Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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23393431
TITLE
Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts.
ABSTRACT
BACKGROUND NlmCategory: 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 NlmCategory: 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 NlmCategory: 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.
DATE PUBLISHED
2013
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2012/05/31
accepted 2012/12/24
epublish 2013/02/05
entrez 2013/02/09 06:00
pubmed 2013/02/09 06:00
medline 2013/07/17 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Vimaleswaran KS Vimaleswaran Karani S KS Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom.
Berry DJ Berry Diane J DJ
Lu C Lu Chen C
Tikkanen E Tikkanen Emmi E
Pilz S Pilz Stefan S
Hiraki LT Hiraki Linda T LT
Cooper JD Cooper Jason D JD
Dastani Z Dastani Zari Z
Li R Li Rui R
Houston DK Houston Denise K DK
Wood AR Wood Andrew R AR
Michaëlsson K Michaëlsson Karl K
Vandenput L Vandenput Liesbeth L
Zgaga L Zgaga Lina L
Yerges-Armstrong LM Yerges-Armstrong Laura M LM
McCarthy MI McCarthy Mark I MI
Dupuis J Dupuis Josée J
Kaakinen M Kaakinen Marika M
Kleber ME Kleber Marcus E ME
Jameson K Jameson Karen K
Arden N Arden Nigel N
Raitakari O Raitakari Olli O
Viikari J Viikari Jorma J
Lohman KK Lohman Kurt K KK
Ferrucci L Ferrucci Luigi L
Melhus H Melhus Håkan H
Ingelsson E Ingelsson Erik E
Byberg L Byberg Liisa L
Lind L Lind Lars L
Lorentzon M Lorentzon Mattias M
Salomaa V Salomaa Veikko V
Campbell H Campbell Harry H
Dunlop M Dunlop Malcolm M
Mitchell BD Mitchell Braxton D BD
Herzig KH Herzig Karl-Heinz KH
Pouta A Pouta Anneli A
Hartikainen AL Hartikainen Anna-Liisa AL
Genetic Investigation of Anthropometric Traits-GIANT Consortium
Streeten EA Streeten Elizabeth A EA
Theodoratou E Theodoratou Evropi E
Jula A Jula Antti A
Wareham NJ Wareham Nicholas J NJ
Ohlsson C Ohlsson Claes C
Frayling TM Frayling Timothy M TM
Kritchevsky SB Kritchevsky Stephen B SB
Spector TD Spector Timothy D TD
Richards JB Richards J Brent JB
Lehtimäki T Lehtimäki Terho T
Ouwehand WH Ouwehand Willem H WH
Kraft P Kraft Peter P
Cooper C Cooper Cyrus C
März W März Winfried W
Power C Power Chris C
Loos RJ Loos Ruth J F RJ
Wang TJ Wang Thomas J TJ
Järvelin MR Järvelin Marjo-Riitta MR
Whittaker JC Whittaker John C JC
Hingorani AD Hingorani Aroon D AD
Hyppönen E Hyppönen Elina E
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Speliotes Elizabeth K EK
Willer Cristen J CJ
Berndt Sonja I SI
Monda Keri L KL
Thorleifsson Gudmar G
Jackson Anne U AU
Allen Hana Lango HL
Lindgren Cecilia M CM
Luan Jian'an J
Mägi Reedik R
Randall Joshua C JC
Vedantam Sailaja S
Winkler Thomas W TW
Qi Lu L
Workalemahu Tsegaselassie T
Heid Iris M IM
Steinthorsdottir Valgerdur V
Stringham Heather M HM
Weedon Michael N MN
Wheeler Eleanor E
Wood Andrew R AR
Ferreira Teresa T
Weyant Robert J RJ
Segrè Ayellet V AV
Estrada Karol K
Liang Liming L
Nemesh James J
Park Ju-Hyun JH
Gustafsson Stefan S
Kilpeläinen Tuomas O TO
Yang Jian J
Bouatia-Naji Nabila N
