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000179585 1001_ $$00000-0001-5165-5769$$aJordahl, Kristina M$$b0
000179585 245__ $$aBeyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.
000179585 260__ $$aPhiladelphia, Pa.$$bAACR$$c2022
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000179585 500__ $$a2022 May 4;31(5):1077-1089
000179585 520__ $$aCurrently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer.Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models.For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif.Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region.The study identifies multifaceted evidence of a possible functional effect for rs1318920.
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000179585 7001_ $$00000-0002-5080-5494$$aShcherbina, Anna$$b1
000179585 7001_ $$aKim, Andre E$$b2
000179585 7001_ $$aSu, Yu-Ru$$b3
000179585 7001_ $$aLin, Yi$$b4
000179585 7001_ $$aWang, Jun$$b5
000179585 7001_ $$aQu, Conghui$$b6
000179585 7001_ $$aAlbanes, Demetrius$$b7
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000179585 7001_ $$aBaurley, James W$$b9
000179585 7001_ $$aBerndt, Sonja I$$b10
000179585 7001_ $$00000-0002-8713-4583$$aBien, Stephanie A$$b11
000179585 7001_ $$00000-0002-8752-8785$$aBishop, D Timothy$$b12
000179585 7001_ $$aBouras, Emmanouil$$b13
000179585 7001_ $$0P:(DE-He78)90d5535ff896e70eed81f4a4f6f22ae2$$aBrenner, Hermann$$b14$$udkfz
000179585 7001_ $$00000-0003-2225-6675$$aBuchanan, Daniel D$$b15
000179585 7001_ $$aBudiarto, Arif$$b16
000179585 7001_ $$00000-0002-5549-2036$$aCampbell, Peter T$$b17
000179585 7001_ $$00000-0002-2925-734X$$aCarreras-Torres, Robert$$b18
000179585 7001_ $$aCasey, Graham$$b19
000179585 7001_ $$aCenggoro, Tjeng Wawan$$b20
000179585 7001_ $$00000-0001-7284-6767$$aChan, Andrew T$$b21
000179585 7001_ $$aConti, David V$$b22
000179585 7001_ $$00000-0003-3099-6462$$aDampier, Christopher H$$b23
000179585 7001_ $$aDevall, Matthew A$$b24
000179585 7001_ $$aDíez-Obrero, Virginia$$b25
000179585 7001_ $$00000-0003-1678-9328$$aDimou, Niki$$b26
000179585 7001_ $$00000-0002-8813-0816$$aDrew, David A$$b27
000179585 7001_ $$00000-0001-8040-3341$$aFigueiredo, Jane C$$b28
000179585 7001_ $$aGallinger, Steven$$b29
000179585 7001_ $$00000-0003-4946-9099$$aGiles, Graham G$$b30
000179585 7001_ $$00000-0001-8656-7822$$aGruber, Stephen B$$b31
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000179585 7001_ $$aLi, Li$$b46
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000179585 7001_ $$00000-0002-6534-335X$$aPalmer, Julie R$$b58
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