Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

Genetic Investigation of Anthropometric Traits-GIANT Consortium; Karani S Vimaleswaran; Diane J Berry; Chen Lu; Emmi Tikkanen; Stefan Pilz; Linda T Hiraki; Jason D Cooper; Zari Dastani; Rui Li; Denise K Houston; Andrew R Wood; Karl Michaëlsson; Liesbeth Vandenput; Lina Zgaga; Laura M Yerges-Armstrong; Mark I McCarthy; Josée Dupuis; Marika Kaakinen; Marcus E Kleber; Karen Jameson; Nigel Arden; Olli Raitakari; Jorma Viikari; Kurt K Lohman; Luigi Ferrucci; Håkan Melhus; Erik Ingelsson; Liisa Byberg; Lars Lind; Mattias Lorentzon; Veikko Salomaa; Harry Campbell; Malcolm Dunlop; Braxton D Mitchell; Karl-Heinz Herzig; Anneli Pouta; Anna-Liisa Hartikainen; Elizabeth A Streeten; Evropi Theodoratou; Antti Jula; Nicholas J Wareham; Claes Ohlsson; Timothy M Frayling; Stephen B Kritchevsky; Timothy D Spector; J Brent Richards; Terho Lehtimäki; Willem H Ouwehand; Peter Kraft; Cyrus Cooper

doi:10.1371/journal.pmed.1001383

Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

Genetic Investigation of Anthropometric Traits-GIANT Consortium, Karani S Vimaleswaran, Diane J Berry, Chen Lu, Emmi Tikkanen, Stefan Pilz, Linda T Hiraki, Jason D Cooper, Zari Dastani, Rui Li, Denise K Houston, Andrew R Wood, Karl Michaëlsson, Liesbeth Vandenput, Lina Zgaga, Laura M Yerges-Armstrong, Mark I McCarthy, Josée Dupuis, Marika Kaakinen, Marcus E KleberKaren Jameson, Nigel Arden, Olli Raitakari, Jorma Viikari, Kurt K Lohman, Luigi Ferrucci, Håkan Melhus, Erik Ingelsson, Liisa Byberg, Lars Lind, Mattias Lorentzon, Veikko Salomaa, Harry Campbell, Malcolm Dunlop, Braxton D Mitchell, Karl-Heinz Herzig, Anneli Pouta, Anna-Liisa Hartikainen, Elizabeth A Streeten, Evropi Theodoratou, Antti Jula, Nicholas J Wareham, Claes Ohlsson, Timothy M Frayling, Stephen B Kritchevsky, Timothy D Spector, J Brent Richards, Terho Lehtimäki, Willem H Ouwehand, Peter Kraft, Cyrus Cooper

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 = 6.52×10). The BMI allele score was associated both with BMI (p = 6.30×10) 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 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. Please see later in the article for the Editors' Summary.

Original language	English
Article number	e1001383
Pages (from-to)	e1001383
Number of pages	13
Journal	PLoS Medicine
Volume	10
Issue number	2
DOIs	https://doi.org/10.1371/journal.pmed.1001383
Publication status	Published - 2013

Keywords / Materials (for Non-textual outputs)

Adult
Aged
Aged, 80 and over
Biological Markers
Body Mass Index
Europe
European Continental Ancestry Group
Evidence-Based Medicine
Female
Genetic Predisposition to Disease
Humans
Linear Models
Male
Mendelian Randomization Analysis
Middle Aged
Multivariate Analysis
North America
Obesity
Phenotype
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
Vitamin D
Vitamin D Deficiency

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10.1371/journal.pmed.1001383

Causal Relationship between Obesity and Vitamin D Status
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.
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http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001383

Cite this

Genetic Investigation of Anthropometric Traits-GIANT Consortium, Vimaleswaran, K. S., Berry, D. J., Lu, C., Tikkanen, E., Pilz, S., Hiraki, L. T., Cooper, J. D., Dastani, Z., Li, R., Houston, D. K., Wood, A. R., Michaëlsson, K., Vandenput, L., Zgaga, L., Yerges-Armstrong, L. M., McCarthy, M. I., Dupuis, J., Kaakinen, M., ... Cooper, C. (2013). Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. PLoS Medicine, 10(2), e1001383. Article e1001383. https://doi.org/10.1371/journal.pmed.1001383

@article{d14a6d5e9c0b44219887aeacf37fb7bd,

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. 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 = 6.52×10). The BMI allele score was associated both with BMI (p = 6.30×10) 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 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. Please see later in the article for the Editors' Summary.",

keywords = "Adult, Aged, Aged, 80 and over, Biological Markers, Body Mass Index, Europe, European Continental Ancestry Group, Evidence-Based Medicine, Female, Genetic Predisposition to Disease, Humans, Linear Models, Male, Mendelian Randomization Analysis, Middle Aged, Multivariate Analysis, North America, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Vitamin D, Vitamin D Deficiency",

