Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk

Zhiyu Xia; Yu Ru Su; Paneen Petersen; Lihong Qi; Andre E. Kim; Jane C. Figueiredo; Yi Lin; Hongmei Nan; Lori C. Sakoda; Demetrius Albanes; Sonja I. Berndt; Stéphane Bézieau; Stephanie Bien; Daniel D. Buchanan; Graham Casey; Andrew T. Chan; David V. Conti; David A. Drew; Steven J. Gallinger; W. James Gauderman; Graham G. Giles; Stephen B. Gruber; Marc J. Gunter; Michael Hoffmeister; Mark A. Jenkins; Amit D. Joshi; Loic Le Marchand; Juan P. Lewinger; Li Li; Noralane M. Lindor; Victor Moreno; Neil Murphy; Rami Nassir; Polly A. Newcomb; Shuji Ogino; Gad Rennert; Mingyang Song; Xiaoliang Wang; Alicja Wolk; Michael O. Woods; Hermann Brenner; Emily White; Martha L. Slattery; Edward L. Giovannucci; Jenny Chang-Claude; Paul D.P. Pharoah; Li Hsu; Peter T. Campbell; Ulrike Peters

doi:10.1002/cam4.2971

Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk

Zhiyu Xia, Yu Ru Su, Paneen Petersen, Lihong Qi, Andre E. Kim, Jane C. Figueiredo, Yi Lin, Hongmei Nan, Lori C. Sakoda, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, Stephanie Bien, Daniel D. Buchanan, Graham Casey, Andrew T. Chan, David V. Conti, David A. Drew, Steven J. Gallinger, W. James GaudermanGraham G. Giles, Stephen B. Gruber, Marc J. Gunter, Michael Hoffmeister, Mark A. Jenkins, Amit D. Joshi, Loic Le Marchand, Juan P. Lewinger, Li Li, Noralane M. Lindor, Victor Moreno, Neil Murphy, Rami Nassir, Polly A. Newcomb, Shuji Ogino, Gad Rennert, Mingyang Song, Xiaoliang Wang, Alicja Wolk, Michael O. Woods, Hermann Brenner, Emily White, Martha L. Slattery, Edward L. Giovannucci, Jenny Chang-Claude, Paul D.P. Pharoah, Li Hsu, Peter T. Campbell, Ulrike Peters

Research

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

3 Scopus citations

Abstract

Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m²) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10⁻⁵), PSMC5 (P = 4.51 × 10⁻⁴) and CD33 (P = 2.71 × 10⁻⁴) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10⁻⁵) and SCN1B (P = 2.76 × 10⁻⁴) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10⁻⁵). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Original language	English (US)
Pages (from-to)	3563-3573
Number of pages	11
Journal	Cancer medicine
Volume	9
Issue number	10
DOIs	https://doi.org/10.1002/cam4.2971
State	Published - May 1 2020

Keywords

BMI
colorectal cancer
diabetes
gene expression
gene-environmental interaction

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

Access to Document

10.1002/cam4.2971

Cite this

Xia, Z., Su, Y. R., Petersen, P., Qi, L., Kim, A. E., Figueiredo, J. C., Lin, Y., Nan, H., Sakoda, L. C., Albanes, D., Berndt, S. I., Bézieau, S., Bien, S., Buchanan, D. D., Casey, G., Chan, A. T., Conti, D. V., Drew, D. A., Gallinger, S. J., ... Peters, U. (2020). Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk. Cancer medicine, 9(10), 3563-3573. https://doi.org/10.1002/cam4.2971

Xia, Z, Su, YR, Petersen, P, Qi, L, Kim, AE, Figueiredo, JC, Lin, Y, Nan, H, Sakoda, LC, Albanes, D, Berndt, SI, Bézieau, S, Bien, S, Buchanan, DD, Casey, G, Chan, AT, Conti, DV, Drew, DA, Gallinger, SJ, Gauderman, WJ, Giles, GG, Gruber, SB, Gunter, MJ, Hoffmeister, M, Jenkins, MA, Joshi, AD, Le Marchand, L, Lewinger, JP, Li, L, Lindor, NM, Moreno, V, Murphy, N, Nassir, R, Newcomb, PA, Ogino, S, Rennert, G, Song, M, Wang, X, Wolk, A, Woods, MO, Brenner, H, White, E, Slattery, ML, Giovannucci, EL, Chang-Claude, J, Pharoah, PDP, Hsu, L, Campbell, PT & Peters, U 2020, 'Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk', Cancer medicine, vol. 9, no. 10, pp. 3563-3573. https://doi.org/10.1002/cam4.2971

