public Health, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 3234427755; Fax: +1 3234427749; Email: haiman{at}usc.edu
Received September 21, 2007; Revised November 12, 2007; Accepted November 29, 2007
Genetic association studies of multiple populations investigate a wider range of risk alleles than studies of a single ethnic group. In this study, we developed a multiethnic tagging strategy, exploiting differences in linkage disequilibrium (LD) structure between populations, to comprehensively capture common genetic variation across 60 genes spanning multiple DNA repair pathways, in five racial/ethnic populations. Over 2600 SNPs were genotyped in each population and single- and multi-marker predictors of common alleles were selected to capture the LD patterns specific to each group. Coding variants (n = 211) were genotyped to test whether combinations of putative functional variants in DNA repair pathway genes could have cumulative effects on risk. Tests of association were conducted in a multiethnic breast cancer study (2093 cases and 2303 controls), with validation of the top allelic associations (P 
0.01) performed in additional studies of 6483 cases and 7309 controls. A variant in the FANCA gene (rs1061646, 0.15–0.68 frequency across populations) was associated with risk in the initial study (P = 0.0052), and in the replication studies (P = 0.032). In a combined analysis (8556 cases and 9605 controls), this SNP yielded an 8% increase in risk per allele. Combinations of coding variants in these genes were not associated with breast cancer and together, these data suggest that common variation in these DNA repair pathway genes are not strongly associated with breast cancer risk. The methods utilized in this study, applied to multiple populations, provide a framework for testing in association studies in diverse populations.