A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.
Wu L., Shi W., Long J., Guo X., Michailidou K., Beesley J., Bolla MK., Shu X-O., Lu Y., Cai Q., Al-Ejeh F., Rozali E., Wang Q., Dennis J., Li B., Zeng C., Feng H., Gusev A., Barfield RT., Andrulis IL., Anton-Culver H., Arndt V., Aronson KJ., Auer PL., Barrdahl M., Baynes C., Beckmann MW., Benitez J., Bermisheva M., Blomqvist C., Bogdanova NV., Bojesen SE., Brauch H., Brenner H., Brinton L., Broberg P., Brucker SY., Burwinkel B., Caldés T., Canzian F., Carter BD., Castelao JE., Chang-Claude J., Chen X., Cheng T-YD., Christiansen H., Clarke CL., NBCS Collaborators None., Collée M., Cornelissen S., Couch FJ., Cox D., Cox A., Cross SS., Cunningham JM., Czene K., Daly MB., Devilee P., Doheny KF., Dörk T., Dos-Santos-Silva I., Dumont M., Dwek M., Eccles DM., Eilber U., Eliassen AH., Engel C., Eriksson M., Fachal L., Fasching PA., Figueroa J., Flesch-Janys D., Fletcher O., Flyger H., Fritschi L., Gabrielson M., Gago-Dominguez M., Gapstur SM., García-Closas M., Gaudet MM., Ghoussaini M., Giles GG., Goldberg MS., Goldgar DE., González-Neira A., Guénel P., Hahnen E., Haiman CA., Håkansson N., Hall P., Hallberg E., Hamann U., Harrington P., Hein A., Hicks B., Hillemanns P., Hollestelle A., Hoover RN., Hopper JL., Huang G., Humphreys K., Hunter DJ., Jakubowska A., Janni W., John EM., Johnson N., Jones K., Jones ME., Jung A., Kaaks R., Kerin MJ., Khusnutdinova E., Kosma V-M., Kristensen VN., Lambrechts D., Le Marchand L., Li J., Lindström S., Lissowska J., Lo W-Y., Loibl S., Lubinski J., Luccarini C., Lux MP., MacInnis RJ., Maishman T., Kostovska IM., Mannermaa A., Manson JE., Margolin S., Mavroudis D., Meijers-Heijboer H., Meindl A., Menon U., Meyer J., Mulligan AM., Neuhausen SL., Nevanlinna H., Neven P., Nielsen SF., Nordestgaard BG., Olopade OI., Olson JE., Olsson H., Peterlongo P., Peto J., Plaseska-Karanfilska D., Prentice R., Presneau N., Pylkäs K., Rack B., Radice P., Rahman N., Rennert G., Rennert HS., Rhenius V., Romero A., Romm J., Rudolph A., Saloustros E., Sandler DP., Sawyer EJ., Schmidt MK., Schmutzler RK., Schneeweiss A., Scott RJ., Scott CG., Seal S., Shah M., Shrubsole MJ., Smeets A., Southey MC., Spinelli JJ., Stone J., Surowy H., Swerdlow AJ., Tamimi RM., Tapper W., Taylor JA., Terry MB., Tessier DC., Thomas A., Thöne K., Tollenaar RAEM., Torres D., Truong T., Untch M., Vachon C., Van Den Berg D., Vincent D., Waisfisz Q., Weinberg CR., Wendt C., Whittemore AS., Wildiers H., Willett WC., Winqvist R., Wolk A., Xia L., Yang XR., Ziogas A., Ziv E., kConFab/AOCS Investigators None., Dunning AM., Pharoah PDP., Simard J., Milne RL., Edwards SL., Kraft P., Easton DF., Chenevix-Trench G., Zheng W.
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.