The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Tove Fall; Sara Hagg; Reedik Maegi; Alexander Ploner; Krista Fischer; Momoko Horikoshi; Antti-Pekka Sarin; Gudmar Thorleifsson; Claes Ladenvall; Mart Kals; Maris Kuningas; Harmen H. M. Draisma; Janina S. Ried; Natalie R. van Zuydam; Ville Huikari; Massimo Mangino; Emily Sonestedt; Beben Benyamin; Christopher P. Nelson; Natalia V. Rivera; Kati Kristiansson; Huei-yi Shen; Aki S. Havulinna; Abbas Dehghan; Louise A. Donnelly; Marika Kaakinen; Marja-Liisa Nuotio; Neil Robertson; Renee F. A. G. de Bruijn; M. Arfan Ikram; Najaf Amin; Anthony J. Balmforth; Peter S. Braund; Alexander S. F. Doney; Angela Doering; Paul Elliott; Tonu Esko; Oscar H. Franco; Solveig Gretarsdottir; Anna-Liisa Hartikainen; Kauko Heikkila; Karl-Heinz Herzig; Hilma Holm; Jouke Jan Hottenga; Elina Hypponen; Thomas Illig; Aaron Isaacs; Bo Isomaa; Martin D. Tobin; George Davey Smith; ENGAGE Consortium

doi:10.1371/journal.pmed.1001474

The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Tove Fall^*, Sara Hagg, Reedik Maegi, Alexander Ploner, Krista Fischer, Momoko Horikoshi, Antti-Pekka Sarin, Gudmar Thorleifsson, Claes Ladenvall, Mart Kals, Maris Kuningas, Harmen H. M. Draisma, Janina S. Ried, Natalie R. van Zuydam, Ville Huikari, Massimo Mangino, Emily Sonestedt, Beben Benyamin, Christopher P. Nelson, Natalia V. RiveraKati Kristiansson, Huei-yi Shen, Aki S. Havulinna, Abbas Dehghan, Louise A. Donnelly, Marika Kaakinen, Marja-Liisa Nuotio, Neil Robertson, Renee F. A. G. de Bruijn, M. Arfan Ikram, Najaf Amin, Anthony J. Balmforth, Peter S. Braund, Alexander S. F. Doney, Angela Doering, Paul Elliott, Tonu Esko, Oscar H. Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkila, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hypponen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Martin D. Tobin, George Davey Smith, ENGAGE Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

168 Citations (Scopus)

Abstract

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: 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

Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

Original language	English
Article number	1001474
Number of pages	15
Journal	PLoS Medicine
Volume	10
Issue number	6
DOIs	https://doi.org/10.1371/journal.pmed.1001474
Publication status	Published - Jun 2013

Keywords

BODY-MASS INDEX
IMPAIRED GLUCOSE-TOLERANCE
GENOME-WIDE ASSOCIATION
HEART-FAILURE
LIFE-STYLE
FTO GENE
DIABETES PREVENTION
OBESITY
RISK
DISEASE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pmed.1001474

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MRC UoB UNITE Unit - Programme 1
Davey Smith, G.
1/06/13 → 31/03/18
Project: Research
CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)
Davey Smith, G.
1/09/07 → 1/09/13
Project: Research

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Fall, T., Hagg, S., Maegi, R., Ploner, A., Fischer, K., Horikoshi, M., Sarin, A.-P., Thorleifsson, G., Ladenvall, C., Kals, M., Kuningas, M., Draisma, H. H. M., Ried, J. S., van Zuydam, N. R., Huikari, V., Mangino, M., Sonestedt, E., Benyamin, B., Nelson, C. P., ... ENGAGE Consortium (2013). The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis. PLoS Medicine, 10(6), Article 1001474. https://doi.org/10.1371/journal.pmed.1001474

@article{18a3ecaa04f44055ba1cb6ece30d7abf,

title = "The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis",

abstract = "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: 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 pConclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.",

keywords = "BODY-MASS INDEX, IMPAIRED GLUCOSE-TOLERANCE, GENOME-WIDE ASSOCIATION, HEART-FAILURE, LIFE-STYLE, FTO GENE, DIABETES PREVENTION, OBESITY, RISK, DISEASE",

