Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.At the Institute of Cancer Research, this work was supported by Cancer Research UK (C1298/A25514). Additional support was provided by the National Cancer Research Network. In Edinburgh, the work was supported by Programme Grant funding from Cancer Research UK (C348/A12076) and by funding for the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre. In Birmingham, funding was provided by Cancer Research UK (C6199/A16459). We are grateful to many colleagues within UK Clinical Genetics Departments (for CORGI) and to many collaborators who participated in the VICTOR, QUASAR2 and SCOT trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). Support from the European Union [FP7/207–2013, grant 258236] and FP7 collaborative project SYSCOL and COST Action in the UK is also acknowledged [BM1206]. The COIN and COIN-B trials were funded by Cancer Research UK and the Medical Research Council and were conducted with the support of the National Institute of Health Research Cancer Research Network. COIN and COIN-B translational studies were supported by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust, Cancer Research Wales and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit (2011–2014). We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) and the Edinburgh Clinical Research Facility (ECRF) Genetics Core, Western General Hospital, Edinburgh, for the generation of genotyping data. We thank the Lothian Birth Cohorts’ members, investigators, research associates, and other team members. We thank the Edinburgh Clinical Research Facility (ECRF) Genetics Core, Western General Hospital, Edinburgh, for genotyping. Lothian Birth Cohorts’ data collection is supported by the Disconnected Mind project (funded by Age UK), and the Biotechnology and Biological Sciences Research Council (BBSRC, for genotyping; BB/F019394/1) and undertaken within the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (funded by the BBSRC and Medical Research Council RC as part of the LLHW [MR/K026992/1]). ET was supported by Cancer Research UK CDF (C31250/A22804). This research has been conducted using the UK Biobank Resource under Application Number 7441. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, University of Edinburgh and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) [104036/Z/14/Z]). CFR was supported by a Marie Sklodowska-Curie Intra-European Fellowship Action and received considerable help from many staff in the Department of Endoscopy at the John Radcliffe Hospital in Oxford. In Finland, this work was supported by grants from the Academy of Finland [Finnish Center of Excellence Program 2012–2017, 250345 and 2018–2025, 312041], the Jane and Aatos Erkko Foundation, the Finnish Cancer Society [personal grant to K.P.], the European Research Council [ERC; 268648], the Sigrid Juselius Foundation, SYSCOL, the Nordic Information for Action eScience Center (NIASC), the Nordic Center of Excellence financed by NordForsk [project 62721, personal grant to K.P.] and State Research Funding of Kuopio University Hospital [B1401]. We acknowledge the computational resources provided by the ELIXIR node, hosted at the CSC–IT Center for Science, Finland, and funded by the Academy of Finland [grants 271642 and 263164], the Ministry of Education and Culture, Finland. V.S. was supported by the Finnish Academy [grant number 139635] and the Finnish Foundation for Cardiovascular Research. J.-P.M. was funded by The Finnish Cancer Foundation and The Jane and Aatos Erkko Foundation. Sample collection and genotyping in the Finnish Twin Cohort has been supported by the Wellcome Trust Sanger Institute, ENGAGE—European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4–2007; [grant agreement number 201413], the National Institute of Alcohol Abuse and Alcoholism [grants AA-12502 and AA-00145; to R.J.R. and K02AA018755 to D.M.D.] and the Academy of Finland [grants 100499, 205585, 265240 and 263278 to J.K.]. The work of the Colon Cancer Family Registry (CCFR) was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under Award number U01 CA167551. The CCFR Illumina GWAS was supported by the NCI/NIH under Award Numbers U01 CA122839 and R01 CA143237 to G.C. The content of this manuscript does not necessarily reflect the views or policies of the NCI or any of the collaborating centres in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR. The CORSA study was funded by FFG BRIDGE (grant 829675, to A.G.), the “Herzfelder’sche Familienstiftung” (grant to A.G.) and was supported by COST Action BM1206. We kindly thank all individuals who agreed to participate in the CORSA study. Furthermore, we thank all cooperating physicians and students and the Biobank Graz of the Medical University of Graz. The DACHS study was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6–1, BR 1704/6–3, BR 1704/6–4, BR 1704/6–6 and CH 117/1–1), and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815 and 01ER1505A, 01ER1505B). We thank all participants and cooperating clinicians, and Ute Handte-Daub, Ansgar Brandhorst, Muhabbet Celik and Ursula Eilber for excellent technical assistance. The Croatian study was supported through the 10,001 Dalmatians Project, and institutional support of University Hospital for Tumours, Sestre milosrdnice University Hospital Center. James East and Simon Leedham were funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed not necessarily those of the NHS, the NIHR or the Department of Health. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, which was funded by the Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. The BCAC study would not have been possible without the contributions of the following: Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou and Joe Dennis. BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A16563). For the BBCS study, we thank Eileen Williams, Elaine Ryder-Mills, Kara Sargus. The BBCS is funded by Cancer Research UK and Breast Cancer Now and acknowledges NHS funding to the National Institute of Health Research (NIHR) Biomedical Research Centre (BRC) and the National Cancer Research Network (NCRN). We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by: 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) (Germany); the Hellenic Health Foundation, the Stavros Niarchos Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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); 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); 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 EPIC-Oxford) (United Kingdom). We thank the SEARCH and EPIC teams, which were funded by a programme grant from Cancer Research UK (C490/A10124) and supported by the UK NIHR BRC at the University of Cambridge. We thank Breast Cancer Now and the Institute of Cancer Research (ICR) for support and funding of the UKBGS, and the study participants, study staff, and the doctors, nurses and other health-care providers and health information sources who have contributed to the study. Genotyping of the PRACTICAL consortium OncoArray was funded by the US National Institutes of Health (NIH) [U19 CA 148537 for ELucidating Loci Involved in Prostate cancer SuscEptibility (ELLIPSE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract number HHSN268201200008I]. Additional analytic support was provided by NIH NCI U01 CA188392 (PI: Schumacher). The PRACTICAL consortium was supported by Cancer Research UK Grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135, European Commission’s Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2–2009–223175), and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative grant: No. 1 U19 CA 148537–01 (the GAME-ON initiative). We would also like to thank the following for funding support: The Institute of Cancer Research and The Everyman Campaign, The Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), The Orchid Cancer Appeal, The National Cancer Research Network UK, The National Cancer Research Institute (NCRI) UK. We are grateful for support of NIHR funding to the NIHR Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, the Spanish Instituto de Salud Carlos III (ISCIII) an initiative of the Spanish Ministry of Economy and Innovation (Spain), and the Xunta de Galicia (Spain)