Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study
Yazhou He,
Maria Timofeeva,
Susan M. Farrington,
Peter Vaughan-Shaw,
Victoria Svinti,
Marion Walker,
Lina Zgaga,
Xiangrui Meng,
Xue Li,
Athina Spiliopoulou,
Xia Jiang,
Elina Hyppönen,
Peter Kraft,
Douglas P. Kiel,
The SUNLIGHT consortium,
Caroline Hayward,
Archie Campbell,
David Porteous,
Katarina Vucic,
Iva Kirac,
Masa Filipovic,
Sarah E. Harris,
Ian J. Deary,
Richard Houlston,
Ian P. Tomlinson,
Harry Campbell,
Evropi Theodoratou,
Malcolm G. Dunlop
Affiliations
Yazhou He
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Maria Timofeeva
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Susan M. Farrington
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Peter Vaughan-Shaw
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Victoria Svinti
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Marion Walker
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Lina Zgaga
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Xiangrui Meng
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh
Xue Li
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh
Athina Spiliopoulou
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh
Xia Jiang
Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health
Elina Hyppönen
Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia
Peter Kraft
Program in Genetic Epidemiology and Statistical Genetics. Department of Epidemiology, Harvard T.H.Chan School of Public Health
Douglas P. Kiel
Institute for Aging Research, Hebrew SeniorLife
The SUNLIGHT consortium
Caroline Hayward
MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital
Archie Campbell
Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh
David Porteous
Generation Scotland, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital Edinburgh
Katarina Vucic
Agency for Medicinal Products and Medical Devices, Department for Quality, Safety and Efficacy Assessment
Iva Kirac
Department of Surgical Oncology, University Hospital for Tumours, Sestre milosrdnice University Hospital Centre
Masa Filipovic
School of Medicine, University of Zagreb
Sarah E. Harris
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh
Ian J. Deary
Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh
Richard Houlston
Division of Genetics and Epidemiology, The Institute of Cancer Research
Ian P. Tomlinson
Institute of Cancer and Genomic Sciences, University of Birmingham
Harry Campbell
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Evropi Theodoratou
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Malcolm G. Dunlop
Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh
Abstract Background Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls (P = 1.47 × 10− 11), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51–2.07, P = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69–1.19, P = 0.48). Conclusions Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.
