Effect of genetically low 25-hydroxyvitamin D on mortality risk: Mendelian randomization analysis in 3 large european cohorts

Thor Aspelund, Martin R. Grübler, Albert V. Smith, Elias F. Gudmundsson, Martin Keppel, Mary Frances Cotch, Tamara B. Harris, Rolf Jorde, Guri Grimnes, Ragnar Joakimsen, Henrik Schirmer, Tom Wilsgaard, Ellisiv B. Mathiesen, Inger Njølstad, Maja Lisa Løchen, Winfried März, Marcus E. Kleber, Andreas Tomaschitz, Diana Grove-Laugesen, Lars RejnmarkKarin M.A. Swart, Ingeborg A. Brouwer, Paul Lips, Natasja M. van Schoor, Christopher T. Sempos, Ramón A. Durazo-Arvizu, Zuzana Škrabáková, Kirsten G. Dowling, Kevin D. Cashman, Mairead Kiely, Stefan Pilz, Vilmundur Gudnason, Gudny Eiriksdottir*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


The aim of this study was to determine if increased mortality associated with low levels of serum 25-hydroxyvitamin D (25(OH)D) reflects a causal relationship by using a Mendelian randomisation (MR) approach with genetic variants in the vitamin D synthesis pathway. Individual participant data from three European cohorts were harmonized with standardization of 25(OH)D according to the Vitamin D Standardization Program. Most relevant single nucleotide polymorphisms of the genes CYP2R1 (rs12794714, rs10741657) and DHCR7/NADSYN1 (rs12785878, rs11234027), were combined in two allelic scores. Cox proportional hazards regression models were used with the ratio estimator and the delta method for calculating the hazards ratio (HR) and standard error of genetically determined 25(OH)D effect on all-cause mortality. We included 10,501 participants (50.1% females, 67.1±10.1 years) of whom 4003 died during a median follow-up of 10.4 years. The observed adjusted HR for all-cause mortality per decrease in 25(OH)D by 20 nmol/L was 1.20 (95% CI: 1.15–1.25). The HR per 20 nmol/L decrease in genetically determined 25(OH)D was 1.32 (95% CI: 0.80–2.24) and 1.35 (95% CI of 0.81 to 2.37) based on the two scores. In conclusion, the results of this MR study in a combined sample from three European cohort studies provide further support for a causal relationship between vitamin D deficiency and increased all-cause mortality. However, as the current study, even with ~10,000 participants, was underpowered for the study of the effect of the allele score on mortality, larger studies on genetics and mortality are needed to improve the precision.

Original languageEnglish
Article number74
Pages (from-to)1-12
Number of pages12
Issue number1
Early online date2 Jan 2019
Publication statusPublished - Jan 2019


21 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Epidemiology and Biostatistics, Amsterdam Public Health, 1081 Amsterdam, The Netherlands; k.swart@vumc.nl (K.M.A.S.); nm.vanschoor@vumc.nl (N.M.v.S.) 22 Department of Health Sciences, Faculty of Sciences and Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands; ingeborg.brouwer@vu.nl 23 Department of Internal Medicine, Endocrine Section, VU University Medical Center, Funding: Age, Gene/Environment Susceptibility Reykjavik Study: This study has been funded by NIH contract N01-AG012100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), an Intramural Research Program Award (ZIAEY000401) from the National Eye Institute, an award from the National Institute on Deafness and Other Communication Disorders (NIDCD) Division of Scientific Programs (IAA Y2-DC_1004-02), The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. Ludwigshafen RIsk and Cardiovascular Health Study: None. Tromsø Study: None.

FundersFunder number
Division of Scientific Programs00-063
National Institutes of HealthN01-AG012100
National Institute on Aging
National Eye InstituteZIAEY000401
National Institute on Deafness and Other Communication DisordersIAA Y2-DC_1004-02


    • Cohorts
    • Individual participant data
    • Mendelian randomization
    • Mortality
    • Standardized 25(OH)D
    • Vitamin D


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