Causal Relationship between Obesity and Vitamin D Status

Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52610). The BMI allele score was associated both with BMI (p = 6.30610) and 25(OH)D (20.06% [95% CI 20.10 to 20.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p#8.07610 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: 24.2 [95% CI 27.1 to 21.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p$0.57 for both vitamin D scores). Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency. Please see later in the article for the Editors’ Summary. Citation: Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, et al. (2013) Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. PLoS Med 10(2): e1001383. doi:10.1371/journal.pmed.1001383 Academic Editor: Cosetta Minelli, Centre for Biomedicine, EURAC, Italy Received May 31, 2012; Accepted December 24, 2012; Published February 5, 2013 Copyright: 2013 Vimaleswaran et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors thank the British Heart Foundation (grant PG/09/023) and the UK Medical Research Council (MRC; grant G0601653) for funding this work. ADH is a British Heart Foundation Senior Research Fellow (Award FS05/125). EH is a Department of Health (UK) Public Health Career Scientist. This work was undertaken at the Centre for Paediatric Epidemiology and Biostatistics, which benefits from funding support from the MRC in its capacity as the MRC Centre of Epidemiology for Child Health. Research at the University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust benefits from RD BMI, body mass index; GIANT, Genetic Investigation of Anthropometric Traits; IV, instrumental variable; MR, Mendelian randomization * E-mail: e.hypponen@ucl.ac.uk . These authors contributed equally to this work. Membership of the Genetic Investigation of Anthropometric Traits (GIANT) consortium is provided in the Acknowledgments. Body Mass Index and 25(OH)D PLOS Medicine | www.plosmedicine.org 2 February 2013 | Volume 10 | Issue 2 | e1001383