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

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 Obon-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

doi:10.1158/1055-9965.EPI-21-1003

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

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 CaseyTjeng 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 Obon-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

Research output: Contribution to journal › Article › peer-review

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 ¼ 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype ¼ 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.

Original language	English (US)
Pages (from-to)	1077-1089
Number of pages	13
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	31
Issue number	5
DOIs	https://doi.org/10.1158/1055-9965.EPI-21-1003
State	Published - May 2022

ASJC Scopus subject areas

Epidemiology
Oncology

Access to Document

10.1158/1055-9965.EPI-21-1003

Cite this

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., ... Peters, U. (2022). Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region. Cancer Epidemiology Biomarkers and Prevention, 31(5), 1077-1089. https://doi.org/10.1158/1055-9965.EPI-21-1003

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, 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, Obon-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 2022, 'Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region', Cancer Epidemiology Biomarkers and Prevention, vol. 31, no. 5, pp. 1077-1089. https://doi.org/10.1158/1055-9965.EPI-21-1003

@article{fd98c570ba604e1080ff75b3b783f31a,

title = "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 ¼ 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype ¼ 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.",

author = "Jordahl, {Kristina M.} and Anna Shcherbina and Kim, {Andre E.} and Su, {Yu Ru} and Yi Lin and Jun Wang and Conghui Qu and Demetrius Albanes and Volker Arndt and Baurley, {James W.} and Berndt, {Sonja I.} and Bien, {Stephanie A.} and Bishop, {D. Timothy} and Emmanouil Bouras and Hermann Brenner and Buchanan, {Daniel D.} and Arif Budiarto and Campbell, {Peter T.} and Robert Carreras-Torres and Graham Casey and Cenggoro, {Tjeng Wawan} and Chan, {Andrew T.} and Conti, {David V.} and Dampier, {Christopher H.} and Devall, {Matthew A.} and Virginia D{\'i}ez-Obrero and Niki Dimou and Drew, {David A.} and Figueiredo, {Jane C.} and Steven Gallinger and Giles, {Graham G.} and Gruber, {Stephen B.} and Andrea Gsur and Gunter, {Marc J.} and Heather Hampel and Sophia Harlid and Harrison, {Tabitha A.} and Akihisa Hidaka and Michael Hoffmeister and Huyghe, {Jeroen R.} and Jenkins, {Mark A.} and Joshi, {Amit D.} and Keku, {Temitope O.} and Larsson, {Susanna C.} and {Le Marchand}, Loic and Lewinger, {Juan Pablo} and Li Li and Bharuno Mahesworo and Victor Moreno and Morrison, {John L.} and Neil Murphy and Hongmei Nan and Rami Nassir and Newcomb, {Polly A.} and Mireia Obon-Santacana and Shuji Ogino and Jennifer Ose and Pai, {Rish K.} and Palmer, {Julie R.} and Nikos Papadimitriou and Bens Pardamean and Peoples, {Anita R.} and Pharoah, {Paul D.P.} and Platz, {Elizabeth A.} and Potter, {John D.} and Prentice, {Ross L.} and Gad Rennert and Edward Ruiz-Narvaez and Sakoda, {Lori C.} and Scacheri, {Peter C.} and Schmit, {Stephanie L.} and Schoen, {Robert E.} and Slattery, {Martha L.} and Stern, {Mariana C.} and Tangen, {Catherine M.} and Thibodeau, {Stephen N.} and Thomas, {Duncan C.} and Yu Tian and Tsilidis, {Konstantinos K.} and Ulrich, {Cornelia M.} and {van Duijnhoven}, {Franzel J.B.} and {Van Guelpen}, Bethany and Kala Visvanathan and Pavel Vodicka and Emily White and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Natalia Zemlianskaia and Jenny Chang-Claude and Gauderman, {W. James} and Li Hsu and Anshul Kundaje and Ulrike Peters",

note = "Funding Information: during the conduct of the study. V. Moreno reports grants from Agency for Management of University and Research Grants (AGAUR) of the Catalan Government and Instituto de Salud Carlos III during the conduct of the study. S. Ogino reports grants from NIH during the conduct of the study. R.K. Pai reports personal fees from Alimentiv Inc, PathAI, Allergan, AbbVie, and Eli Lilly outside the submitted work. J.R. Palmer reports grants from NIH during the conduct of the study. P.D.P. Pharoah reports grants from Cancer Research UK during the conduct of the study. E.A. Platz reports grants from NCI and AICR during the conduct of the study as well as personal fees from American Association for Cancer Research outside the submitted work. R.L. Prentice reports grants from NHLBI/NIH during the conduct of the study. L.C. Sakoda reports grants from NCI during the conduct of the study as well as grants from NCI and personal fees from NIH outside the submitted work. P.C. Scacheri reports grants and personal fees from Kronos Bio outside the submitted work. S.L. Schmit reports grants from NIEHS during the conduct of the study. R.E. Schoen reports grants from Freenome, Immunovia, and Exact outside the submitted work. M.L. Slattery reports grants from NCI during the conduct of the study. M.C. Stern reports grants from University of Southern California during the conduct of the study. C.M. Ulrich reports, as cancer center director, having oversight over research fundedbyseveralpharmaceutical companies, but has not receiveddirect funding. B.Van Guelpen reports grants from Swedish Research Council, through Biobank Sweden, during the conduct of the study. A. Wolk reports grants from The Swedish Cancer Foundation and The Swedish Research Council/SIMPLER during the conduct of the study. A. Kundaje reports personal fees from Ilumina Inc. and Open Targets (GSK) outside the submitted work. No disclosures were reported by the other authors. Funding Information: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). Cancer data were provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health. This research has been conducted using the UK Biobank Resource under Application Number 8614. We would also like to acknowledge data from VITAL, WHI. We thank all participants and cooperating clinicians, and everyone who provided excellent technical assistance from the following organizations, registries, and consortia: Colon CFR; Seattle CCFR; Hormones and Colon Cancer study (CORE Studies); CLUE II; CPS-II; Czech Republic CCS; DACHS; EPIC; Harvard cohorts (HPFS, NHS); Channing Division of Network Medicine; Department of Medicine, Brigham and Women{\textquoteright}s Hospital and Harvard T.H. Chan School of Public Health; Kentucky Cancer Registry; LCCS: We acknowledge the contributions of Jennifer Barrett, Robin Waxman, Gillian Smith and Emma Northwood in conducting this study; PLCO Cancer Screening Trial; District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results program; SELECT; WHI. GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, U01 CA164930, R01201407). The Editor-in-Chief of Cancer Epidemiology, Biomarkers & Prevention is an author on this article. In keeping with AACR editorial policy, a senior member of the Cancer Epidemiology, Biomarkers & Prevention editorial team managed the consideration process for this submission and independently rendered the final decision concerning acceptability. Funding Information: K.M. Jordahl reports grants from NCI (T32-CA094880) during the conduct of the study. A. Shcherbina reports other support from Insitro, Inc and personal fees from Bristol-Myers Squibb, Inc outside the submitted work. Y.-R. Su reports grants from NIH during the conduct of the study. S.A. Bien is an employee of and holds stock in Adaptive Biotechnologies. G. Casey reports grants from NIH during the conduct of the study. A.T. Chan reports personal fees from Bayer Pharma AG and Boehringer Ingelheim and grants and personal fees from Pfizer Inc. outside the submitted work. C.H. Dampier reports grants from NIH during the conduct of the study. D.A. Drew reports grants from NIH during the conduct of the study. G.G. Giles reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. S.B. Gruber reports other support from Brogent International LLC outside the submitted work. H. Hampel reports other support from Myriad Genetics, Inc during the conduct of the study as well as other support from Invitae, Genome Medical, Promega, and GI OnDEMAND outside the submitted work. M.A. Jenkins reports grants from NIH and National Health and Medical Research Council, Australia during the conduct of the study. L. Le Marchand reports grants from NCI Publisher Copyright: {\textcopyright}2022 American Association for Cancer Research",

year = "2022",

month = may,

doi = "10.1158/1055-9965.EPI-21-1003",

language = "English (US)",

volume = "31",

pages = "1077--1089",

journal = "Cancer Epidemiology Biomarkers and Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "5",

}

TY - JOUR

T1 - Beyond GWAS of Colorectal Cancer

T2 - Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

AU - Jordahl, Kristina M.

