Dataset Information

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

ABSTRACT:

Background

Currently 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.

Methods

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.

Results

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.

Conclusions

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.

Impact

The study identifies multifaceted evidence of a possible functional effect for rs1318920.

SUBMITTER: Jordahl KM

PROVIDER: S-EPMC9081195 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Jordahl Kristina M KM Shcherbina Anna A Kim Andre E AE Su Yu-Ru YR Lin Yi Y Wang Jun J Qu Conghui C Albanes Demetrius D Arndt Volker V Baurley James W JW Berndt Sonja I SI Bien Stephanie A SA Bishop D Timothy DT Bouras Emmanouil E Brenner Hermann H Buchanan Daniel D DD Budiarto Arif A Campbell Peter T PT Carreras-Torres Robert R Casey Graham G Cenggoro Tjeng Wawan TW Chan Andrew T AT Conti David V DV Dampier Christopher H CH Devall Matthew A MA Díez-Obrero Virginia V Dimou Niki N Drew David A DA Figueiredo Jane C JC Gallinger Steven S Giles Graham G GG Gruber Stephen B SB Gsur Andrea A Gunter Marc J MJ Hampel Heather H Harlid Sophia S Harrison Tabitha A TA Hidaka Akihisa A Hoffmeister Michael M Huyghe Jeroen R JR Jenkins Mark A MA Joshi Amit D AD Keku Temitope O TO Larsson Susanna C SC Le Marchand Loic L Lewinger Juan Pablo JP Li Li L Mahesworo Bharuno B Moreno Victor V Morrison John L JL Murphy Neil N Nan Hongmei H Nassir Rami R Newcomb Polly A PA Obón-Santacana Mireia M Ogino Shuji S Ose Jennifer J Pai Rish K RK Palmer Julie R JR Papadimitriou Nikos N Pardamean Bens B Peoples Anita R AR Pharoah Paul D P PDP Platz Elizabeth A EA Potter John D JD Prentice Ross L RL Rennert Gad G Ruiz-Narvaez Edward E Sakoda Lori C LC Scacheri Peter C PC Schmit Stephanie L SL Schoen Robert E RE Slattery Martha L ML Stern Mariana C MC Tangen Catherine M CM Thibodeau Stephen N SN Thomas Duncan C DC Tian Yu Y Tsilidis Konstantinos K KK Ulrich Cornelia M CM van Duijnhoven Franzel J B FJB Van Guelpen Bethany B Visvanathan Kala K Vodicka Pavel P White Emily E Wolk Alicja A Woods Michael O MO Wu Anna H AH Zemlianskaia Natalia N Chang-Claude Jenny J Gauderman W James WJ Hsu Li L Kundaje Anshul A Peters Ulrike U

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20220501 5

<h4>Background</h4>Currently 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.<h4>Methods</h4>Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compa ...[more]

PMID: 35438744

Similar Datasets

Project description:Background: Previous observational studies have provided inconsistent evidence for the association between alcohol consumption and the risk of colorectal cancer (CRC). To assess this potential causal effect, we performed bidirectional Mendelian randomization (MR) analysis. Methods: We selected six single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) associated with alcohol consumption (ever versus never drinker) and two SNPs representing the number of drinks per week from a genome-wide association study (GWAS) of the Japanese population. Summary data for CRC were obtained from a GWAS meta-analysis in the Japanese population of 6,692 CRC cases and 27,178 controls. MR analysis was performed by the inverse-variance weighted (IVW) method primarily, supplemented with several sensitivity methods including the weighted median method, maximum likelihood method, MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger regression, Causal Analysis Using Summary Effect estimates (CAUSE) method, as well as constrained maximum likelihood and model averaging and Bayesian information criterion (cML-MA-BIC) method. Multivariable Mendelian randomization (MMR) analyses were used to adjust for potential confounders. Reverse MR analyses were also performed to assess the potential causal effect of CRC on alcohol consumption. Results: Genetically predicted alcohol consumption (ever versus never drinker) was positively associated with the risk of CRC (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.05-1.12, p = 1.51 × 10-5 by IVW). The number of alcoholic drinks per week was also associated with an increased risk of CRC (OR = 1.39, 95%CI: 1.27-1.52, p = 5.29 × 10-13 by IVW). Sensitivity analysis yielded similar results. Reverse MR analyses found no evidence that CRC contributes to either ever drinkers (OR = 1.00, 95%CI: 0.99-1.00, p = 0.339 by IVW) or added number of drinks per week (OR = 1.01, 95%CI: 0.98-1.05, p = 0.545 by IVW). Conclusion: Our study suggested a potential causal association between alcohol consumption and the risk of CRC among Asians. Reducing drinking may be beneficial to the prevention and management of CRC.

Dataset Information

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Background

Methods

Results

Conclusions

Impact

Publications

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.

Similar Datasets

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