Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

Susan Martin; Jessica Tyrrell; E Louise Thomas; Matthew J Bown; Andrew R Wood; Robin N Beaumont; Lam C Tsoi; Philip E Stuart; James T Elder; Philip Law; Richard Houlston; Christopher Kabrhel; Nikos Papadimitriou; Marc J Gunter; Caroline J Bull; Joshua A Bell; Emma E Vincent; Naveed Sattar; Malcolm G Dunlop; Ian Pm Tomlinson; Jimmy D Bell; Timothy M Frayling; Hanieh Yaghootkar

doi:10.7554/eLife.72452

Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

Susan Martin, Jessica Tyrrell, E Louise Thomas, Matthew J Bown, Andrew R Wood, Robin N Beaumont, Lam C Tsoi, Philip E Stuart, James T Elder, Philip Law, Richard Houlston, Christopher Kabrhel, Nikos Papadimitriou, Marc J Gunter, Caroline J Bull, Joshua A Bell, Emma E Vincent, Naveed Sattar, Malcolm G Dunlop, Ian Pm TomlinsonJimmy D Bell, Timothy M Frayling, Hanieh Yaghootkar

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

Original language	English
Journal	eLIFE
Volume	11
DOIs	https://doi.org/10.7554/eLife.72452
Publication status	Published - 25 Jan 2022

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10.7554/eLife.72452

elife-72452-v1
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Martin, S., Tyrrell, J., Thomas, E. L., Bown, M. J., Wood, A. R., Beaumont, R. N., Tsoi, L. C., Stuart, P. E., Elder, J. T., Law, P., Houlston, R., Kabrhel, C., Papadimitriou, N., Gunter, M. J., Bull, C. J., Bell, J. A., Vincent, E. E., Sattar, N., Dunlop, M. G., ... Yaghootkar, H. (2022). Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation. eLIFE, 11. https://doi.org/10.7554/eLife.72452

@article{059f8bf3d81e4b37a29224f79b27577c,

title = "Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation",

author = "Susan Martin and Jessica Tyrrell and Thomas, {E Louise} and Bown, {Matthew J} and Wood, {Andrew R} and Beaumont, {Robin N} and Tsoi, {Lam C} and Stuart, {Philip E} and Elder, {James T} and Philip Law and Richard Houlston and Christopher Kabrhel and Nikos Papadimitriou and Gunter, {Marc J} and Bull, {Caroline J} and Bell, {Joshua A} and Vincent, {Emma E} and Naveed Sattar and Dunlop, {Malcolm G} and Tomlinson, {Ian Pm} and Bell, {Jimmy D} and Frayling, {Timothy M} and Hanieh Yaghootkar",

