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2019-01-01

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Discovery of common and rare genetic risk variants for colorectal cancer

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https://doi.org/10.1038/s41588-018-0286-6

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To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

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Càncer colorectal, Avaluació del risc per la salut

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Colorectal cancer, Health risk assessment

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Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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HUYGHE, Jeroen r., BIEN, Stephanie a., HARRISON, Tabitha a., KANG, Hyun min, CHEN, Sai, SCHMIT, Stephanie l., CONTI, David v., QU, Conghui, JEON, Jihyoun, EDLUND, Christopher k., GREENSIDE, Peyton, THIBODEAU, Stephen n., VODICKOVA, Ludmila, SHAH, Mitul, RASKIN, Leon, WEIGL, Korbinian, SEMINARA, Daniela, WOODS, Michael o., JOSHI, Amit d., WHITE, Emily, LINDOR, Noralane m., ENGLISH, Dallas r., CROSS, Amanda j., JENKINS, Mark a., LOUIE, Tin l., WOLK, Alicja, PHAROAH, Paul d. p., VAN KRANEN, Henk, SINNOTT-ARMSTRONG, Nasa a., KWEON, Sun-seog, SHIN, Min-ho, HOFFMEISTER, Michael, ELIAS, Sjoerd g., ANDERSON, Kristin, LARSSON, Susanna c., HAMPE, Jochen, PEARLMAN, Rachel, HOFER, Philipp, NELSON, Sarah c., HARLID, Sophia, LI, Christopher i., RIBOLI, Elio, MELAS, Marilena, WIN, Aung ko, ARNAU COLLELL, Coral, LI, Li, BAMIA, Christina, VAN GUELPEN, Bethany, CHANG-CLAUDE, Jenny, GSUR, Andrea, ZAIDI, Syed h., SMITH, Joshua d., LEJBKOWICZ, Flavio, VAN DEN BERG, David j., KÜRY, Sébastien, TANGEN, Catherine m., PETERS, Ulrike, NEWCOMB, Polly a., KÜHN, Tilman, FISCHER, Rocky, PRENTICE, Ross l., WAINBERG, Michael, ALONSO AGUADO, Maria henar, CAMPBELL, Peter t., STADLER, Zsofia k., CHAN, Andrew t., LING, Hua, KOOPERBERG, Charles, GRUBER, Stephen b., WU, Anna h. wu, SCHAFMAYER, Clemens, MASALA, Giovanna, SLATTERY, Martha l., KOBAYASHI, Emiko, VYMETALKOVA, Veronika, FITZGERALD, Liesel m., SCHUMACHER, Fredrick r., HEE CHO, Sang, PLATZ, Elizabeth a., ABECASIS, Gonçalo r., ONLAND-MORET, N. charlotte, CUK, Katarina, SU, Yu-ru, SCACHERI, Peter c., RENNERT, Gad, STEGMAIER, Christa, CASEY, Graham, CHIRLAQUE, María dolores, BÉZIEAU, Stéphane, PARDINI, Barbara, HSU, Wan-ling, JACOBS, Eric j., BASSIK, Michael c., TRICHOPOULOU, Antonia, BOEHM, Juergen, SOUTHEY, Melissa c., RODRÍGUEZ BARRANCO, Miguel, JACKSON, Rebecca d., ALBANES, Demetrius, SHELFORD, Tameka, BISHOP, D. timothy, MYTE, Robin, LAURIE, Cecelia a., ZANKE, Brent w., IBÁÑEZ SANZ, Gemma, NACCARATI, Alessio, BRENNER, Hermann, CASTELLVÍ BEL, Sergi, OFFIT, Kenneth, LINDBLOM, Annika, CARLSON, Christopher s., EASTON, Douglas f., HAILE, Robert w., FIGUEIREDO, Jane c., BURNETT-HARTMAN, Andrea, WEINSTEIN, Stephanie j., CURTIS, Keith r., GILES, Graham g., HUNTER, David j., BERNDT, Sonja i., FORMAN, David, IDOS, Gregory e., MURPHY, Neil, TOLAND, Amanda e., BOEING, Heiner, CONNOLLY, Charles m., MÄNNISTÖ, Satu, LIN, Yi, MCNEIL, Caroline e., JOSHU, Corinne e., OGINO, Shuji, HAMPEL, Heather, BUTTERBACH, Katja, HUDSON, Thomas j., MARKOWITZ, Sanford d., Joseph Vijai, HAYES, Richard b., GONG, Jian, KEKU, Temitope o., SHULMAN, Katerina, MARCHAND, Loïc le, MILNE, Roger l., THOMAS, Sushma s., SCHOEN, Robert e., KEY, Timothy j., SAKODA, Lori c., FESKENS, Edith j. m., BUCHANAN, Daniel d., GALA, Manish, GAUDERMAN, W. james, ARNDT, Volker, PUGH, Elizabeth, SIERI, Sabina, BUCH, Stephan, HSU, Li, ZHENG, Wei, PINCHEV, Mila, LEVINE, David m., KIM, Hyeong rok, CAAN, Bette j., GRADY, William m., VODICKA, Pavel, KOLONEL, Laurence n., WOLF, C. roland, HOPPER, John l., NICKERSON, Deborah a., CHANOCK, Stephen j., BARON, John a., GALLINGER, Steven, VAN DUIJNHOVEN, Franzel j. b., ULRICH, Cornelia m., GOODMAN, Phyllis j., LEE, Soo chin, INGERSOLL, Roxann, MORENO AGUADO, Víctor, PERDUCA, Vittorio, POTTER, John d., MARTÍN SÁNCHEZ, Vicente, DUGGAN, David, KUNDAJE, Anshul, ZHANG, Qing, LEMIRE, Mathieu, BANBURY, Barbara l., THOMAS, Duncan c., HUANG, Wen-yi, GROVE, John s., DOHENY, Kimberly f., RENNERT, Hedy s., PARFREY, Patrick s., GILLANDERS, Elizabeth, MORENO, Lorena, CHAPELLE, Albert de la, ELLIOTT, Faye, GUNTER, Marc j., BREZINA, Stefanie, LEAL, Suzanne m., LIEB, Wolfgang, ROMM, Jane, VISVANATHAN, Kala. Discovery of common and rare genetic risk variants for colorectal cancer. _Nature Genetics_. 2019. Vol. 51, núm. 1, pàgs. 76-87. [consulta: 9 de febrer de 2026]. ISSN: 1061-4036. [Disponible a: https://hdl.handle.net/2445/171679]

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