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000157420 0247_ $$2doi$$a10.1016/j.ajhg.2020.07.006
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000157420 0247_ $$2ISSN$$a1537-6605
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000157420 041__ $$aeng
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000157420 1001_ $$aThomas, Minta$$b0
000157420 245__ $$aGenome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
000157420 260__ $$aNew York, NY$$bElsevier$$c2020
000157420 3367_ $$2DRIVER$$aarticle
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000157420 500__ $$a2020 Sep 3;107(3):432-444
000157420 520__ $$aAccurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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000157420 7001_ $$aSakoda, Lori C$$b1
000157420 7001_ $$0P:(DE-He78)6c5d058b7552d071a7fa4c5e943fff0f$$aHoffmeister, Michael$$b2$$udkfz
000157420 7001_ $$aRosenthal, Elisabeth A$$b3
000157420 7001_ $$aLee, Jeffrey K$$b4
000157420 7001_ $$avan Duijnhoven, Franzel J B$$b5
000157420 7001_ $$aPlatz, Elizabeth A$$b6
000157420 7001_ $$aWu, Anna H$$b7
000157420 7001_ $$aDampier, Christopher H$$b8
000157420 7001_ $$ade la Chapelle, Albert$$b9
000157420 7001_ $$aWolk, Alicja$$b10
000157420 7001_ $$aJoshi, Amit D$$b11
000157420 7001_ $$aBurnett-Hartman, Andrea$$b12
000157420 7001_ $$aGsur, Andrea$$b13
000157420 7001_ $$aLindblom, Annika$$b14
000157420 7001_ $$aCastells, Antoni$$b15
000157420 7001_ $$aWin, Aung Ko$$b16
000157420 7001_ $$aNamjou, Bahram$$b17
000157420 7001_ $$aVan Guelpen, Bethany$$b18
000157420 7001_ $$aTangen, Catherine M$$b19
000157420 7001_ $$aHe, Qianchuan$$b20
000157420 7001_ $$aLi, Christopher I$$b21
000157420 7001_ $$aSchafmayer, Clemens$$b22
000157420 7001_ $$aJoshu, Corinne E$$b23
000157420 7001_ $$aUlrich, Cornelia M$$b24
000157420 7001_ $$aBishop, D Timothy$$b25
000157420 7001_ $$aBuchanan, Daniel D$$b26
000157420 7001_ $$aSchaid, Daniel$$b27
000157420 7001_ $$aDrew, David A$$b28
000157420 7001_ $$aMuller, David C$$b29
000157420 7001_ $$aDuggan, David$$b30
000157420 7001_ $$aCrosslin, David R$$b31
000157420 7001_ $$aAlbanes, Demetrius$$b32
000157420 7001_ $$aGiovannucci, Edward L$$b33
000157420 7001_ $$aLarson, Eric$$b34
000157420 7001_ $$aQu, Flora$$b35
000157420 7001_ $$aMentch, Frank$$b36
000157420 7001_ $$aGiles, Graham G$$b37
000157420 7001_ $$aHakonarson, Hakon$$b38
000157420 7001_ $$aHampel, Heather$$b39
000157420 7001_ $$aStanaway, Ian B$$b40
000157420 7001_ $$aFigueiredo, Jane C$$b41
000157420 7001_ $$aHuyghe, Jeroen R$$b42
000157420 7001_ $$aMinnier, Jessica$$b43
000157420 7001_ $$0P:(DE-He78)c259d6cc99edf5c7bc7ce22c7f87c253$$aChang-Claude, Jenny$$b44$$udkfz
000157420 7001_ $$aHampe, Jochen$$b45
000157420 7001_ $$aHarley, John B$$b46
000157420 7001_ $$aVisvanathan, Kala$$b47
000157420 7001_ $$aCurtis, Keith R$$b48
000157420 7001_ $$aOffit, Kenneth$$b49
000157420 7001_ $$aLi, Li$$b50
000157420 7001_ $$aLe Marchand, Loic$$b51
000157420 7001_ $$aVodickova, Ludmila$$b52
000157420 7001_ $$aGunter, Marc J$$b53
000157420 7001_ $$aJenkins, Mark A$$b54
000157420 7001_ $$aSlattery, Martha L$$b55
000157420 7001_ $$aLemire, Mathieu$$b56
000157420 7001_ $$aWoods, Michael O$$b57
000157420 7001_ $$aSong, Mingyang$$b58
000157420 7001_ $$aMurphy, Neil$$b59
000157420 7001_ $$aLindor, Noralane M$$b60
000157420 7001_ $$aDikilitas, Ozan$$b61
000157420 7001_ $$aPharoah, Paul D P$$b62
000157420 7001_ $$aCampbell, Peter T$$b63
000157420 7001_ $$aNewcomb, Polly A$$b64
000157420 7001_ $$aMilne, Roger L$$b65
000157420 7001_ $$aMacInnis, Robert J$$b66
000157420 7001_ $$aCastellví-Bel, Sergi$$b67
000157420 7001_ $$aOgino, Shuji$$b68
000157420 7001_ $$aBerndt, Sonja I$$b69
000157420 7001_ $$aBézieau, Stéphane$$b70
000157420 7001_ $$aThibodeau, Stephen N$$b71
000157420 7001_ $$aGallinger, Steven J$$b72
000157420 7001_ $$aZaidi, Syed H$$b73
000157420 7001_ $$aHarrison, Tabitha A$$b74
000157420 7001_ $$aKeku, Temitope O$$b75
000157420 7001_ $$aHudson, Thomas J$$b76
000157420 7001_ $$aVymetalkova, Veronika$$b77
000157420 7001_ $$aMoreno, Victor$$b78
000157420 7001_ $$aMartín, Vicente$$b79
000157420 7001_ $$0P:(DE-He78)d023fdf423d87ee6c710e34dd7581fa0$$aArndt, Volker$$b80$$udkfz
000157420 7001_ $$aWei, Wei-Qi$$b81
000157420 7001_ $$aChung, Wendy$$b82
000157420 7001_ $$aSu, Yu-Ru$$b83
000157420 7001_ $$aHayes, Richard B$$b84
000157420 7001_ $$aWhite, Emily$$b85
000157420 7001_ $$aVodicka, Pavel$$b86
000157420 7001_ $$aCasey, Graham$$b87
000157420 7001_ $$aGruber, Stephen B$$b88
000157420 7001_ $$aSchoen, Robert E$$b89
000157420 7001_ $$aChan, Andrew T$$b90
000157420 7001_ $$aPotter, John D$$b91
000157420 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b92$$udkfz
000157420 7001_ $$aJarvik, Gail P$$b93
000157420 7001_ $$aCorley, Douglas A$$b94
000157420 7001_ $$aPeters, Ulrike$$b95
000157420 7001_ $$aHsu, Li$$b96
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