Esko Tõnu T
Feitosa Mary F MF
Kutalik Zoltán Z
Mangino Massimo M
Raychaudhuri Soumya S
Scherag Andre A
Smith Albert Vernon AV
Welch Ryan R
Zhao Jing Hua JH
Aben Katja K KK
Absher Devin M DM
Amin Najaf N
Dixon Anna L AL
Fisher Eva E
Glazer Nicole L NL
Goddard Michael E ME
Heard-Costa Nancy L NL
Hoesel Volker V
Hottenga Jouke-Jan JJ
Johansson Åsa
Johnson Toby T
Ketkar Shamika S
Lamina Claudia C
Li Shengxu S
Moffatt Miriam F MF
Myers Richard H RH
Narisu Narisu N
Perry John R B JR
Peters Marjolein J MJ
Preuss Michael M
Ripatti Samuli S
Rivadeneira Fernando F
Sandholt Camilla C
Scott Laura J LJ
Timpson Nicholas J NJ
Tyrer Jonathan P JP
van Wingerden Sophie S
Watanabe Richard M RM
White Charles C CC
Wiklund Fredrik F
Barlassina Christina C
Chasman Daniel I DI
Cooper Matthew N MN
Jansson John-Olov JO
Lawrence Robert W RW
Pellikka Niina N
Prokopenko Inga I
Shi Jianxin J
Thiering Elisabeth E
Alavere Helene H
Alibrandi Maria T S MT
Almgren Peter P
Arnold Alice M AM
Aspelund Thor T
Atwood Larry D LD
Balkau Beverley B
Balmforth Anthony J AJ
Bennett Amanda J AJ
Ben-Shlomo Yoav Y
Bergman Richard N RN
Bergmann Sven S
Biebermann Heike H
Blakemore Alexandra I F AI
Boes Tanja T
Bonnycastle Lori L LL
Bornstein Stefan R SR
Brown Morris J MJ
Buchanan Thomas A TA
Busonero Fabio F
Campbell Harry H
Cappuccio Francesco P FP
Cavalcanti-Proença Christine C
Chen Yii-Der Ida YD
Chen Chih-Mei CM
Chines Peter S PS
Clarke Robert R
Coin Lachlan L
Connell John J
Day Ian N M IN
Heijer Martin den Md
Duan Jubao J
Ebrahim Shah S
Elliott Paul P
Elosua Roberto R
Eiriksdottir Gudny G
Erdos Michael R MR
Eriksson Johan G JG
Facheris Maurizio F MF
Felix Stephan B SB
Fischer-Posovszky Pamela P
Folsom Aaron R AR
Friedrich Nele N
Freimer Nelson B NB
Fu Mao M
Gaget Stefan S
Gejman Pablo V PV
Geus Eco J C EJ
Gieger Christian C
Gjesing Anette P AP
Goel Anuj A
Goyette Philippe P
Grallert Harald H
Gräßler Jürgen J
Greenawalt Danielle M DM
Groves Christopher J CJ
Gudnason Vilmundur V
Guiducci Candace C
Hartikainen Anna-Liisa AL
Hassanali Neelam N
Hall Alistair S AS
Havulinna Aki S AS
Hayward Caroline C
Heath Andrew C AC
Hengstenberg Christian C
Hicks Andrew A AA
Hinney Anke A
Hofman Albert A
Homuth Georg G
Hui Jennie J
Igl Wilmar W
Iribarren Carlos C
Isomaa Bo B
Jacobs Kevin B KB
Jarick Ivonne I
Jewell Elizabeth E
John Ulrich U
Jørgensen Torben T
Jousilahti Pekka P
Jula Antti A
Kaakinen Marika M
Kajantie Eero E
Kaplan Lee M LM
Kathiresan Sekar S
Kettunen Johannes J
Kinnunen Leena L
Knowles Joshua W JW
Kolcic Ivana I
König Inke R IR
Koskinen Seppo S
Kovacs Peter P
Kuusisto Johanna J
Kraft Peter P
Kvaløy Kirsti K
Laitinen Jaana J
Lantieri Olivier O
Lanzani Chiara C
Launer Lenore J LJ
Lecoeur Cecile C
Lehtimäki Terho T
Lettre Guillaume G
Liu Jianjun J
Lokki Marja-Liisa ML
Lorentzon Mattias M
Luben Robert N RN
Ludwig Barbara B
Manunta Paolo P
Marek Diana D
Marre Michel M
Martin Nicholas G NG
McArdle Wendy L WL
McCarthy Anne A
McKnight Barbara B
Meitinger Thomas T
Melander Olle O
Meyre David D
Midthjell Kristian K
Montgomery Grant W GW
Morken Mario A MA
Morris Andrew P AP
