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; 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

doi:10.1186/s12916-018-1119-2

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
, 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

^*Corresponding author for this work

The University of Edinburgh
West China Hospital of Sichuan University
Trinity College Dublin
Harvard T.H. Chan School of Public Health
Karolinska Institute
University of South Australia
UCL Great Ormond Street Institute of Child Health
Harvard Medical School
Massachusetts Institute of Technology
Croatian Agency for Medicinal Products and Medical Devices
University Hospital Centre Zagreb
Institute of Cancer Research
University of Birmingham

Research output: Contribution to journal › Journal article › Research › peer-review

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.

Original language	English
Article number	142
Journal	BMC Medicine
Volume	16
Issue number	1
ISSN	1741-7015
DOIs	https://doi.org/10.1186/s12916-018-1119-2
Publication status	Published - 14. Aug 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Funding

We acknowledge support from program grant no. C348/A18927 from Cancer Research UK. The work was also supported by a project grant (to MGD) within the MRC Human Genetics Unit Centre Grant (U127527202 and U127527198 from 1/4/18). YH, XL and XM are supported by the China Scholarship Council. ET is supported by a CRUK Career Development Fellowship (grant no.C31250/A22804). IJD and SEH are supported by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, which is funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (grant no. MR/K026992/1). The Lothian Birth Cohort studies are funded by Age UK (Disconnected Mind project) and the Biotechnology and Biological Sciences Research Council (grant no. BB/F019394/1). Genotyping of the GS:SFHS samples was carried out by the Edinburgh 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), Reference 104036/Z/14/Z). GS:SFHS received core support from the Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. The MRC provides core funding to the QTL in Health and Disease research program at the MRC HGU, IGMM, University of Edinburgh.

Keywords

Colorectal cancer
Mendelian randomisation
Vitamin D

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He, Y., Timofeeva, M., Farrington, S. M., Vaughan-Shaw, P., Svinti, V., Walker, M., Zgaga, L., Meng, X., Li, X., Spiliopoulou, A., Jiang, X., Hyppönen, E., Kraft, P., Kiel, D. P., Hayward, C., Campbell, A., Porteous, D., Vucic, K., Kirac, I., ... Dunlop, M. G. (2018). Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: A large Mendelian randomisation study. BMC Medicine, 16(1), Article 142. https://doi.org/10.1186/s12916-018-1119-2

@article{6a21bc1361454a599761f2f0a61729ee,

title = "Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: A large Mendelian randomisation study",

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.",

keywords = "Colorectal cancer, Mendelian randomisation, Vitamin D",

author = "Yazhou He and Maria Timofeeva and Farrington, \{Susan M.\} and Peter Vaughan-Shaw and Victoria Svinti and Marion Walker and Lina Zgaga and Xiangrui Meng and Xue Li and Athina Spiliopoulou and Xia Jiang and Elina Hypp{\"o}nen and Peter Kraft and Kiel, \{Douglas P.\} and Caroline Hayward and Archie Campbell and David Porteous and Katarina Vucic and Iva Kirac and Masa Filipovic and Harris, \{Sarah E.\} and Deary, \{Ian J.\} and Richard Houlston and Tomlinson, \{Ian P.\} and Harry Campbell and Evropi Theodoratou and Dunlop, \{Malcolm G.\}",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = aug,

day = "14",

doi = "10.1186/s12916-018-1119-2",

language = "English",

volume = "16",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

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He, Y, Timofeeva, M, Farrington, SM, Vaughan-Shaw, P, Svinti, V, Walker, M, Zgaga, L, Meng, X, Li, X, Spiliopoulou, A, Jiang, X, Hyppönen, E, Kraft, P, Kiel, DP, Hayward, C, Campbell, A, Porteous, D, Vucic, K, Kirac, I, Filipovic, M, Harris, SE, Deary, IJ, Houlston, R, Tomlinson, IP, Campbell, H, Theodoratou, E & Dunlop, MG 2018, 'Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: A large Mendelian randomisation study', BMC Medicine, vol. 16, no. 1, 142. https://doi.org/10.1186/s12916-018-1119-2

TY - JOUR

T1 - Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk

T2 - A large Mendelian randomisation study

AU - He, Yazhou

AU - Timofeeva, Maria

AU - Farrington, Susan M.

AU - Vaughan-Shaw, Peter

AU - Svinti, Victoria

AU - Walker, Marion

AU - Zgaga, Lina

AU - Meng, Xiangrui

AU - Li, Xue

AU - Spiliopoulou, Athina

AU - Jiang, Xia

AU - Hyppönen, Elina

AU - Kraft, Peter

AU - Kiel, Douglas P.

AU - Hayward, Caroline

AU - Campbell, Archie

AU - Porteous, David

AU - Vucic, Katarina

AU - Kirac, Iva

AU - Filipovic, Masa

AU - Harris, Sarah E.

AU - Deary, Ian J.

AU - Houlston, Richard

AU - Tomlinson, Ian P.

AU - Campbell, Harry

AU - Theodoratou, Evropi

AU - Dunlop, Malcolm G.

PY - 2018/8/14

Y1 - 2018/8/14

N2 - 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.

AB - 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.

KW - Colorectal cancer

KW - Mendelian randomisation

KW - Vitamin D

U2 - 10.1186/s12916-018-1119-2

DO - 10.1186/s12916-018-1119-2

M3 - Journal article

C2 - 30103784

AN - SCOPUS:85051735522

SN - 1741-7015

VL - 16

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 142

ER -

Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: A large Mendelian randomisation study

Abstract

Bibliographical note

Funding

Keywords

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