note = "Funding Information: PLCO: 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. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. Funding Information: SMS and REACH: This work was supported by the National Cancer Institute grant P01 CA074184 to JDP and PAN, grants R01 CA097325, R03 CA153323, and K05 CA152715 to PAN, and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to ANB-H). Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G{\'e}n{\'e}rale de l{\textquoteright}Education Nationale, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluc{\'i}a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Sk{\aa}ne and V{\"a}sterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Funding Information: HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). Funding Information: CLUE II funding was from the National Cancer Institute (U01 CA86308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Funding Information: DACHS: This work was supported by the 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), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). Funding Information: Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726. Funding Information: NCCCS I & II: We acknowledge funding support for this project from the National Institutes of Health, R01 CA66635 and P30 DK034987. Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-W{\"u}rttemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: HY is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). SM and TMF are funded by the MRC (MR/T002239/1). CJB is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). JAB works in a unit funded by the UK MRC (MC_UU_00011/1) and the University of Bristol. EEV is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R21 CA191312, R01201407). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685. Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigaci{\'o}n Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, PI20/00113, PI20/00226, Acci{\'o}n Transversal de C{\'a}ncer), Xunta de Galicia (PGIDIT07PX-IB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncolog{\'i}a” AEG (Asociaci{\'o}n Espa{\~n}ola de Gastroenterolog{\'i}a), Fundaci{\'o}n Privada Olga Torres, FP7 CHIBCHA Consortium, Ag{\`e}ncia de Gesti{\'o} d{\textquoteright}Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d{\textquoteright}Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Actions BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region V{\"a}sterbotten; Knut and Alice Wallenberg Foundation; Lion{\textquoteright}s Cancer Research Foundation at Ume{\aa} University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Ume{\aa} University, Ume{\aa}, Sweden. Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute´s Distinguished Professor Award to Alicja Wolk. Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2, and the Stockholm County Council (ALF project). Funding Information: CPS-II: We thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from 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. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: NSHDS investigators thank the Biobank Research Unit at Ume{\aa} University, the V{\"a}sterbotten Intervention Programme, the Northern Sweden MONICA study and Region V{\"a}sterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d{\textquoteright}Huzes and the Dutch Cancer Society (UM 2012-5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through life-style intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: CORSA: “{\"O}sterreichische Nationalbank Jubil{\"a}umsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Funding Information: MECC: This work was supported by the National Institutes of Health, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). Funding Information: The Colon Cancer Family Registry (CCFR, https://www.coloncfr.org) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The CCFR Set-1 (Illumina 1 M/1M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143247 (to GC). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to SBG). The CCFR Set-4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG), and through generous support from the Ontario Ministry of Research and Innovation. The SFCCR Illumina HumanCytoSNP array was supported in part through NCI/NIH awards U01 CA074794 (to JDP) and /U24 CA074794 and R01 CA076366 (to PAN). The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. Funding Information: ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupe-ment 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). Funding Information: This research has been conducted using the UK Biobank Resource under Application Number {\textquoteleft}9072{\textquoteright} and {\textquoteleft}9055{\textquoteright}. We acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work. We acknowledge use of high-performance computing funded by an MRC Clinical Research Infrastructure award (MRC Grant: MR/M008924/1). Funding Information: Czech Republic CCS: This work was supported by the Czech Science Foundation (20-03997 S) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants NV18/03/00199 and NU21-07-00247). Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, U.S. Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). We wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and G{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Funding Information: WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by 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), and Junta de Castilla y Le{\'o}n (grant LE22A10-2). Sample collection of this work was supported by the 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. Funding Information: ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184 [Li/Ulrich], U01 CA206110 [Ulrich/Li/Siegel/Figueireido/Colditz], 2P30CA015704-40 [Gilliland], R01 CA207371 [Ulrich/Li]), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Funding Information: Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: SELECT: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10 CA37429 (CD Blanke), and UM1 CA182883 (CM Tangen/IM Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} Martin et al.",

year = "2022",

month = jan,

day = "25",

doi = "10.7554/eLife.72452",

language = "English",

volume = "11",

journal = "eLIFE",

issn = "2050-084X",

publisher = "ELIFE SCIENCES PUBLICATIONS LTD",

}

Martin, S, Tyrrell, J, Thomas, EL, Bown, MJ, Wood, AR, Beaumont, RN, Tsoi, LC, Stuart, PE, Elder, JT, Law, P, Houlston, R, Kabrhel, C, Papadimitriou, N, Gunter, MJ, Bull, CJ, Bell, JA, Vincent, EE, Sattar, N, Dunlop, MG, Tomlinson, IP, Bell, JD, Frayling, TM & Yaghootkar, H 2022, 'Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation', eLIFE, vol. 11. https://doi.org/10.7554/eLife.72452

