Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.
Milne RL., Burwinkel B., Michailidou K., Arias-Perez J-I., Zamora MP., Menéndez-Rodríguez P., Hardisson D., Mendiola M., González-Neira A., Pita G., Alonso MR., Dennis J., Wang Q., Bolla MK., Swerdlow A., Ashworth A., Orr N., Schoemaker M., Ko Y-D., Brauch H., Hamann U., GENICA Network None., Andrulis IL., Knight JA., Glendon G., Tchatchou S., kConFab Investigators None., Australian Ovarian Cancer Study Group None., Matsuo K., Ito H., Iwata H., Tajima K., Li J., Brand JS., Brenner H., Dieffenbach AK., Arndt V., Stegmaier C., Lambrechts D., Peuteman G., Christiaens M-R., Smeets A., Jakubowska A., Lubinski J., Jaworska-Bieniek K., Durda K., Hartman M., Hui M., Yen Lim W., Wan Chan C., Marme F., Yang R., Bugert P., Lindblom A., Margolin S., García-Closas M., Chanock SJ., Lissowska J., Figueroa JD., Bojesen SE., Nordestgaard BG., Flyger H., Hooning MJ., Kriege M., van den Ouweland AMW., Koppert LB., Fletcher O., Johnson N., dos-Santos-Silva I., Peto J., Zheng W., Deming-Halverson S., Shrubsole MJ., Long J., Chang-Claude J., Rudolph A., Seibold P., Flesch-Janys D., Winqvist R., Pylkäs K., Jukkola-Vuorinen A., Grip M., Cox A., Cross SS., Reed MWR., Schmidt MK., Broeks A., Cornelissen S., Braaf L., Kang D., Choi J-Y., Park SK., Noh D-Y., Simard J., Dumont M., Goldberg MS., Labrèche F., Fasching PA., Hein A., Ekici AB., Beckmann MW., Radice P., Peterlongo P., Azzollini J., Barile M., Sawyer E., Tomlinson I., Kerin M., Miller N., Hopper JL., Schmidt DF., Makalic E., Southey MC., Hwang Teo S., Har Yip C., Sivanandan K., Tay W-T., Shen C-Y., Hsiung C-N., Yu J-C., Hou M-F., Guénel P., Truong T., Sanchez M., Mulot C., Blot W., Cai Q., Nevanlinna H., Muranen TA., Aittomäki K., Blomqvist C., Wu AH., Tseng C-C., Van Den Berg D., Stram DO., Bogdanova N., Dörk T., Muir K., Lophatananon A., Stewart-Brown S., Siriwanarangsan P., Mannermaa A., Kataja V., Kosma V-M., Hartikainen JM., Shu X-O., Lu W., Gao Y-T., Zhang B., Couch FJ., Toland AE., TNBCC None., Yannoukakos D., Sangrajrang S., McKay J., Wang X., Olson JE., Vachon C., Purrington K., Severi G., Baglietto L., Haiman CA., Henderson BE., Schumacher F., Le Marchand L., Devilee P., Tollenaar RAEM., Seynaeve C., Czene K., Eriksson M., Humphreys K., Darabi H., Ahmed S., Shah M., Pharoah PDP., Hall P., Giles GG., Benítez J., Dunning AM., Chenevix-Trench G., Easton DF.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.