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

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 JamesonNigel 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, Winfried März, Chris Power, Ruth J F Loos, Thomas J. Wang, Marjo Riitta Järvelin, John C. Whittaker, Aroon D. Hingorani, Elina Hyppönen

Research output: Contribution to journalArticle

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/m2 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. Please see later in the article for the Editors' Summary.

Original languageEnglish (US)
Article numbere1001383
JournalPLoS Medicine
Volume10
Issue number2
DOIs
StatePublished - 2013
Externally publishedYes

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Mendelian Randomization Analysis
Vitamin D
Body Mass Index
Obesity
Meta-Analysis
Vitamin D Deficiency
Alleles
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Causal Relationship between Obesity and Vitamin D Status : Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. / Vimaleswaran, Karani S.; Berry, Diane J.; Lu, Chen; Tikkanen, Emmi; Pilz, Stefan; Hiraki, Linda T.; Cooper, Jason D.; Dastani, Zari; Li, Rui; Houston, Denise K.; Wood, Andrew R.; Michaëlsson, Karl; Vandenput, Liesbeth; Zgaga, Lina; Yerges-Armstrong, Laura M.; McCarthy, Mark I.; Dupuis, Josée; Kaakinen, Marika; Kleber, Marcus E.; Jameson, Karen; Arden, Nigel; Raitakari, Olli; Viikari, Jorma; Lohman, Kurt K.; Ferrucci, Luigi; Melhus, Håkan; Ingelsson, Erik; Byberg, Liisa; Lind, Lars; Lorentzon, Mattias; Salomaa, Veikko; Campbell, Harry; Dunlop, Malcolm; Mitchell, Braxton D.; Herzig, Karl Heinz; Pouta, Anneli; Hartikainen, Anna Liisa; Streeten, Elizabeth A.; Theodoratou, Evropi; Jula, Antti; Wareham, Nicholas J.; Ohlsson, Claes; Frayling, Timothy M.; Kritchevsky, Stephen B.; Spector, Timothy D.; Richards, J. Brent; Lehtimäki, Terho; Ouwehand, Willem H.; Kraft, Peter; Cooper, Cyrus; März, Winfried; Power, Chris; Loos, Ruth J F; Wang, Thomas J.; Järvelin, Marjo Riitta; Whittaker, John C.; Hingorani, Aroon D.; Hyppönen, Elina.

In: PLoS Medicine, Vol. 10, No. 2, e1001383, 2013.

Research output: Contribution to journalArticle

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, KH, Pouta, A, Hartikainen, AL, 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, März, W, Power, C, Loos, RJF, Wang, TJ, Järvelin, MR, Whittaker, JC, Hingorani, AD & Hyppönen, E 2013, 'Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts', PLoS Medicine, vol. 10, no. 2, e1001383. https://doi.org/10.1371/journal.pmed.1001383
Vimaleswaran, Karani S. ; Berry, Diane J. ; Lu, Chen ; Tikkanen, Emmi ; Pilz, Stefan ; Hiraki, Linda T. ; Cooper, Jason D. ; Dastani, Zari ; Li, Rui ; Houston, Denise K. ; Wood, Andrew R. ; Michaëlsson, Karl ; Vandenput, Liesbeth ; Zgaga, Lina ; Yerges-Armstrong, Laura M. ; McCarthy, Mark I. ; Dupuis, Josée ; Kaakinen, Marika ; Kleber, Marcus E. ; Jameson, Karen ; Arden, Nigel ; Raitakari, Olli ; Viikari, Jorma ; Lohman, Kurt K. ; Ferrucci, Luigi ; Melhus, Håkan ; Ingelsson, Erik ; Byberg, Liisa ; Lind, Lars ; Lorentzon, Mattias ; Salomaa, Veikko ; Campbell, Harry ; Dunlop, Malcolm ; Mitchell, Braxton D. ; Herzig, Karl Heinz ; Pouta, Anneli ; Hartikainen, Anna Liisa ; Streeten, Elizabeth A. ; Theodoratou, Evropi ; Jula, Antti ; Wareham, Nicholas J. ; Ohlsson, Claes ; Frayling, Timothy M. ; Kritchevsky, Stephen B. ; Spector, Timothy D. ; Richards, J. Brent ; Lehtimäki, Terho ; Ouwehand, Willem H. ; Kraft, Peter ; Cooper, Cyrus ; März, Winfried ; Power, Chris ; Loos, Ruth J F ; Wang, Thomas J. ; Järvelin, Marjo Riitta ; Whittaker, John C. ; Hingorani, Aroon D. ; Hyppönen, Elina. / Causal Relationship between Obesity and Vitamin D Status : Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. In: PLoS Medicine. 2013 ; Vol. 10, No. 2.
@article{f8aa5c30a6f04b18ac1bacd2eef63717,
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/m2 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. Please see later in the article for the Editors' Summary.",
author = "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 Herzig, {Karl Heinz} and Anneli Pouta and Hartikainen, {Anna Liisa} 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 and Winfried M{\"a}rz and Chris Power and Loos, {Ruth J F} and Wang, {Thomas J.} and J{\"a}rvelin, {Marjo Riitta} and Whittaker, {John C.} and Hingorani, {Aroon D.} and Elina Hypp{\"o}nen",
year = "2013",
doi = "10.1371/journal.pmed.1001383",
language = "English (US)",
volume = "10",
journal = "Nature Clinical Practice Oncology",
issn = "1759-4774",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Causal Relationship between Obesity and Vitamin D Status

T2 - Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

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

AU - März, Winfried

AU - Power, Chris

AU - Loos, Ruth J F

AU - Wang, Thomas J.

AU - Järvelin, Marjo Riitta

AU - Whittaker, John C.

AU - Hingorani, Aroon D.

AU - Hyppönen, Elina

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/m2 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. 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/m2 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. Please see later in the article for the Editors' Summary.

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