Archambault, Alexi NSu, Yu-RuJeon, JihyounThomas, MintaLin, YiConti, David VWin, Aung KoSakoda, Lori CLansdorp-Vogelaar, IrisPeterse, Elisabeth F PZauber, Ann GDuggan, DavidHolowatyj, Andreana NHuyghe, Jeroen RBrenner, HermannCotterchio, MichelleBézieau, StéphaneSchmit, Stephanie LEdlund, Christopher KSouthey, Melissa CMacInnis, Robert JCampbell, Peter TChang-Claude, JennySlattery, Martha LChan, Andrew TJoshi, Amit DSong, MingyangCao, YinWoods, Michael OWhite, EmilyWeinstein, Stephanie JUlrich, Cornelia MHoffmeister, MichaelBien, Stephanie AHarrison, Tabitha AHampe, JochenLi, Christopher ISchafmayer, ClemensOffit, KennethPharoah, Paul DMoreno, VictorLindblom, AnnikaWolk, AlicjaWu, Anna HLi, LiGunter, Marc JGsur, AndreaKeku, Temitope OPearlman, RachelBishop, D TimothyCastellví-Bel, SergiMoreira, LeticiaVodicka, PavelKampman, EllenGiles, Graham GAlbanes, DemetriusBaron, John ABerndt, Sonja IBrezina, StefanieBuch, StephanBuchanan, Daniel DTrichopoulou, AntoniaSeveri, GianlucaChirlaque, María-DoloresSanchez-Perez, Maria-JosePalli, DomenicoKühn, TilmanMurphy, NeilCross, Amanda JBurnett-Hartman, Andrea NChanock, Stephen Jde la Chapelle, AlbertEaston, Douglas FElliott, FayeEnglish, Dallas RFeskens, Edith J MFitzGerald, Liesel MGoodman, Phyllis JHopper, John LHudson, Thomas JHunter, David JJacobs, Eric JJoshu, Corinne EKüry, SébastienMarkowitz, Sanford DMilne, Roger LPlatz, Elizabeth ARennert, GadRennert, Hedy SSchumacher, Fredrick RSandler, Robert SSeminara, DanielaTangen, Catherine MThibodeau, Stephen NToland, Amanda Evan Duijnhoven, Franzel J BVisvanathan, KalaVodickova, LudmilaPotter, John DMännistö, SatuWeigl, KorbinianFigueiredo, JaneMartín, VicenteLarsson, Susanna CParfrey, Patrick SHuang, Wen-YiLenz, Heinz-JosefCastelao, Jose EGago-Dominguez, ManuelaMuñoz-Garzón, VictorMancao, ChristophHaiman, Christopher AWilkens, Lynne RSiegel, ErinBarry, ElizabethYounghusband, BanVan Guelpen, BethanyHarlid, SophiaZeleniuch-Jacquotte, AnneLiang, Peter SDu, MengmengCasey, GrahamLindor, Noralane MLe Marchand, LoicGallinger, Steven JJenkins, Mark ANewcomb, Polly AGruber, Stephen BSchoen, Robert EHampel, HeatherCorley, Douglas AHsu, LiPeters, UlrikeHayes, Richard B2023-02-082023-02-082019-12-19http://hdl.handle.net/10668/14866Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.enColon CancerEOCRCPenetranceSNPAge of OnsetCase-Control StudiesCohort StudiesColorectal NeoplasmsDNA Mutational AnalysisDatasets as TopicFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotyping TechniquesHumansLife StyleMaleMedical History TakingMiddle AgedMutation RatePolymorphism, Single NucleotideRisk FactorsWhole Genome Sequencingresearch article31866242open access10.1053/j.gastro.2019.12.0121528-0012PMC7103489https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489/pdf