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

0568390 - ÚEM 2023 RIV US eng J - Journal Article
Jordahl, K.M. - Shcherbina, A. - Kim, A.E. - Su, Y.R. - Lin, Y. - Wang, J. - Qu, C. - Albanes, D. - Arndt, V. - Baurley, J.W. - Berndt, S.I. - Bien, S.A. - Bishop, D.T. - Bouras, E. - Brenner, H. - Buchanan, D.D. - Budiarto, A. - Campbell, P.T. - Carreras-Torres, R. - Casey, G. - Cenggoro, T.W. - Chan, A. - Conti, D.V. - Dampier, Ch.H. - Devall, M.A. - Diez-Obrero, V. - Dimou, N. - Vodička, Pavel … Total 80 authors
Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.
Cancer Epidemiology Biomarkers & Prevention. Roč. 31, č. 5 (2022), s. 1077-1089. ISSN 1055-9965. E-ISSN 1538-7755
Institutional support: RVO:68378041
Keywords : association * expression * enzymes * risk
OECD category: Genetics and heredity (medical genetics to be 3)
Impact factor: 3.8, year: 2022
Method of publishing: Open access
https://aacrjournals.org/cebp/article-abstract/31/5/1077/694750/Beyond-GWAS-of-Colorectal-Cancer-Evidence-of?redirectedFrom=fulltext

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 associ-ation 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 anda 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 r(2) > 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 non-drinkers 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.
Permanent Link: https://hdl.handle.net/11104/0339837