Discovery of common and rare genetic risk variants for colorectal cancer

Jeroen R. Huyghe, Stephanie A. Bien, Tabitha A. Harrison, Hyun Min Kang, Sai Chen, Stephanie L. Schmit, David V. Conti, Conghui Qu, Jihyoun Jeon, Christopher K. Edlund, Peyton Greenside, Michael Wainberg, Fredrick R. Schumacher, Joshua D. Smith, David M. Levine, Sarah C. Nelson, Nasa A. Sinnott-Armstrong, Demetrius Albanes, M. Henar Alonso, Kristin AndersonCoral Arnau-Collell, Volker Arndt, Christina Bamia, Barbara L. Banbury, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Juergen Boehm, Heiner Boeing, Hermann Brenner, Stefanie Brezina, Stephan Buch, Daniel D. Buchanan, Andrea Burnett-Hartman, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Maria Dolores Chirlaque, Sang Hee Cho, Charles M. Connolly, Amanda J. Cross, Katarina Cuk, Keith R. Curtis, Sabina Sieri

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)76-87
Number of pages12
JournalNature Genetics
Issue number1
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Genetics


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