AU - Shcherbina, Anna

AU - Kim, Andre E.

AU - Su, Yu Ru

AU - Lin, Yi

AU - Wang, Jun

AU - Qu, Conghui

AU - Albanes, Demetrius

AU - Arndt, Volker

AU - Baurley, James W.

AU - Berndt, Sonja I.

AU - Bien, Stephanie A.

AU - Bishop, D. Timothy

AU - Bouras, Emmanouil

AU - Brenner, Hermann

AU - Buchanan, Daniel D.

AU - Budiarto, Arif

AU - Campbell, Peter T.

AU - Carreras-Torres, Robert

AU - Casey, Graham

AU - Cenggoro, Tjeng Wawan

AU - Chan, Andrew T.

AU - Conti, David V.

AU - Dampier, Christopher H.

AU - Devall, Matthew A.

AU - Díez-Obrero, Virginia

AU - Dimou, Niki

AU - Drew, David A.

AU - Figueiredo, Jane C.

AU - Gallinger, Steven

AU - Giles, Graham G.

AU - Gruber, Stephen B.

AU - Gsur, Andrea

AU - Gunter, Marc J.

AU - Hampel, Heather

AU - Harlid, Sophia

AU - Harrison, Tabitha A.

AU - Hidaka, Akihisa

AU - Hoffmeister, Michael

AU - Huyghe, Jeroen R.

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Keku, Temitope O.

AU - Larsson, Susanna C.

AU - Le Marchand, Loic

AU - Lewinger, Juan Pablo

AU - Li, Li

AU - Mahesworo, Bharuno

AU - Moreno, Victor

AU - Morrison, John L.

AU - Murphy, Neil

AU - Nan, Hongmei

AU - Nassir, Rami

AU - Newcomb, Polly A.

AU - Obon-Santacana, Mireia

AU - Ogino, Shuji

AU - Ose, Jennifer

AU - Pai, Rish K.

AU - Palmer, Julie R.

AU - Papadimitriou, Nikos

AU - Pardamean, Bens

AU - Peoples, Anita R.

AU - Pharoah, Paul D.P.

AU - Platz, Elizabeth A.

AU - Potter, John D.

AU - Prentice, Ross L.

AU - Rennert, Gad

AU - Ruiz-Narvaez, Edward

AU - Sakoda, Lori C.

AU - Scacheri, Peter C.

AU - Schmit, Stephanie L.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - Stern, Mariana C.

AU - Tangen, Catherine M.

AU - Thibodeau, Stephen N.

AU - Thomas, Duncan C.

AU - Tian, Yu

AU - Tsilidis, Konstantinos K.

AU - Ulrich, Cornelia M.

AU - van Duijnhoven, Franzel J.B.

