Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
Michailidou K., Beesley J., Lindstrom S., Canisius S., Dennis J., Lush MJ., Maranian MJ., Bolla MK., Wang Q., Shah M., Perkins BJ., Czene K., Eriksson M., Darabi H., Brand JS., Bojesen SE., Nordestgaard BG., Flyger H., Nielsen SF., Rahman N., Turnbull C., BOCS None., Fletcher O., Peto J., Gibson L., dos-Santos-Silva I., Chang-Claude J., Flesch-Janys D., Rudolph A., Eilber U., Behrens S., Nevanlinna H., Muranen TA., Aittomäki K., Blomqvist C., Khan S., Aaltonen K., Ahsan H., Kibriya MG., Whittemore AS., John EM., Malone KE., Gammon MD., Santella RM., Ursin G., Makalic E., Schmidt DF., Casey G., Hunter DJ., Gapstur SM., Gaudet MM., Diver WR., Haiman CA., Schumacher F., Henderson BE., Le Marchand L., Berg CD., Chanock SJ., Figueroa J., Hoover RN., Lambrechts D., Neven P., Wildiers H., van Limbergen E., Schmidt MK., Broeks A., Verhoef S., Cornelissen S., Couch FJ., Olson JE., Hallberg E., Vachon C., Waisfisz Q., Meijers-Heijboer H., Adank MA., van der Luijt RB., Li J., Liu J., Humphreys K., Kang D., Choi J-Y., Park SK., Yoo K-Y., Matsuo K., Ito H., Iwata H., Tajima K., Guénel P., Truong T., Mulot C., Sanchez M., Burwinkel B., Marme F., Surowy H., Sohn C., Wu AH., Tseng C-C., Van Den Berg D., Stram DO., González-Neira A., Benitez J., Zamora MP., Perez JIA., Shu X-O., Lu W., Gao Y-T., Cai H., Cox A., Cross SS., Reed MWR., Andrulis IL., Knight JA., Glendon G., Mulligan AM., Sawyer EJ., Tomlinson I., Kerin MJ., Miller N., kConFab Investigators None., AOCS Group None., Lindblom A., Margolin S., Teo SH., Yip CH., Taib NAM., Tan G-H., Hooning MJ., Hollestelle A., Martens JWM., Collée JM., Blot W., Signorello LB., Cai Q., Hopper JL., Southey MC., Tsimiklis H., Apicella C., Shen C-Y., Hsiung C-N., Wu P-E., Hou M-F., Kristensen VN., Nord S., Alnaes GIG., NBCS None., Giles GG., Milne RL., McLean C., Canzian F., Trichopoulos D., Peeters P., Lund E., Sund M., Khaw K-T., Gunter MJ., Palli D., Mortensen LM., Dossus L., Huerta J-M., Meindl A., Schmutzler RK., Sutter C., Yang R., Muir K., Lophatananon A., Stewart-Brown S., Siriwanarangsan P., Hartman M., Miao H., Chia KS., Chan CW., Fasching PA., Hein A., Beckmann MW., Haeberle L., Brenner H., Dieffenbach AK., Arndt V., Stegmaier C., Ashworth A., Orr N., Schoemaker MJ., Swerdlow AJ., Brinton L., Garcia-Closas M., Zheng W., Halverson SL., Shrubsole M., Long J., Goldberg MS., Labrèche F., Dumont M., Winqvist R., Pylkäs K., Jukkola-Vuorinen A., Grip M., Brauch H., Hamann U., Brüning T., GENICA Network None., Radice P., Peterlongo P., Manoukian S., Bernard L., Bogdanova NV., Dörk T., Mannermaa A., Kataja V., Kosma V-M., Hartikainen JM., Devilee P., Tollenaar RAEM., Seynaeve C., Van Asperen CJ., Jakubowska A., Lubinski J., Jaworska K., Huzarski T., Sangrajrang S., Gaborieau V., Brennan P., McKay J., Slager S., Toland AE., Ambrosone CB., Yannoukakos D., Kabisch M., Torres D., Neuhausen SL., Anton-Culver H., Luccarini C., Baynes C., Ahmed S., Healey CS., Tessier DC., Vincent D., Bacot F., Pita G., Alonso MR., Álvarez N., Herrero D., Simard J., Pharoah PPDP., Kraft P., Dunning AM., Chenevix-Trench G., Hall P., Easton DF.
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.