@article{429f8375dae246e9ae4f78f6c96122c4,

title = "Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk",

abstract = "Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.",

keywords = "BMI, colorectal cancer, diabetes, gene expression, gene-environmental interaction",

author = "Zhiyu Xia and Su, {Yu Ru} and Paneen Petersen and Lihong Qi and Kim, {Andre E.} and Figueiredo, {Jane C.} and Yi Lin and Hongmei Nan and Sakoda, {Lori C.} and Demetrius Albanes and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Stephanie Bien and Buchanan, {Daniel D.} and Graham Casey and Chan, {Andrew T.} and Conti, {David V.} and Drew, {David A.} and Gallinger, {Steven J.} and Gauderman, {W. James} and Giles, {Graham G.} and Gruber, {Stephen B.} and Gunter, {Marc J.} and Michael Hoffmeister and Jenkins, {Mark A.} and Joshi, {Amit D.} and {Le Marchand}, Loic and Lewinger, {Juan P.} and Li Li and Lindor, {Noralane M.} and Victor Moreno and Neil Murphy and Rami Nassir and Newcomb, {Polly A.} and Shuji Ogino and Gad Rennert and Mingyang Song and Xiaoliang Wang and Alicja Wolk and Woods, {Michael O.} and Hermann Brenner and Emily White and Slattery, {Martha L.} and Giovannucci, {Edward L.} and Jenny Chang-Claude and Pharoah, {Paul D.P.} and Li Hsu and Campbell, {Peter T.} and Ulrike Peters",

note = "Funding Information: ASTERISK: We are very grateful to Dr Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. CPS‐II: The authors thank the CPS‐II participants and Study Management Group for their invaluable contributions to this research. The authors acknowledge the contribution to this study from the central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. DACHS: We thank all participants and cooperating clinicians, and Ute Handte‐Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. Harvard cohorts (HPFS, NHS, PHS): The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard TH Chan School of Public Health, and those of participating registries as required. We thank the participants and staff of the HPFS, NHS, and PHS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. Kentucky: We acknowledge the staff at the Kentucky Cancer Registry. PLCO: The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc Most importantly, we thank the study participants for their contributions that made this study possible. PMH‐SCCFR: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer and Seattle Cancer Family Registry studies (CORE Studies). SEARCH: We thank the SEARCH team. WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents% 20 %20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf . Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization. Funding Information: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R01201407); Center for Inherited Disease Research (CIDR) (X01‐HG008596 and X‐01‐HG007585); NIH/NCI Cancer Center Support Grant P30 CA015704; Hospital Clinical Research Program (PHRC‐BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes); Regional Council of Pays de la Loire, the Groupement des Entreprises Fran{\c c}aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G{\'e}n{\'e}tique and the Ligue R{\'e}gionale Contre le Cancer (LRCC). Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by US Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. COLO2&3: National Institutes of Health (R01 CA60987); National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA122839, R01 CA143247); NCI/NIH (grant number U01 CA167551); Australasian Colorectal Cancer Family Registry (grant numbers U01 CA074778 and U01/U24 CA097735); USC Consortium Colorectal Cancer Family Registry (grant numbers U01/U24 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (grant number U01/U24 CA074794); University of Hawaii Colorectal Cancer Family Registry (grant number U01/U24 CA074806; National Cancer Institute, National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407); National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678); The American Cancer Society; German Research Council (BR 1704/6‐1, BR 1704/6‐3, BR 1704/6‐4, CH 117/1‐1, HO 5117/2‐1, HE 5998/2‐1, KL 2354/3‐1, RO 2270/8‐1 and BR 1704/17‐1); Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B); National Institutes of Health (R01 CA48998 to M. L. Slattery); National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735); National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, and R35 CA197735) and PHS by the National Institutes of Health (R01 CA042182); Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI‐8); NCI R01CA136726); VicHealth and Cancer Council Victoria; Australian NHMRC grants 509348, 209057, 251553 and 504711; Cancer Council Victoria; National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA063464); National Institutes of Health, US Department of Health and Human Services (R01 CA81488; Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); National Cancer Institute of Canada grants (18223 and 18226); Canadian Cancer Society Research Institute; National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438; NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute´s Distinguished Professor Award; National Institutes of Health (K05 CA154337); National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C; Colorectal Cancer Genetics & Genomics; Instituto de Salud Carlos III, co‐funded by FEDER funds –a way to build Europe– (grants PI14‐613 and PI09‐1286); Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723); Junta de Castilla y Le{\'o}n (grant LE22A10‐2); Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d{\textquoteright}Oncolog{\'i}a de Catalunya (XBTC); Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology; National Institutes of Health (R01 CA076366 and U01 CA074794). Funding Information: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R01201407); Center for Inherited Disease Research (CIDR) (X01-HG008596 and X-01-HG007585); NIH/NCI Cancer Center Support Grant P30 CA015704; Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes); Regional Council of Pays de la Loire, the Groupement des Entreprises Fran?aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G?n?tique and the Ligue R?gionale Contre le Cancer (LRCC). Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by US Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. COLO2&3: National Institutes of Health (R01 CA60987); National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA122839, R01 CA143247); NCI/NIH (grant number U01 CA167551); Australasian Colorectal Cancer Family Registry (grant numbers U01 CA074778 and U01/U24 CA097735); USC Consortium Colorectal Cancer Family Registry (grant numbers U01/U24 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (grant number U01/U24 CA074794); University of Hawaii Colorectal Cancer Family Registry (grant number U01/U24 CA074806; National Cancer Institute, National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407); National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678); The American Cancer Society; German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1); Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B); National Institutes of Health (R01 CA48998 to M. L. Slattery); National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735); National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, and R35 CA197735) and PHS by the National Institutes of Health (R01 CA042182); Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726); VicHealth and Cancer Council Victoria; Australian NHMRC grants 509348, 209057, 251553 and 504711; Cancer Council Victoria; National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA063464); National Institutes of Health, US Department of Health and Human Services (R01 CA81488; Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); National Cancer Institute of Canada grants (18223 and 18226); Canadian Cancer Society Research Institute; National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438; NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute?s Distinguished Professor Award; National Institutes of Health (K05 CA154337); National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C; Colorectal Cancer Genetics & Genomics; Instituto de Salud Carlos III, co-funded by FEDER funds ?a way to build Europe? (grants PI14-613 and PI09-1286); Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723); Junta de Castilla y Le?n (grant LE22A10-2); Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d?Oncolog?a de Catalunya (XBTC); Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology; National Institutes of Health (R01 CA076366 and U01 CA074794). ASTERISK: We are very grateful to Dr Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. Publisher Copyright: {\textcopyright} 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