AU - Van Guelpen, Bethany

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Zemlianskaia, Natalia

AU - Chang-Claude, Jenny

AU - Gauderman, W. James

AU - Hsu, Li

AU - Kundaje, Anshul

AU - Peters, Ulrike

N1 - Funding Information: during the conduct of the study. V. Moreno reports grants from Agency for Management of University and Research Grants (AGAUR) of the Catalan Government and Instituto de Salud Carlos III during the conduct of the study. S. Ogino reports grants from NIH during the conduct of the study. R.K. Pai reports personal fees from Alimentiv Inc, PathAI, Allergan, AbbVie, and Eli Lilly outside the submitted work. J.R. Palmer reports grants from NIH during the conduct of the study. P.D.P. Pharoah reports grants from Cancer Research UK during the conduct of the study. E.A. Platz reports grants from NCI and AICR during the conduct of the study as well as personal fees from American Association for Cancer Research outside the submitted work. R.L. Prentice reports grants from NHLBI/NIH during the conduct of the study. L.C. Sakoda reports grants from NCI during the conduct of the study as well as grants from NCI and personal fees from NIH outside the submitted work. P.C. Scacheri reports grants and personal fees from Kronos Bio outside the submitted work. S.L. Schmit reports grants from NIEHS during the conduct of the study. R.E. Schoen reports grants from Freenome, Immunovia, and Exact outside the submitted work. M.L. Slattery reports grants from NCI during the conduct of the study. M.C. Stern reports grants from University of Southern California during the conduct of the study. C.M. Ulrich reports, as cancer center director, having oversight over research fundedbyseveralpharmaceutical companies, but has not receiveddirect funding. B.Van Guelpen reports grants from Swedish Research Council, through Biobank Sweden, during the conduct of the study. A. Wolk reports grants from The Swedish Cancer Foundation and The Swedish Research Council/SIMPLER during the conduct of the study. A. Kundaje reports personal fees from Ilumina Inc. and Open Targets (GSK) outside the submitted work. No disclosures were reported by the other authors. Funding Information: Genotyping services were provided by the Center for Inherited Disease Research (CIDR). Cancer data were provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health. This research has been conducted using the UK Biobank Resource under Application Number 8614. We would also like to acknowledge data from VITAL, WHI. We thank all participants and cooperating clinicians, and everyone who provided excellent technical assistance from the following organizations, registries, and consortia: Colon CFR; Seattle CCFR; Hormones and Colon Cancer study (CORE Studies); CLUE II; CPS-II; Czech Republic CCS; DACHS; EPIC; Harvard cohorts (HPFS, NHS); Channing Division of Network Medicine; Department of Medicine, Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health; Kentucky Cancer Registry; LCCS: We acknowledge the contributions of Jennifer Barrett, Robin Waxman, Gillian Smith and Emma Northwood in conducting this study; PLCO Cancer Screening Trial; District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results program; SELECT; WHI. GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, U01 CA164930, R01201407). The Editor-in-Chief of Cancer Epidemiology, Biomarkers & Prevention is an author on this article. In keeping with AACR editorial policy, a senior member of the Cancer Epidemiology, Biomarkers & Prevention editorial team managed the consideration process for this submission and independently rendered the final decision concerning acceptability. Funding Information: K.M. Jordahl reports grants from NCI (T32-CA094880) during the conduct of the study. A. Shcherbina reports other support from Insitro, Inc and personal fees from Bristol-Myers Squibb, Inc outside the submitted work. Y.-R. Su reports grants from NIH during the conduct of the study. S.A. Bien is an employee of and holds stock in Adaptive Biotechnologies. G. Casey reports grants from NIH during the conduct of the study. A.T. Chan reports personal fees from Bayer Pharma AG and Boehringer Ingelheim and grants and personal fees from Pfizer Inc. outside the submitted work. C.H. Dampier reports grants from NIH during the conduct of the study. D.A. Drew reports grants from NIH during the conduct of the study. G.G. Giles reports grants from National Health and Medical Research Council (Australia) during the conduct of the study. S.B. Gruber reports other support from Brogent International LLC outside the submitted work. H. Hampel reports other support from Myriad Genetics, Inc during the conduct of the study as well as other support from Invitae, Genome Medical, Promega, and GI OnDEMAND outside the submitted work. M.A. Jenkins reports grants from NIH and National Health and Medical Research Council, Australia during the conduct of the study. L. Le Marchand reports grants from NCI Publisher Copyright: ©2022 American Association for Cancer Research

PY - 2022/5

Y1 - 2022/5

N2 - 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 ¼ 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype ¼ 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.

AB - 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 ¼ 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype ¼ 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.

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U2 - 10.1158/1055-9965.EPI-21-1003

DO - 10.1158/1055-9965.EPI-21-1003

M3 - Article

C2 - 35438744

AN - SCOPUS:85129781310

SN - 1055-9965

VL - 31

SP - 1077

EP - 1089

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

IS - 5

ER -

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

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