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

Authors

Jordahl KM , Shcherbina A , Kim AE , Su YR , Lin Y , Wang J , Qu C , Albanes D , Arndt V , Baurley JW , Berndt SI , Bien SA , Bishop DT , Bouras E , Brenner H , Buchanan DD , Budiarto A , Campbell PT , Carreras-Torres R , Casey G , ...show more Cenggoro TW , Chan AT , Conti DV , Dampier CH , Devall MA , Díez-Obrero V , Dimou N , Drew DA , Figueiredo JC , Gallinger S , Giles GG , Gruber SB , Gsur A , Gunter MJ , Hampel H , Harlid S , Harrison TA , Hidaka A , Hoffmeister M , Huyghe JR , Jenkins MA , Joshi AD , Keku TO , Larsson SC , Le Marchand L , Lewinger JP , Li L , Mahesworo B , Moreno V , Morrison JL , Murphy N , Nan H , Nassir R , Newcomb PA , Obón-Santacana M , Ogino S , Ose J , Pai RK , Palmer JR , Papadimitriou N , Pardamean B , Peoples AR , Pharoah PDP , Platz EA , Potter JD , Prentice RL , Rennert G , Ruiz-Narvaez E , Sakoda LC , Scacheri PC , Schmit SL , Schoen RE , Slattery ML , Stern MC , Tangen CM , Thibodeau SN , Thomas DC , Tian Y , Tsilidis KK , Ulrich CM , van Duijnhoven FJB , Van Guelpen B , Visvanathan K , Vodicka P , White E , Wolk A , Woods MO , Wu AH , Zemlianskaia N , Chang-Claude J , Gauderman WJ , Hsu L , Kundaje A , Peters U

Affiliations

• Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
• Department of Genetics, Stanford University, Stanford, California.
• Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
• Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
• Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
• Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
• Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
• Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
• Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.

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.