year = "2020",

month = may,

day = "1",

doi = "10.1002/cam4.2971",

language = "English (US)",

volume = "9",

pages = "3563--3573",

journal = "Cancer Medicine",

issn = "2045-7634",

publisher = "John Wiley and Sons Ltd",

number = "10",

}

TY - JOUR

T1 - Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk

AU - Xia, Zhiyu

AU - Su, Yu Ru

AU - Petersen, Paneen

AU - Qi, Lihong

AU - Kim, Andre E.

AU - Figueiredo, Jane C.

AU - Lin, Yi

AU - Nan, Hongmei

AU - Sakoda, Lori C.

AU - Albanes, Demetrius

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Bien, Stephanie

AU - Buchanan, Daniel D.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Conti, David V.

AU - Drew, David A.

AU - Gallinger, Steven J.

AU - Gauderman, W. James

AU - Giles, Graham G.

AU - Gruber, Stephen B.

AU - Gunter, Marc J.

AU - Hoffmeister, Michael

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Le Marchand, Loic

AU - Lewinger, Juan P.

AU - Li, Li

AU - Lindor, Noralane M.

AU - Moreno, Victor

AU - Murphy, Neil

AU - Nassir, Rami

AU - Newcomb, Polly A.

AU - Ogino, Shuji

AU - Rennert, Gad

AU - Song, Mingyang

AU - Wang, Xiaoliang

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Brenner, Hermann

AU - White, Emily

AU - Slattery, Martha L.

AU - Giovannucci, Edward L.

AU - Chang-Claude, Jenny

AU - Pharoah, Paul D.P.

AU - Hsu, Li

AU - Campbell, Peter T.

