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dc.contributor.authorHe, Yen_US
dc.contributor.authorTimofeeva, Men_US
dc.contributor.authorFarrington, SMen_US
dc.contributor.authorVaughan-Shaw, Pen_US
dc.contributor.authorSvinti, Ven_US
dc.contributor.authorWalker, Men_US
dc.contributor.authorZgaga, Len_US
dc.contributor.authorMeng, Xen_US
dc.contributor.authorLi, Xen_US
dc.contributor.authorSpiliopoulou, Aen_US
dc.contributor.authorJiang, Xen_US
dc.contributor.authorHyppönen, Een_US
dc.contributor.authorKraft, Pen_US
dc.contributor.authorKiel, DPen_US
dc.contributor.authorSUNLIGHT consortiumen_US
dc.contributor.authorHayward, Cen_US
dc.contributor.authorCampbell, Aen_US
dc.contributor.authorPorteous, Den_US
dc.contributor.authorVucic, Ken_US
dc.contributor.authorKirac, Ien_US
dc.contributor.authorFilipovic, Men_US
dc.contributor.authorHarris, SEen_US
dc.contributor.authorDeary, IJen_US
dc.contributor.authorHoulston, Ren_US
dc.contributor.authorTomlinson, IPen_US
dc.contributor.authorCampbell, Hen_US
dc.contributor.authorTheodoratou, Een_US
dc.contributor.authorDunlop, MGen_US
dc.identifier.citationBMC Med, 2018, 16 (1), pp. 142 - ?en_US
dc.description.abstractBACKGROUND: 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.en_US
dc.format.extent142 - ?en_US
dc.subjectColorectal canceren_US
dc.subjectMendelian randomisationen_US
dc.subjectVitamin Den_US
dc.subjectCase-Control Studiesen_US
dc.subjectColorectal Neoplasmsen_US
dc.subjectMendelian Randomization Analysisen_US
dc.subjectMiddle Ageden_US
dc.subjectRisk Factorsen_US
dc.subjectVitamin Den_US
dc.titleExploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study.en_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBMC Meden_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorHoulston, Richarden_US

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