title: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.
abstract: 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.
  
  
  RESULTS
  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(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ 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: -4.2 [95% CI -7.1 to -1.3], 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.
authors: Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom.
authors: Karani S
authors: KS
authors: Vimaleswaran
authors: Diane J
authors: DJ
authors: Berry
authors: Chen
authors: C
authors: Lu
authors: Emmi
authors: E
authors: Tikkanen
authors: Stefan
authors: S
authors: Pilz
authors: Linda T
authors: LT
authors: Hiraki
authors: Jason D
authors: JD
authors: Cooper
authors: Zari
authors: Z
authors: Dastani
authors: Rui
authors: R
authors: Li
authors: Denise K
authors: DK
authors: Houston
authors: Andrew R
authors: AR
authors: Wood
authors: Karl
authors: K
authors: Michaëlsson
authors: Liesbeth
authors: L
authors: Vandenput
authors: Lina
authors: L
authors: Zgaga
authors: Laura M
authors: LM
authors: Yerges-Armstrong
authors: Mark I
authors: MI
authors: McCarthy
authors: Josée
authors: J
authors: Dupuis
authors: Marika
authors: M
authors: Kaakinen
authors: Marcus E
authors: ME
authors: Kleber
authors: Karen
authors: K
authors: Jameson
authors: Nigel
authors: N
authors: Arden
authors: Olli
authors: O
authors: Raitakari
authors: Jorma
authors: J
authors: Viikari
authors: Kurt K
authors: KK
authors: Lohman
authors: Luigi
authors: L
authors: Ferrucci
authors: Håkan
authors: H
authors: Melhus
authors: Erik
authors: E
authors: Ingelsson
authors: Liisa
authors: L
authors: Byberg
authors: Lars
authors: L
authors: Lind
authors: Mattias
authors: M
authors: Lorentzon
authors: Veikko
authors: V
authors: Salomaa
authors: Harry
authors: H
authors: Campbell
authors: Malcolm
authors: M
authors: Dunlop
authors: Braxton D
authors: BD
authors: Mitchell
authors: Karl-Heinz
authors: KH
authors: Herzig
authors: Anneli
authors: A
authors: Pouta
authors: Anna-Liisa
authors: AL
authors: Hartikainen
authors: Elizabeth A
authors: EA
authors: Streeten
authors: Evropi
authors: E
authors: Theodoratou
authors: Antti
authors: A
authors: Jula
authors: Nicholas J
authors: NJ
authors: Wareham
authors: Claes
authors: C
authors: Ohlsson
authors: Timothy M
authors: TM
authors: Frayling
authors: Stephen B
authors: SB
authors: Kritchevsky
authors: Timothy D
authors: TD
authors: Spector
authors: J Brent
authors: JB
authors: Richards
authors: Terho
authors: T
authors: Lehtimäki
authors: Willem H
authors: WH
authors: Ouwehand
authors: Peter
authors: P
authors: Kraft
authors: Cyrus
authors: C
authors: Cooper
authors: Winfried
authors: W
authors: März
authors: Chris
authors: C
authors: Power
authors: Ruth J F
authors: RJ
authors: Loos
authors: Thomas J
authors: TJ
authors: Wang
authors: Marjo-Riitta
authors: MR
authors: Järvelin
authors: John C
authors: JC
authors: Whittaker
authors: Aroon D
authors: AD
authors: Hingorani
authors: Elina
authors: E
authors: Hyppönen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D005060:Europe; D019317:Evidence-Based Medicine; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016014:Linear Models; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D015999:Multivariate Analysis; D009656:North America; D009765:Obesity / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014808:Vitamin D Deficiency / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000517:prevention & control; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers; D014807:Vitamin D; C104450:25-hydroxyvitamin D
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