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Discovery of common and rare genetic risk variants for colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Huyghe JR

PROVIDER: S-EPMC6358437 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Discovery of common and rare genetic risk variants for colorectal cancer.

Huyghe Jeroen R JR Bien Stephanie A SA Harrison Tabitha A TA Kang Hyun Min HM Chen Sai S Schmit Stephanie L SL Conti David V DV Qu Conghui C Jeon Jihyoun J Edlund Christopher K CK Greenside Peyton P Wainberg Michael M Schumacher Fredrick R FR Smith Joshua D JD Levine David M DM Nelson Sarah C SC Sinnott-Armstrong Nasa A NA Albanes Demetrius D Alonso M Henar MH Anderson Kristin K Arnau-Collell Coral C Arndt Volker V Bamia Christina C Banbury Barbara L BL Baron John A JA Berndt Sonja I SI Bézieau Stéphane S Bishop D Timothy DT Boehm Juergen J Boeing Heiner H Brenner Hermann H Brezina Stefanie S Buch Stephan S Buchanan Daniel D DD Burnett-Hartman Andrea A Butterbach Katja K Caan Bette J BJ Campbell Peter T PT Carlson Christopher S CS Castellví-Bel Sergi S Chan Andrew T AT Chang-Claude Jenny J Chanock Stephen J SJ Chirlaque Maria-Dolores MD Cho Sang Hee SH Connolly Charles M CM Cross Amanda J AJ Cuk Katarina K Curtis Keith R KR de la Chapelle Albert A Doheny Kimberly F KF Duggan David D Easton Douglas F DF Elias Sjoerd G SG Elliott Faye F English Dallas R DR Feskens Edith J M EJM Figueiredo Jane C JC Fischer Rocky R FitzGerald Liesel M LM Forman David D Gala Manish M Gallinger Steven S Gauderman W James WJ Giles Graham G GG Gillanders Elizabeth E Gong Jian J Goodman Phyllis J PJ Grady William M WM Grove John S JS Gsur Andrea A Gunter Marc J MJ Haile Robert W RW Hampe Jochen J Hampel Heather H Harlid Sophia S Hayes Richard B RB Hofer Philipp P Hoffmeister Michael M Hopper John L JL Hsu Wan-Ling WL Huang Wen-Yi WY Hudson Thomas J TJ Hunter David J DJ Ibañez-Sanz Gemma G Idos Gregory E GE Ingersoll Roxann R Jackson Rebecca D RD Jacobs Eric J EJ Jenkins Mark A MA Joshi Amit D AD Joshu Corinne E CE Keku Temitope O TO Key Timothy J TJ Kim Hyeong Rok HR Kobayashi Emiko E Kolonel Laurence N LN Kooperberg Charles C Kühn Tilman T Küry Sébastien S Kweon Sun-Seog SS Larsson Susanna C SC Laurie Cecelia A CA Le Marchand Loic L Leal Suzanne M SM Lee Soo Chin SC Lejbkowicz Flavio F Lemire Mathieu M Li Christopher I CI Li Li L Lieb Wolfgang W Lin Yi Y Lindblom Annika A Lindor Noralane M NM Ling Hua H Louie Tin L TL Männistö Satu S Markowitz Sanford D SD Martín Vicente V Masala Giovanna G McNeil Caroline E CE Melas Marilena M Milne Roger L RL Moreno Lorena L Murphy Neil N Myte Robin R Naccarati Alessio A Newcomb Polly A PA Offit Kenneth K Ogino Shuji S Onland-Moret N Charlotte NC Pardini Barbara B Parfrey Patrick S PS Pearlman Rachel R Perduca Vittorio V Pharoah Paul D P PDP Pinchev Mila M Platz Elizabeth A EA Prentice Ross L RL Pugh Elizabeth E Raskin Leon L Rennert Gad G Rennert Hedy S HS Riboli Elio E Rodríguez-Barranco Miguel M Romm Jane J Sakoda Lori C LC Schafmayer Clemens C Schoen Robert E RE Seminara Daniela D Shah Mitul M Shelford Tameka T Shin Min-Ho MH Shulman Katerina K Sieri Sabina S Slattery Martha L ML Southey Melissa C MC Stadler Zsofia K ZK Stegmaier Christa C Su Yu-Ru YR Tangen Catherine M CM Thibodeau Stephen N SN Thomas Duncan C DC Thomas Sushma S SS Toland Amanda E AE Trichopoulou Antonia A Ulrich Cornelia M CM Van Den Berg David J DJ van Duijnhoven Franzel J B FJB Van Guelpen Bethany B van Kranen Henk H Vijai Joseph J Visvanathan Kala K Vodicka Pavel P Vodickova Ludmila L Vymetalkova Veronika V Weigl Korbinian K Weinstein Stephanie J SJ White Emily E Win Aung Ko AK Wolf C Roland CR Wolk Alicja A Woods Michael O MO Wu Anna H AH Zaidi Syed H SH Zanke Brent W BW Zhang Qing Q Zheng Wei W Scacheri Peter C PC Potter John D JD Bassik Michael C MC Kundaje Anshul A Casey Graham G Moreno Victor V Abecasis Goncalo R GR Nickerson Deborah A DA Gruber Stephen B SB Hsu Li L Peters Ulrike U

Nature genetics 20181203 1

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 ...[more]

PMID: 30510241

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Project description:ObjectiveColorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data.DesignNine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks.ResultsThe median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk.ConclusionGenotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.

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Discovery of common and rare genetic risk variants for colorectal cancer.

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Discovery of common and rare genetic risk variants for colorectal cancer.

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