AU - Peters, Ulrike

N1 - Funding Information: ASTERISK: We are very grateful to Dr Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. CPS‐II: The authors thank the CPS‐II participants and Study Management Group for their invaluable contributions to this research. The authors acknowledge the contribution to this study from the central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. DACHS: We thank all participants and cooperating clinicians, and Ute Handte‐Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. Harvard cohorts (HPFS, NHS, PHS): The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard TH Chan School of Public Health, and those of participating registries as required. We thank the participants and staff of the HPFS, NHS, and PHS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. Kentucky: We acknowledge the staff at the Kentucky Cancer Registry. PLCO: The authors thank the PLCO Cancer Screening Trial screening center investigators and the staff from Information Management Services Inc and Westat Inc Most importantly, we thank the study participants for their contributions that made this study possible. PMH‐SCCFR: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer and Seattle Cancer Family Registry studies (CORE Studies). SEARCH: We thank the SEARCH team. WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents% 20 %20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf . Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization. Funding Information: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R01201407); Center for Inherited Disease Research (CIDR) (X01‐HG008596 and X‐01‐HG007585); NIH/NCI Cancer Center Support Grant P30 CA015704; Hospital Clinical Research Program (PHRC‐BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes); Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by US Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. COLO2&3: National Institutes of Health (R01 CA60987); National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA122839, R01 CA143247); NCI/NIH (grant number U01 CA167551); Australasian Colorectal Cancer Family Registry (grant numbers U01 CA074778 and U01/U24 CA097735); USC Consortium Colorectal Cancer Family Registry (grant numbers U01/U24 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (grant number U01/U24 CA074794); University of Hawaii Colorectal Cancer Family Registry (grant number U01/U24 CA074806; National Cancer Institute, National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407); National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678); The American Cancer Society; German Research Council (BR 1704/6‐1, BR 1704/6‐3, BR 1704/6‐4, CH 117/1‐1, HO 5117/2‐1, HE 5998/2‐1, KL 2354/3‐1, RO 2270/8‐1 and BR 1704/17‐1); Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B); National Institutes of Health (R01 CA48998 to M. L. Slattery); National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735); National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, and R35 CA197735) and PHS by the National Institutes of Health (R01 CA042182); Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI‐8); NCI R01CA136726); VicHealth and Cancer Council Victoria; Australian NHMRC grants 509348, 209057, 251553 and 504711; Cancer Council Victoria; National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA063464); National Institutes of Health, US Department of Health and Human Services (R01 CA81488; Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); National Cancer Institute of Canada grants (18223 and 18226); Canadian Cancer Society Research Institute; National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438; NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute´s Distinguished Professor Award; National Institutes of Health (K05 CA154337); National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C; Colorectal Cancer Genetics & Genomics; Instituto de Salud Carlos III, co‐funded by FEDER funds –a way to build Europe– (grants PI14‐613 and PI09‐1286); Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723); Junta de Castilla y León (grant LE22A10‐2); Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC); Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology; National Institutes of Health (R01 CA076366 and U01 CA074794). Funding Information: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R01201407); Center for Inherited Disease Research (CIDR) (X01-HG008596 and X-01-HG007585); NIH/NCI Cancer Center Support Grant P30 CA015704; Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes); Regional Council of Pays de la Loire, the Groupement des Entreprises Fran?aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne G?n?tique and the Ligue R?gionale Contre le Cancer (LRCC). Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by US Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. COLO2&3: National Institutes of Health (R01 CA60987); National Cancer Institute (NCI), National Institutes of Health (NIH) (grant numbers U01 CA122839, R01 CA143247); NCI/NIH (grant number U01 CA167551); Australasian Colorectal Cancer Family Registry (grant numbers U01 CA074778 and U01/U24 CA097735); USC Consortium Colorectal Cancer Family Registry (grant numbers U01/U24 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (grant number U01/U24 CA074794); University of Hawaii Colorectal Cancer Family Registry (grant number U01/U24 CA074806; National Cancer Institute, National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407); National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678); The American Cancer Society; German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1); Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B); National Institutes of Health (R01 CA48998 to M. L. Slattery); National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, and R35 CA197735); National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, and R35 CA197735) and PHS by the National Institutes of Health (R01 CA042182); Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726); VicHealth and Cancer Council Victoria; Australian NHMRC grants 509348, 209057, 251553 and 504711; Cancer Council Victoria; National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA063464); National Institutes of Health, US Department of Health and Human Services (R01 CA81488; Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Serivces (U01 CA74783); National Cancer Institute of Canada grants (18223 and 18226); Canadian Cancer Society Research Institute; National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation; Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438; NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute?s Distinguished Professor Award; National Institutes of Health (K05 CA154337); National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C; Colorectal Cancer Genetics & Genomics; Instituto de Salud Carlos III, co-funded by FEDER funds ?a way to build Europe? (grants PI14-613 and PI09-1286); Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723); Junta de Castilla y Le?n (grant LE22A10-2); Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d?Oncolog?a de Catalunya (XBTC); Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology; National Institutes of Health (R01 CA076366 and U01 CA074794). ASTERISK: We are very grateful to Dr Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. Publisher Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

AB - Background: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Results: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5). Conclusions: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

KW - BMI

KW - colorectal cancer

KW - diabetes

KW - gene expression

KW - gene-environmental interaction

UR - http://www.scopus.com/inward/record.url?scp=85082127119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082127119&partnerID=8YFLogxK

U2 - 10.1002/cam4.2971

DO - 10.1002/cam4.2971

M3 - Article

C2 - 32207560

AN - SCOPUS:85082127119

SN - 2045-7634

VL - 9

SP - 3563

EP - 3573

JO - Cancer Medicine

JF - Cancer Medicine

IS - 10

ER -

Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk

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