Mulic Rosanda R
Ngwa Julius S JS
Nelis Mari M
Neville Matt J MJ
Nyholt Dale R DR
O'Donnell Christopher J CJ
O'Rahilly Stephen S
Ong Ken K KK
Oostra Ben B
Paré Guillaume G
Parker Alex N AN
Perola Markus M
Pichler Irene I
Pietiläinen Kirsi H KH
Platou Carl G P CG
Polasek Ozren O
Pouta Anneli A
Rafelt Suzanne S
Raitakari Olli O
Rayner Nigel W NW
Ridderstråle Martin M
Rief Winfried W
Ruokonen Aimo A
Robertson Neil R NR
Rzehak Peter P
Salomaa Veikko V
Sanders Alan R AR
Sandhu Manjinder S MS
Sanna Serena S
Saramies Jouko J
Savolainen Markku J MJ
Scherag Susann S
Schipf Sabine S
Schreiber Stefan S
Schunkert Heribert H
Silander Kaisa K
Sinisalo Juha J
Siscovick David S DS
Smit Jan H JH
Soranzo Nicole N
Sovio Ulla U
Stephens Jonathan J
Surakka Ida I
Swift Amy J AJ
Tammesoo Mari-Liis ML
Tardif Jean-Claude JC
Teder-Laving Maris M
Teslovich Tanya M TM
Thompson John R JR
Thomson Brian B
Tönjes Anke A
Tuomi Tiinamaija T
van Meurs Joyce B J JB
van Ommen Gert-Jan GJ
Vatin Vincent V
Viikari Jorma J
Visvikis-Siest Sophie S
Vitart Veronique V
Vogel Carla I G CI
Voight Benjamin F BF
Waite Lindsay L LL
Wallaschofski Henri H
Walters G Bragi GB
Widen Elisabeth E
Wiegand Susanna S
Wild Sarah H SH
Willemsen Gonneke G
Witte Daniel R DR
Witteman Jacqueline C JC
Xu Jianfeng J
Zhang Qunyuan Q
Zgaga Lina L
Ziegler Andreas A
Zitting Paavo P
Beilby John P JP
Farooqi I Sadaf IS
Hebebrand Johannes J
Huikuri Heikki V HV
James Alan L AL
Kähönen Mika M
Levinson Douglas F DF
Macciardi Fabio F
Nieminen Markku S MS
Ohlsson Claes C
Palmer Lyle J LJ
Ridker Paul M PM
Stumvoll Michael M
Beckmann Jacques S JS
Boeing Heiner H
Boerwinkle Eric E
Boomsma Dorret I DI
Caulfield Mark J MJ
Chanock Stephen J SJ
Collins Francis S FS
Cupples L Adrienne LA
Smith George Davey GD
Erdmann Jeanette J
Froguel Philippe P
Grönberg Henrik H
Gyllensten Ulf U
Hall Per P
Hansen Torben T
Harris Tamara B TB
Hattersley Andrew T AT
Hayes Richard B RB
Heinrich Joachim J
Hu Frank B FB
Hveem Kristian K
Illig Thomas T
Jarvelin Marjo-Riitta MR
Kaprio Jaakko J
Karpe Fredrik F
Khaw Kay-Tee KT
Kiemeney Lambertus A LA
Krude Heiko H
Laakso Markku M
Lawlor Debbie A DA
Metspalu Andres A
Munroe Patricia B PB
Ouwehand Willem H WH
Pedersen Oluf O
Penninx Brenda W BW
Peters Annette A
Pramstaller Peter P PP
Quertermous Thomas T
Reinehr Thomas T
Rissanen Aila A
Rudan Igor I
Samani Nilesh J NJ
Schwarz Peter E H PE
Shuldiner Alan R AR
Spector Timothy D TD
Tuomilehto Jaakko J
Uda Manuela M
Uitterlinden André A
Valle Timo T TT
Wabitsch Martin M
Waeber Gérard G
Wareham Nicholas J NJ
Watkins Hugh H
Wilson James F JF
Wright Alan F AF
Zillikens M Carola MC
Chatterjee Nilanjan N
McCarroll Steven A SA
Purcell Shaun S
Schadt Eric E EE
Visscher Peter M PM
Assimes Themistocles L TL
Borecki Ingrid B IB
Deloukas Panos P
Fox Caroline S CS
Groop Leif C LC
Haritunians Talin T
Hunter David J DJ
Kaplan Robert C RC
Mohlke Karen L KL
O'Connell Jeffrey R JR
Peltonen Leena L
Schlessinger David D
Strachan David P DP
van Duijn Cornelia M CM
Wichmann H-Erich HE
Frayling Timothy M TM
Thorsteinsdottir Unnur U
Abecasis Gonçalo R GR
