| Title: | Beyond GWAS of colorectal cancer: Evidence of interaction with alcohol consumption and putative causal variant for the 10q24.2 region |
| Journal: | Cancer Epidemiology Biomarkers & Prevention |
| Published: | 24 Feb 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35438744/ |
| DOI: | https://doi.org/10.1158/1055-9965.epi-21-1003 |
| URL: | https://aacrjournals.org/cebp/article-pdf/31/5/1077/3119542/1077.pdf |
Publication 18690
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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.</p>
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.</p>
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.</p>
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.</p>
IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.</p>
7 Keywords
- Alcohol Drinking
- Colorectal Neoplasms
- Electron Transport Complex IV
- Genome-Wide Association Study
- Humans
- Polymorphism, Single Nucleotide
- Risk Factors
94 Authors
- Kristina M Jordahl
- Anna Shcherbina
- Andre E Kim
- Yu-Ru Su
- Yi Lin
- Jun Wang
- Conghui Qu
- Demetrius Albanes
- Volker Arndt
- James W Baurley
- Sonja I Berndt
- Stephanie A Bien
- D Timothy Bishop
- Emmanouil Bouras
- Hermann Brenner
- Daniel D Buchanan
- Arif Budiarto
- Peter T Campbell
- Robert Carreras-Torres
- Graham Casey
- Tjeng Wawan Cenggoro
- Andrew T Chan
- David V Conti
- Christopher H Dampier
- Matthew A Devall
- Virginia Díez-Obrero
- Niki Dimou
- David A Drew
- Jane C Figueiredo
- Steven Gallinger
- Graham G Giles
- Stephen B Gruber
- Andrea Gsur
- Marc J Gunter
- Heather Hampel
- Sophia Harlid
- Tabitha A Harrison
- Akihisa Hidaka
- Michael Hoffmeister
- Jeroen R Huyghe
- Mark A Jenkins
- Amit D Joshi
- Temitope O Keku
- Susanna C Larsson
- Loic Le Marchand
- Juan Pablo Lewinger
- Li Li
- Bharuno Mahesworo
- Victor Moreno
- John L Morrison
- Neil Murphy
- Hongmei Nan
- Rami Nassir
- Polly A Newcomb
- Mireia Obón-Santacana
- Shuji Ogino
- Jennifer Ose
- Rish K Pai
- Julie R Palmer
- Nikos Papadimitriou
- Bens Pardamean
- Anita R Peoples
- Paul D P Pharoah
- Elizabeth A Platz
- John D Potter
- Ross L Prentice
- Gad Rennert
- Edward Ruiz-Narvaez
- Lori C Sakoda
- Peter C Scacheri
- Stephanie L Schmit
- Robert E Schoen
- Martha L Slattery
- Mariana C Stern
- Catherine M Tangen
- Stephen N Thibodeau
- Duncan C Thomas
- Yu Tian
- Konstantinos K Tsilidis
- Cornelia M Ulrich
- Franzel J B van Duijnhoven
- Bethany Van Guelpen
- Kala Visvanathan
- Pavel Vodicka
- Emily White
- Alicja Wolk
- Michael O Woods
- Anna H Wu
- Natalia Zemlianskaia
- Jenny Chang-Claude
- W James Gauderman
- Li Hsu
- Anshul Kundaje
- Ulrike Peters
1 Application
| Application ID | Title |
|---|---|
| 8614 | Evaluating genome-wide association and gene-environment interaction in colorectal cancer |
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