Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

David Jarvis¹, Jonathan S Mitchell¹, Philip J Law¹, Kimmo Palin^{2

3}, Sari Tuupanen^{2

3}, Alexandra Gylfe^{2

3}, Ulrika A Hänninen^{2

3}, Tatiana Cajuso^{2

3}, Tomas Tanskanen^{2

3}, Johanna Kondelin^{2

3}, Eevi Kaasinen^{2

3}, Antti-Pekka Sarin⁴, Jaakko Kaprio^{4

5}, Johan G Eriksson^{5

6

7}, Harri Rissanen⁵, Paul Knekt⁵, Eero Pukkala^{8

9}, Pekka Jousilahti⁵, Veikko Salomaa⁵, Samuli Ripatti⁴, Aarno Palotie^{4

10

11

12}, Heikki Järvinen¹³, Laura Renkonen-Sinisalo¹⁴, Anna Lepistö¹⁴, Jan Böhm¹⁵, Jukka-Pekka Meklin¹⁶, Nada A Al-Tassan¹⁷, Claire Palles¹⁸, Lynn Martin¹⁸, Ella Barclay¹⁸, Susan M Farrington^{19

20}, Maria N Timofeeva¹⁹, Brian F Meyer¹⁷, Salma M Wakil¹⁷, Harry Campbell²¹, Christopher G Smith²², Shelley Idziaszczyk²², Timothy S Maughan²³, Richard Kaplan²⁴, Rachel Kerr²⁵, David Kerr²⁶, Daniel D Buchanan^{27

28}, Aung K Win²⁸, John L Hopper²⁸, Mark A Jenkins²⁸, Noralane M Lindor²⁹, Polly A Newcomb³⁰, Steve Gallinger³¹, David Conti³², Fred Schumacher³², Graham Casey³², Jussi Taipale^{2

3

33}, Lauri A Aaltonen^{2

3}, Jeremy P Cheadle²², Malcolm G Dunlop¹⁹, Ian P Tomlinson¹⁸, Richard S Houlston¹

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
² Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki 00014, Helsinki, Finland.
³ Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00014, Finland.
⁴ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
⁵ National Institute for Health and Welfare, Helsinki 00271, Finland.
⁶ Folkhälsan Research Centre, Helsinki 00250, Finland.
⁷ Unit of General Practice and Primary Health Care, University of Helsinki, Helsinki University Hospital, Helsinki 00014, Finland.
⁸ Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki 00130, Finland.
⁹ School of Health Sciences, University of Tampere, Tampere 33014, Finland.
¹⁰ Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹³ Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki 00029, Finland.
¹⁴ Department of Surgery, Abdominal Center, Helsinki University Hospital Helsinki 00029, Finland.
¹⁵ Department of Pathology, Central Finland Central Hospital, Jyväskylä 40620, Finland.
¹⁶ Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä 40620, Finland.
¹⁷ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
¹⁸ Wellcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.
¹⁹ Colon Cancer Genetics Group, MRC Human Genetics Unit, The University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
²⁰ The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Edinburgh EH25 9RG, UK.
²¹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
²² Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
²³ CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
²⁴ MRC Clinical Trials Unit, Aviation House, London WC2B 6NH, UK.
²⁵ Department of Oncology, Oxford Cancer Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
²⁶ Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
²⁷ Department of Pathology, Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁸ Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁹ Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
³⁰ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
³¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
³² Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³³ Department of Biosciences and Nutrition, SciLife Center, Karolinska Institutet, Solna SE 141 83, Sweden.

PMID: 27336604
PMCID: PMC4947703
DOI: 10.1038/bjc.2016.188

Meta-Analysis

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

David Jarvis et al. Br J Cancer. 2016.

. 2016 Jul 12;115(2):266-72.

doi: 10.1038/bjc.2016.188. Epub 2016 Jun 23.

Authors

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
² Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki 00014, Helsinki, Finland.
³ Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00014, Finland.
⁴ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki 00014, Finland.
⁵ National Institute for Health and Welfare, Helsinki 00271, Finland.
⁶ Folkhälsan Research Centre, Helsinki 00250, Finland.
⁷ Unit of General Practice and Primary Health Care, University of Helsinki, Helsinki University Hospital, Helsinki 00014, Finland.
⁸ Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki 00130, Finland.
⁹ School of Health Sciences, University of Tampere, Tampere 33014, Finland.
¹⁰ Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹³ Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki 00029, Finland.
¹⁴ Department of Surgery, Abdominal Center, Helsinki University Hospital Helsinki 00029, Finland.
¹⁵ Department of Pathology, Central Finland Central Hospital, Jyväskylä 40620, Finland.
¹⁶ Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä 40620, Finland.
¹⁷ Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia.
¹⁸ Wellcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Centre, Oxford OX3 7BN, UK.
¹⁹ Colon Cancer Genetics Group, MRC Human Genetics Unit, The University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
²⁰ The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Edinburgh EH25 9RG, UK.
²¹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK.
²² Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
²³ CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
²⁴ MRC Clinical Trials Unit, Aviation House, London WC2B 6NH, UK.
²⁵ Department of Oncology, Oxford Cancer Centre, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
²⁶ Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
²⁷ Department of Pathology, Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁸ Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC 3010, Australia.
²⁹ Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ 85259, USA.
³⁰ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
³¹ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
³² Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
³³ Department of Biosciences and Nutrition, SciLife Center, Karolinska Institutet, Solna SE 141 83, Sweden.

PMID: 27336604
PMCID: PMC4947703
DOI: 10.1038/bjc.2016.188

Abstract

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.

Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.

Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively.

Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

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Figures

**Figure 1**
**MR results of adiposity traits on CRC risk from seven GWAS studies and the meta-analysis.** (A) Adult BMI; (B) adult WHR; (C) childhood obesity (CO); and (D) birth weight (BW). Boxes denote OR point estimates, with their areas proportional to the inverse variance weight of the estimate. Horizontal lines represent 95% CIs. The diamond represents the summary Ors, computed under a fixed-effects model, with 95% CI given by the width of the diamond. The unbroken vertical line is at the null value (OR=1.0).

See this image and copyright information in PMC

References

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Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Affiliations

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Authors

Affiliations

Abstract

Figures

References

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical