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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23824655
TITLE
The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
METHODS AND FINDINGS NlmCategory: RESULTS
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n  =  198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0.001).
CONCLUSIONS NlmCategory: CONCLUSIONS
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
DATE PUBLISHED
2013
HISTORY
PUBSTATUS PUBSTATUSDATE
ppublish 2013/06
received 2012/12/03
accepted 2013/05/14
epublish 2013/06/25
entrez 2013/07/05 06:00
pubmed 2013/07/05 06:00
medline 2014/03/22 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Fall T Fall Tove T Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Hägg S Hägg Sara S
Mägi R Mägi Reedik R
Ploner A Ploner Alexander A
Fischer K Fischer Krista K
Horikoshi M Horikoshi Momoko M
Sarin AP Sarin Antti-Pekka AP
Thorleifsson G Thorleifsson Gudmar G
Ladenvall C Ladenvall Claes C
Kals M Kals Mart M
Kuningas M Kuningas Maris M
Draisma HH Draisma Harmen H M HH
Ried JS Ried Janina S JS
van Zuydam NR van Zuydam Natalie R NR
Huikari V Huikari Ville V
Mangino M Mangino Massimo M
Sonestedt E Sonestedt Emily E
Benyamin B Benyamin Beben B
Nelson CP Nelson Christopher P CP
Rivera NV Rivera Natalia V NV
Kristiansson K Kristiansson Kati K
Shen HY Shen Huei-Yi HY
Havulinna AS Havulinna Aki S AS
Dehghan A Dehghan Abbas A
Donnelly LA Donnelly Louise A LA
Kaakinen M Kaakinen Marika M
Nuotio ML Nuotio Marja-Liisa ML
Robertson N Robertson Neil N
de Bruijn RF de Bruijn Renée F A G RF
Ikram MA Ikram M Arfan MA
Amin N Amin Najaf N
Balmforth AJ Balmforth Anthony J AJ
Braund PS Braund Peter S PS
Doney AS Doney Alexander S F AS
Döring A Döring Angela A
Elliott P Elliott Paul P
Esko T Esko Tõnu T
Franco OH Franco Oscar H OH
Gretarsdottir S Gretarsdottir Solveig S
Hartikainen AL Hartikainen Anna-Liisa AL
Heikkilä K Heikkilä Kauko K
Herzig KH Herzig Karl-Heinz KH
Holm H Holm Hilma H
Hottenga JJ Hottenga Jouke Jan JJ
Hyppönen E Hyppönen Elina E
Illig T Illig Thomas T
Isaacs A Isaacs Aaron A
Isomaa B Isomaa Bo B
Karssen LC Karssen Lennart C LC
Kettunen J Kettunen Johannes J
Koenig W Koenig Wolfgang W
Kuulasmaa K Kuulasmaa Kari K
Laatikainen T Laatikainen Tiina T
Laitinen J Laitinen Jaana J
Lindgren C Lindgren Cecilia C
Lyssenko V Lyssenko Valeriya V
Läärä E Läärä Esa E
Rayner NW Rayner Nigel W NW
Männistö S Männistö Satu S
Pouta A Pouta Anneli A
Rathmann W Rathmann Wolfgang W
Rivadeneira F Rivadeneira Fernando F
Ruokonen A Ruokonen Aimo A
Savolainen MJ Savolainen Markku J MJ
Sijbrands EJ Sijbrands Eric J G EJ
Small KS Small Kerrin S KS
Smit JH Smit Jan H JH
Steinthorsdottir V Steinthorsdottir Valgerdur V
Syvänen AC Syvänen Ann-Christine AC
Taanila A Taanila Anja A
Tobin MD Tobin Martin D MD
Uitterlinden AG Uitterlinden Andre G AG
Willems SM Willems Sara M SM
Willemsen G Willemsen Gonneke G
Witteman J Witteman Jacqueline J
Perola M Perola Markus M
Evans A Evans Alun A
Ferrières J Ferrières Jean J
Virtamo J Virtamo Jarmo J
Kee F Kee Frank F
Tregouet DA Tregouet David-Alexandre DA
Arveiler D Arveiler Dominique D
Amouyel P Amouyel Philippe P
Ferrario MM Ferrario Marco M MM
Brambilla P Brambilla Paolo P
Hall AS Hall Alistair S AS
Heath AC Heath Andrew C AC
Madden PA Madden Pamela A F PA
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Whitfield JB Whitfield John B JB
Jula A Jula Antti A
Knekt P Knekt Paul P
Oostra B Oostra Ben B
van Duijn CM van Duijn Cornelia M CM
Penninx BW Penninx Brenda W J H BW
Smith GD Smith George Davey GD
Kaprio J Kaprio Jaakko J
Samani NJ Samani Nilesh J NJ
Gieger C Gieger Christian C
Peters A Peters Annette A
Wichmann HE Wichmann H Erich HE
Boomsma DI Boomsma Dorret I DI
de Geus EJ de Geus Eco J C EJ
Tuomi T Tuomi TiinaMaija T
Power C Power Chris C
Hammond CJ Hammond Christopher J CJ
Spector TD Spector Tim D TD
Lind L Lind Lars L
Orho-Melander M Orho-Melander Marju M
Palmer CN Palmer Colin Neil Alexander CN
Morris AD Morris Andrew D AD
Groop L Groop Leif L
Järvelin MR Järvelin Marjo-Riitta MR
Salomaa V Salomaa Veikko V
Vartiainen E Vartiainen Erkki E
Hofman A Hofman Albert A
Ripatti S Ripatti Samuli S
Metspalu A Metspalu Andres A
Thorsteinsdottir U Thorsteinsdottir Unnur U
Stefansson K Stefansson Kari K
Pedersen NL Pedersen Nancy L NL
McCarthy MI McCarthy Mark I MI
Ingelsson E Ingelsson Erik E
Prokopenko I Prokopenko Inga I
European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium
INVESTIGATORS
JOURNAL
VOLUME: 10
ISSUE: 6
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
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
01GS0834 PHS HHS United States
050-060-810 PHS HHS United States
090532 Wellcome Trust United Kingdom
10-000-1002 PHS HHS United States
104781 PHS HHS United States
11-0312 PHS HHS United States
120315 PHS HHS United States
129418 PHS HHS United States
129494 PHS HHS United States
129680 PHS HHS United States
139635 PHS HHS United States
141054 PHS HHS United States
17155/2004 PHS HHS United States
1RC2 MH089995-01 NIMH NIH HHS United States
1RC2MH089951-01 NIMH NIH HHS United States
1RL1MH083268-01 NIMH NIH HHS United States
201413 PHS HHS United States
213506 PHS HHS United States
230374 PHS HHS United States
241944 Medical Research Council United Kingdom
31160008 PHS HHS United States
31737/1997 PHS HHS United States
339462 Medical Research Council United Kingdom
389875 Medical Research Council United Kingdom
389891 Medical Research Council United Kingdom
389892 Medical Research Council United Kingdom
389927 Medical Research Council United Kingdom
389938 Medical Research Council United Kingdom
400-05-717 PHS HHS United States
41795/1993 PHS HHS United States
442915 Medical Research Council United Kingdom
442981 Medical Research Council United Kingdom
480-04-004 PHS HHS United States
496739 Medical Research Council United Kingdom
552485 Medical Research Council United Kingdom
552498 Medical Research Council United Kingdom
56-464-14192 PHS HHS United States
5R01HL087679-02 NHLBI NIH HHS United States
5R01MH63706 NIMH NIH HHS United States
904-61-090 PHS HHS United States
904-61-193 PHS HHS United States
911-03-012 PHS HHS United States
911-09-032 PHS HHS United States
918-76-619 PHS HHS United States
9783/1986 PHS HHS United States
985-10-002 PHS HHS United States
A7960034 PHS HHS United States
A79801419 PHS HHS United States
A79906588 PHS HHS United States
AA07535 NIAAA NIH HHS United States
AA10248 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA13326 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA15416 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
AG028555 NIA NIH HHS United States
AG04563 NIA NIH HHS United States
AG08724 NIA NIH HHS United States
AG08861 NIA NIH HHS United States
AG10175 NIA NIH HHS United States
CEED3 223211 PHS HHS United States
CT-2006-019473 CIT NIH HHS United States
CT-2006-037593 CIT NIH HHS United States
DA12854 NIDA NIH HHS United States
DK U01-066134 NIDDK NIH HHS United States
DP0212016 NCCDPHP CDC HHS United States
DP0343921 NCCDPHP CDC HHS United States
DP0770096 NCCDPHP CDC HHS United States
ETF9353 PHS HHS United States
EU/QLRT-2001-01254 PHS HHS United States
EU/WLRT-2001-01254 PHS HHS United States
FP6 STRP 018947 OFP OPHS HHS United States
FP7-HEALTH-F4-2007 OFP OPHS HHS United States
FP7/2007-2013 OFP OPHS HHS United States
G0500539 Medical Research Council United Kingdom
G0600705 Medical Research Council United Kingdom
G0801056 Medical Research Council United Kingdom
G0902313 Medical Research Council United Kingdom
GR072960 Wellcome Trust United Kingdom
I 480-05-003 PHS HHS United States
K05 AA017688 NIAAA NIH HHS United States
MH66206 NIMH NIH HHS United States
N01-CN-45165 NCI NIH HHS United States
N01-RC-37004 CCR NIH HHS United States
N01-RC-45035 CCR NIH HHS United States
PG/09/023/26806 British Heart Foundation United Kingdom
QLG1-CT-2000-0164 CIT NIH HHS United States
QLG2-CT-2002-01254 CIT NIH HHS United States
R01 MH059160 NIMH NIH HHS United States
R01D0042157-01A PHS HHS United States
R01EY018246-01-1 NEI NIH HHS United States
R01HL089650-02 NHLBI NIH HHS United States
SF0180142S08 SBRP NIH HHS United States
SRF/01/010 Department of Health United Kingdom
U24 MH068457-06 NIMH NIH HHS United States
Biotechnology and Biological Sciences Research Council United Kingdom
British Heart Foundation United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adiposity genetics
Body Mass Index genetics
Cardiovascular Diseases metabolism
Case-Control Studies metabolism
Confounding Factors (Epidemiology) metabolism
Genetic Association Studies metabolism
Humans metabolism
Mendelian Randomization Analysis metabolism
Meta-Analysis as Topic metabolism
Polymorphism, Single Nucleotide genetics
Proteins genetics
Quantitative Trait, Heritable genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 FTO protein, human
0 Proteins
OTHER ID's
OTHERID SOURCE
PMC3692470 NLM