Barroso Inês I
Boehnke Michael M
Stefansson Kari K
North Kari E KE
McCarthy Mark I MI
Hirschhorn Joel N JN
Ingelsson Erik E
Loos Ruth J F RJ
JOURNAL
VOLUME: 10
ISSUE: 2
TITLE: PLoS medicine
ISOABBREVIATION: PLoS Med.
YEAR: 2013
MONTH:
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1549-1676
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Med
COUNTRY: United States
ISSNLINKING: 1549-1277
NLMUNIQUEID: 101231360
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Multicenter Study
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
12076 Cancer Research UK United Kingdom
13085 Arthritis Research UK United Kingdom
13147 Arthritis Research UK United Kingdom
13157 Arthritis Research UK United Kingdom
13181 Arthritis Research UK United Kingdom
13230 Arthritis Research UK United Kingdom
14136 Cancer Research UK United Kingdom
16095 Arthritis Research UK United Kingdom
16349 Arthritis Research UK United Kingdom
17265 Arthritis Research UK United Kingdom
17413 Arthritis Research UK United Kingdom
17702 Arthritis Research UK United Kingdom
CZH/4/529 Chief Scientist Office United Kingdom
FS05/125 British Heart Foundation United Kingdom
G0400491 Medical Research Council United Kingdom
G0601653 Medical Research Council United Kingdom
G0801056 Medical Research Council United Kingdom
G1000143 Medical Research Council United Kingdom
K01 AG030506 NIA NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
MC_PC_U127561128 Medical Research Council United Kingdom
MC_U106179471 Medical Research Council United Kingdom
MC_U106188470 Medical Research Council United Kingdom
MC_U127527198 Medical Research Council United Kingdom
MC_U147574215 Medical Research Council United Kingdom
MC_U147574217 Medical Research Council United Kingdom
MC_U147574221 Medical Research Council United Kingdom
MC_U147574233 Medical Research Council United Kingdom
MC_U147574236 Medical Research Council United Kingdom
MC_U147585819 Medical Research Council United Kingdom
MC_U147585824 Medical Research Council United Kingdom
MC_U147585827 Medical Research Council United Kingdom
MC_UP_A620_1014 Medical Research Council United Kingdom
P30 AG021332 NIA NIH HHS United States
PG/09/023 British Heart Foundation United Kingdom
PG/09/023/26806 British Heart Foundation United Kingdom
Department of Health United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Aged
Aged, 80 and over
Biomarkers blood
Body Mass Index blood
Europe blood
European Continental Ancestry Group genetics
Evidence-Based Medicine genetics
Female genetics
Genetic Predisposition to Disease genetics
Humans genetics
Linear Models genetics
Male genetics
Mendelian Randomization Analysis genetics
Middle Aged genetics
Multivariate Analysis genetics
North America genetics
Obesity therapy
Phenotype therapy
Polymorphism, Single Nucleotide therapy
Risk Assessment therapy
Risk Factors therapy
Vitamin D blood
Vitamin D Deficiency prevention & control
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Biomarkers
1406-16-2 Vitamin D
64719-49-9 25-hydroxyvitamin D
OTHER ID's
OTHERID SOURCE
PMC3564800 NLM