author = "Tove Fall and Sara Hagg and Reedik Maegi and Alexander Ploner and Krista Fischer and Momoko Horikoshi and Antti-Pekka Sarin and Gudmar Thorleifsson and Claes Ladenvall and Mart Kals and Maris Kuningas and Draisma, {Harmen H. M.} and Ried, {Janina S.} and {van Zuydam}, {Natalie R.} and Ville Huikari and Massimo Mangino and Emily Sonestedt and Beben Benyamin and Nelson, {Christopher P.} and Rivera, {Natalia V.} and Kati Kristiansson and Huei-yi Shen and Havulinna, {Aki S.} and Abbas Dehghan and Donnelly, {Louise A.} and Marika Kaakinen and Marja-Liisa Nuotio and Neil Robertson and {de Bruijn}, {Renee F. A. G.} and Ikram, {M. Arfan} and Najaf Amin and Balmforth, {Anthony J.} and Braund, {Peter S.} and Doney, {Alexander S. F.} and Angela Doering and Paul Elliott and Tonu Esko and Franco, {Oscar H.} and Solveig Gretarsdottir and Anna-Liisa Hartikainen and Kauko Heikkila and Karl-Heinz Herzig and Hilma Holm and Hottenga, {Jouke Jan} and Elina Hypponen and Thomas Illig and Aaron Isaacs and Bo Isomaa and Tobin, {Martin D.} and Smith, {George Davey} and {ENGAGE Consortium}",

year = "2013",

month = jun,

doi = "10.1371/journal.pmed.1001474",

language = "English",

volume = "10",

journal = "PLoS Medicine",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "6",

}

Fall, T, Hagg, S, Maegi, R, Ploner, A, Fischer, K, Horikoshi, M, Sarin, A-P, Thorleifsson, G, Ladenvall, C, Kals, M, Kuningas, M, Draisma, HHM, Ried, JS, van Zuydam, NR, Huikari, V, Mangino, M, Sonestedt, E, Benyamin, B, Nelson, CP, Rivera, NV, Kristiansson, K, Shen, H, Havulinna, AS, Dehghan, A, Donnelly, LA, Kaakinen, M, Nuotio, M-L, Robertson, N, de Bruijn, RFAG, Ikram, MA, Amin, N, Balmforth, AJ, Braund, PS, Doney, ASF, Doering, A, Elliott, P, Esko, T, Franco, OH, Gretarsdottir, S, Hartikainen, A-L, Heikkila, K, Herzig, K-H, Holm, H, Hottenga, JJ, Hypponen, E, Illig, T, Isaacs, A, Isomaa, B, Tobin, MD, Smith, GD & ENGAGE Consortium 2013, 'The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis', PLoS Medicine, vol. 10, no. 6, 1001474. https://doi.org/10.1371/journal.pmed.1001474

TY - JOUR

T1 - The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

AU - Fall, Tove

AU - Hagg, Sara

AU - Maegi, Reedik

AU - Ploner, Alexander

AU - Fischer, Krista

AU - Horikoshi, Momoko

AU - Sarin, Antti-Pekka

AU - Thorleifsson, Gudmar

AU - Ladenvall, Claes

AU - Kals, Mart

AU - Kuningas, Maris

AU - Draisma, Harmen H. M.

AU - Ried, Janina S.

AU - van Zuydam, Natalie R.

AU - Huikari, Ville

AU - Mangino, Massimo

AU - Sonestedt, Emily

AU - Benyamin, Beben

AU - Nelson, Christopher P.

AU - Rivera, Natalia V.

AU - Kristiansson, Kati

AU - Shen, Huei-yi

AU - Havulinna, Aki S.

AU - Dehghan, Abbas

AU - Donnelly, Louise A.

AU - Kaakinen, Marika

AU - Nuotio, Marja-Liisa

AU - Robertson, Neil

AU - de Bruijn, Renee F. A. G.

AU - Ikram, M. Arfan

AU - Amin, Najaf

AU - Balmforth, Anthony J.

AU - Braund, Peter S.

AU - Doney, Alexander S. F.

AU - Doering, Angela

AU - Elliott, Paul

AU - Esko, Tonu

AU - Franco, Oscar H.

AU - Gretarsdottir, Solveig

AU - Hartikainen, Anna-Liisa

AU - Heikkila, Kauko

AU - Herzig, Karl-Heinz

AU - Holm, Hilma

AU - Hottenga, Jouke Jan

AU - Hypponen, Elina

AU - Illig, Thomas

AU - Isaacs, Aaron

AU - Isomaa, Bo

AU - Tobin, Martin D.

AU - Smith, George Davey

AU - ENGAGE Consortium

PY - 2013/6

Y1 - 2013/6

N2 - 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: 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 pConclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

AB - 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: 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 pConclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

KW - BODY-MASS INDEX

KW - IMPAIRED GLUCOSE-TOLERANCE

KW - GENOME-WIDE ASSOCIATION

KW - HEART-FAILURE

KW - LIFE-STYLE

KW - FTO GENE

KW - DIABETES PREVENTION

KW - OBESITY

KW - RISK

KW - DISEASE

U2 - 10.1371/journal.pmed.1001474

DO - 10.1371/journal.pmed.1001474

M3 - Article (Academic Journal)

C2 - 23824655

SN - 1549-1277

VL - 10

JO - PLoS Medicine

JF - PLoS Medicine

IS - 6

M1 - 1001474

ER -

The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis

Abstract

Keywords

UN SDGs

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Projects

MRC UoB UNITE Unit - Programme 1

CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)

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