Novel Common Genetic Susceptibility Loci for Colorectal Cancer
Authors: Schmit Stephanie L , Edlund Christopher K , Schumacher Fredrick R , Gong Jian , Harrison Tabitha A , Huyghe Jeroen R , Qu Chenxu , Melas Marilena , Van Den Berg David J , Wang Hansong , Tring Stephanie , Plummer Sarah J , Albanes Demetrius , Alonso M Henar , Amos Christopher I , Anton Kristen , Aragaki Aaron K , Arndt Volker , Barry Elizabeth L , Berndt Sonja I , Bezieau Stéphane , Bien Stephanie , Bloomer Amanda , Boehm Juergen , Boutron-Ruault Marie-Christine , Brenner Hermann , Brezina Stefanie , Buchanan Daniel D , Butterbach Katja , Caan Bette J , Campbell Peter T , Carlson Christopher S , Castelao Jose E , Chan Andrew T , Chang-Claude Jenny , Chanock Stephen J , Cheng Iona , Cheng Ya-Wen , Chin Lee Soo , Church James M , Church Timothy , Coetzee Gerhard A , Cotterchio Michelle , Cruz Correa Marcia , Curtis Keith R , Duggan David , Easton Douglas F , English Dallas , Feskens Edith J M , Fischer Rocky , FitzGerald Liesel M , Fortini Barbara K , Fritsche Lars G , Fuchs Charles S , Gago-Dominguez Manuela , Gala Manish , Gallinger Steven J , Gauderman W James , Giles Graham G , Giovannucci Edward L , Gogarten Stephanie M , Gonzalez-Villalpando Clicerio , Gonzalez-Villalpando Elena M , Grady William M , Greenson Joel K , Gsur Andrea , Gunter Marc , Haiman Christopher A , Hampe Jochen , Harlid Sophia , Harju John F , Hayes Richard B , Hofer Philipp , Hoffmeister Michael , Hopper John L , Huang Shu-Chen , Huerta Jose Maria , Hudson Thomas J , Hunter David J , Idos Gregory E , Iwasaki Motoki , Jackson Rebecca D , Jacobs Eric J , Jee Sun Ha , Jenkins Mark A , Jia Wei-Hua , Jiao Shuo , Joshi Amit D , Kolonel Laurence N , Kono Suminori , Kooperberg Charles , Krogh Vittorio , Kuehn Tilman , Küry Sébastien , LaCroix Andrea , Laurie Cecelia A , Lejbkowicz Flavio , Lemire Mathieu , Lenz Heinz-Josef , Levine David , Li Christopher I , Li Li , Lieb Wolfgang , Lin Yi , Lindor Noralane M , Liu Yun-Ru , Loupakis Fotios , Lu Yingchang , Luh Frank , Ma Jing , Mancao Christoph , Manion Frank J , Markowitz Sanford D , Martin Vicente , Matsuda Koichi , Matsuo Keitaro , McDonnell Kevin J , McNeil Caroline E , Milne Roger , Molina Antonio J , Mukherjee Bhramar , Murphy Neil , Newcomb Polly A , Offit Kenneth , Omichessan Hanane , Palli Domenico , Cotoré Jesus P Paredes , Pérez-Mayoral Julyann , Pharoah Paul D , Potter John D , Qu Conghui , Raskin Leon , Rennert Gad , Rennert Hedy S , Riggs Bridget M , Schafmayer Clemens , Schoen Robert E , Sellers Thomas A , Seminara Daniela , Severi Gianluca , Shi Wei , Shibata David , Shu Xiao-Ou , Siegel Erin M , Slattery Martha L , Southey Melissa , Stadler Zsofia K , Stern Mariana C , Stintzing Sebastian , Taverna Darin , Thibodeau Stephen N , Thomas Duncan C , Trichopoulou Antonia , Tsugane Shoichiro , Ulrich Cornelia M , van Duijnhoven Franzel J B , van Guelpan Bethany , Vijai Joseph , Virtamo Jarmo , Weinstein Stephanie J , White Emily , Win Aung Ko , Wolk Alicja , Woods Michael , Wu Anna H , Wu Kana , Xiang Yong-Bing , Yen Yun , Zanke Brent W , Zeng Yi-Xin , Zhang Ben , Zubair Niha , Kweon Sun-Seog , Figueiredo Jane C , Zheng Wei , Marchand Loic Le , Lindblom Annika , Moreno Victor , Peters Ulrike , Casey Graham , Hsu Li , Conti David V , Gruber Stephen B 
Published: April 2018

Abstract

Background
Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods
We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results
The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions
This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.