TY - JOUR

T1 - Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation

AU - Martin, Susan

AU - Tyrrell, Jessica

AU - Thomas, E Louise

AU - Bown, Matthew J

AU - Wood, Andrew R

AU - Beaumont, Robin N

AU - Tsoi, Lam C

AU - Stuart, Philip E

AU - Elder, James T

AU - Law, Philip

AU - Houlston, Richard

AU - Kabrhel, Christopher

AU - Papadimitriou, Nikos

AU - Gunter, Marc J

AU - Bull, Caroline J

AU - Bell, Joshua A

AU - Vincent, Emma E

AU - Sattar, Naveed

AU - Dunlop, Malcolm G

AU - Tomlinson, Ian Pm

AU - Bell, Jimmy D

AU - Frayling, Timothy M

AU - Yaghootkar, Hanieh

N1 - Funding Information: PLCO: 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. Funding was provided by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. Funding Information: SMS and REACH: This work was supported by the National Cancer Institute grant P01 CA074184 to JDP and PAN, grants R01 CA097325, R03 CA153323, and K05 CA152715 to PAN, and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to ANB-H). Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). Funding Information: HCES-CRC: the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350; P01 CA196569; R01 CA201407) and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). Funding Information: CLUE II funding was from the National Cancer Institute (U01 CA86308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Funding Information: DACHS: This work was supported by the 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), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). Funding Information: Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726. Funding Information: NCCCS I & II: We acknowledge funding support for this project from the National Institutes of Health, R01 CA66635 and P30 DK034987. Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: HY is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). SM and TMF are funded by the MRC (MR/T002239/1). CJB is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). JAB works in a unit funded by the UK MRC (MC_UU_00011/1) and the University of Bristol. EEV is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003) and PHS by the National Institutes of Health (R01 CA042182). Funding Information: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R21 CA191312, R01201407). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685. Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, PI20/00113, PI20/00226, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PX-IB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya) and COST Actions BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region Västerbotten; Knut and Alice Wallenberg Foundation; Lion’s Cancer Research Foundation at Umeå University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umeå University, Umeå, Sweden. Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute´s Distinguished Professor Award to Alicja Wolk. Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council; K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2, and the Stockholm County Council (ALF project). Funding Information: CPS-II: We thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. We would also like to acknowledge the contribution to this study from 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. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: NSHDS investigators thank the Biobank Research Unit at Umeå University, the Västerbotten Intervention Programme, the Northern Sweden MONICA study and Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012-5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through life-style intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: CORSA: “Österreichische Nationalbank Jubiläumsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Funding Information: MECC: This work was supported by the National Institutes of Health, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). Funding Information: The Colon Cancer Family Registry (CCFR, https://www.coloncfr.org) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following U.S. state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). The CCFR Set-1 (Illumina 1 M/1M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143247 (to GC). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to SBG). The CCFR Set-4 (Illumina OncoArray 600K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG), and through generous support from the Ontario Ministry of Research and Innovation. The SFCCR Illumina HumanCytoSNP array was supported in part through NCI/NIH awards U01 CA074794 (to JDP) and /U24 CA074794 and R01 CA076366 (to PAN). The content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. Funding Information: ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupe-ment des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). Funding Information: This research has been conducted using the UK Biobank Resource under Application Number ‘9072’ and ‘9055’. We acknowledge the use of the University of Exeter High-Performance Computing (HPC) facility in carrying out this work. We acknowledge use of high-performance computing funded by an MRC Clinical Research Infrastructure award (MRC Grant: MR/M008924/1). Funding Information: Czech Republic CCS: This work was supported by the Czech Science Foundation (20-03997 S) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants NV18/03/00199 and NU21-07-00247). Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, U.S. Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). We wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Funding Information: WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by 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), and Junta de Castilla y León (grant LE22A10-2). Sample collection of this work was supported by the 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. Funding Information: ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184 [Li/Ulrich], U01 CA206110 [Ulrich/Li/Siegel/Figueireido/Colditz], 2P30CA015704-40 [Gilliland], R01 CA207371 [Ulrich/Li]), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Funding Information: Cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: SELECT: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10 CA37429 (CD Blanke), and UM1 CA182883 (CM Tangen/IM Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © Martin et al.

PY - 2022/1/25

Y1 - 2022/1/25

U2 - 10.7554/eLife.72452

DO - 10.7554/eLife.72452

M3 - Article

SN - 2050-084X

VL - 11

JO - eLIFE

JF - eLIFE

ER -