Genome-wide association study identifies novel breast cancer susceptibility loci.
Easton DF., Pooley KA., Dunning AM., Pharoah PDP., Thompson D., Ballinger DG., Struewing JP., Morrison J., Field H., Luben R., Wareham N., Ahmed S., Healey CS., Bowman R., SEARCH collaborators None., Meyer KB., Haiman CA., Kolonel LK., Henderson BE., Le Marchand L., Brennan P., Sangrajrang S., Gaborieau V., Odefrey F., Shen C-Y., Wu P-E., Wang H-C., Eccles D., Evans DG., Peto J., Fletcher O., Johnson N., Seal S., Stratton MR., Rahman N., Chenevix-Trench G., Bojesen SE., Nordestgaard BG., Axelsson CK., Garcia-Closas M., Brinton L., Chanock S., Lissowska J., Peplonska B., Nevanlinna H., Fagerholm R., Eerola H., Kang D., Yoo K-Y., Noh D-Y., Ahn S-H., Hunter DJ., Hankinson SE., Cox DG., Hall P., Wedren S., Liu J., Low Y-L., Bogdanova N., Schürmann P., Dörk T., Tollenaar RAEM., Jacobi CE., Devilee P., Klijn JGM., Sigurdson AJ., Doody MM., Alexander BH., Zhang J., Cox A., Brock IW., MacPherson G., Reed MWR., Couch FJ., Goode EL., Olson JE., Meijers-Heijboer H., van den Ouweland A., Uitterlinden A., Rivadeneira F., Milne RL., Ribas G., Gonzalez-Neira A., Benitez J., Hopper JL., McCredie M., Southey M., Giles GG., Schroen C., Justenhoven C., Brauch H., Hamann U., Ko Y-D., Spurdle AB., Beesley J., Chen X., kConFab None., AOCS Management Group None., Mannermaa A., Kosma V-M., Kataja V., Hartikainen J., Day NE., Cox DR., Ponder BAJ.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.