author = "{Genetic Investigation of Anthropometric Traits-GIANT Consortium} and Vimaleswaran, {Karani S} and Berry, {Diane J} and Chen Lu and Emmi Tikkanen and Stefan Pilz and Hiraki, {Linda T} and Cooper, {Jason D} and Zari Dastani and Rui Li and Houston, {Denise K} and Wood, {Andrew R} and Karl Micha{\"e}lsson and Liesbeth Vandenput and Lina Zgaga and Yerges-Armstrong, {Laura M} and McCarthy, {Mark I} and Jos{\'e}e Dupuis and Marika Kaakinen and Kleber, {Marcus E} and Karen Jameson and Nigel Arden and Olli Raitakari and Jorma Viikari and Lohman, {Kurt K} and Luigi Ferrucci and H{\aa}kan Melhus and Erik Ingelsson and Liisa Byberg and Lars Lind and Mattias Lorentzon and Veikko Salomaa and Harry Campbell and Malcolm Dunlop and Mitchell, {Braxton D} and Karl-Heinz Herzig and Anneli Pouta and Anna-Liisa Hartikainen and Streeten, {Elizabeth A} and Evropi Theodoratou and Antti Jula and Wareham, {Nicholas J} and Claes Ohlsson and Frayling, {Timothy M} and Kritchevsky, {Stephen B} and Spector, {Timothy D} and Richards, {J Brent} and Terho Lehtim{\"a}ki and Ouwehand, {Willem H} and Peter Kraft and Cyrus Cooper",

note = "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. ",

year = "2013",

doi = "10.1371/journal.pmed.1001383",

language = "English",

volume = "10",

pages = "e1001383",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "2",

}

Genetic Investigation of Anthropometric Traits-GIANT Consortium, Vimaleswaran, KS, Berry, DJ, Lu, C, Tikkanen, E, Pilz, S, Hiraki, LT, Cooper, JD, Dastani, Z, Li, R, Houston, DK, Wood, AR, Michaëlsson, K, Vandenput, L, Zgaga, L, Yerges-Armstrong, LM, McCarthy, MI, Dupuis, J, Kaakinen, M, Kleber, ME, Jameson, K, Arden, N, Raitakari, O, Viikari, J, Lohman, KK, Ferrucci, L, Melhus, H, Ingelsson, E, Byberg, L, Lind, L, Lorentzon, M, Salomaa, V, Campbell, H , Dunlop, M, Mitchell, BD, Herzig, K-H, Pouta, A, Hartikainen, A-L, Streeten, EA, Theodoratou, E, Jula, A, Wareham, NJ, Ohlsson, C, Frayling, TM, Kritchevsky, SB, Spector, TD, Richards, JB, Lehtimäki, T, Ouwehand, WH, Kraft, P & Cooper, C 2013, 'Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts', PLoS Medicine, vol. 10, no. 2, e1001383, pp. e1001383. https://doi.org/10.1371/journal.pmed.1001383

Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. / Genetic Investigation of Anthropometric Traits-GIANT Consortium; Vimaleswaran, Karani S; Berry, Diane J et al.
In: PLoS Medicine, Vol. 10, No. 2, e1001383, 2013, p. e1001383.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Causal Relationship between Obesity and Vitamin D Status

T2 - Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

AU - Genetic Investigation of Anthropometric Traits-GIANT Consortium

AU - Vimaleswaran, Karani S

AU - Berry, Diane J

AU - Lu, Chen

AU - Tikkanen, Emmi

AU - Pilz, Stefan

AU - Hiraki, Linda T

AU - Cooper, Jason D

AU - Dastani, Zari

AU - Li, Rui

AU - Houston, Denise K

AU - Wood, Andrew R

AU - Michaëlsson, Karl

AU - Vandenput, Liesbeth

AU - Zgaga, Lina

AU - Yerges-Armstrong, Laura M

AU - McCarthy, Mark I

AU - Dupuis, Josée

AU - Kaakinen, Marika

AU - Kleber, Marcus E

AU - Jameson, Karen

AU - Arden, Nigel

AU - Raitakari, Olli

AU - Viikari, Jorma

AU - Lohman, Kurt K

AU - Ferrucci, Luigi

AU - Melhus, Håkan

AU - Ingelsson, Erik

AU - Byberg, Liisa

AU - Lind, Lars

AU - Lorentzon, Mattias

AU - Salomaa, Veikko

AU - Campbell, Harry

AU - Dunlop, Malcolm

AU - Mitchell, Braxton D

AU - Herzig, Karl-Heinz

AU - Pouta, Anneli

AU - Hartikainen, Anna-Liisa

AU - Streeten, Elizabeth A

AU - Theodoratou, Evropi

AU - Jula, Antti

AU - Wareham, Nicholas J

AU - Ohlsson, Claes

AU - Frayling, Timothy M

AU - Kritchevsky, Stephen B

AU - Spector, Timothy D

AU - Richards, J Brent

AU - Lehtimäki, Terho

AU - Ouwehand, Willem H

AU - Kraft, Peter

AU - Cooper, Cyrus

N1 - 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.

PY - 2013

Y1 - 2013

N2 - 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 = 6.52×10). The BMI allele score was associated both with BMI (p = 6.30×10) 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 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. Please see later in the article for the Editors' Summary.

AB - 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 = 6.52×10). The BMI allele score was associated both with BMI (p = 6.30×10) 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 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. Please see later in the article for the Editors' Summary.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biological Markers

KW - Body Mass Index

KW - Europe

KW - European Continental Ancestry Group

KW - Evidence-Based Medicine

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Linear Models

KW - Male

KW - Mendelian Randomization Analysis

KW - Middle Aged

KW - Multivariate Analysis

KW - North America

KW - Obesity

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Risk Assessment

KW - Risk Factors

KW - Vitamin D

KW - Vitamin D Deficiency

U2 - 10.1371/journal.pmed.1001383

DO - 10.1371/journal.pmed.1001383

M3 - Article

C2 - 23393431

AN - SCOPUS:84874505939

SN - 1549-1277

VL - 10

SP - e1001383

JO - PLoS Medicine

JF - PLoS Medicine

IS - 2

M1 - e1001383

ER -

Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

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Keywords / Materials (for Non-textual outputs)

Access to Document

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