Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region
Authors: Jordahl Kristina M. , Shcherbina Anna , Kim Andre E. , Su Yu-Ru , Lin Yi , Wang Jun , Qu Conghui , Albanes Demetrius , Arndt Volker , Baurley James W. , Berndt Sonja I. , Bien Stephanie A. , Bishop D. Timothy , Bouras Emmanouil , Brenner Hermann , Buchanan Daniel D. , Budiarto Arif , Campbell Peter T. , Carreras-Torres Robert , Casey Graham , Cenggoro Tjeng Wawan , Chan Andrew T. , Conti David V. , Dampier Christopher H. , Devall Matthew A. , Díez-Obrero Virginia , Dimou Niki , Drew David A. , Figueiredo Jane C. , Gallinger Steven , Giles Graham G. , Gruber Stephen B. , Gsur Andrea , Gunter Marc J. , Hampel Heather , Harlid Sophia , Harrison Tabitha A. , Hidaka Akihisa , Hoffmeister Michael , Huyghe Jeroen R. , Jenkins Mark A. , Joshi Amit D. , Keku Temitope O. , Larsson Susanna C. , Le Marchand Loic , Lewinger Juan Pablo , Li Li , Mahesworo Bharuno , Moreno Victor , Morrison John L. , Murphy Neil , Nan Hongmei , Nassir Rami , Newcomb Polly A. , Obón-Santacana Mireia , Ogino Shuji , Ose Jennifer , Pai Rish K. , Palmer Julie R. , Papadimitriou Nikos , Pardamean Bens , Peoples Anita R. , Pharoah Paul D.P. , Platz Elizabeth A. , Potter John D. , Prentice Ross L. , Rennert Gad , Ruiz-Narvaez Edward , Sakoda Lori C. , Scacheri Peter C. , Schmit Stephanie L. , Schoen Robert E. , Slattery Martha L. , Stern Mariana C. , Tangen Catherine M. , Thibodeau Stephen N. , Thomas Duncan C. , Tian Yu , Tsilidis Konstantinos K. , Ulrich Cornelia M. , van Duijnhoven Franzel J.B. , Van Guelpen Bethany , Visvanathan Kala , Vodicka Pavel , White Emily , Wolk Alicja , Woods Michael O. , Wu Anna H. , Zemlianskaia Natalia , Chang-Claude Jenny , Gauderman W. James , Hsu Li , Kundaje Anshul , Peters Ulrike 
Published: April 2022

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 (&gt;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 &gt; 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.