The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis

Tove Fall; Sara Hägg; Reedik Mägi; 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; Renée F A G de Bruijn; M Arfan Ikram; Najaf Amin; Anthony J Balmforth; Peter S Braund; Alexander S F Doney; Angela Döring; Paul Elliott; Tõnu Esko; Oscar H Franco; Solveig Gretarsdottir; Anna-Liisa Hartikainen; Kauko Heikkilä; Karl-Heinz Herzig; Hilma Holm; Jouke Jan Hottenga; Elina Hyppönen; Thomas Illig; Aaron Isaacs; Bo Isomaa; Lennart C Karssen; Johannes Kettunen; European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium

doi:10.1371/journal.pmed.1001474

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis

Tove Fall^*, Sara Hägg, Reedik Mägi, 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, Renée F A G de Bruijn, M Arfan Ikram, Najaf Amin, Anthony J Balmforth, Peter S Braund, Alexander S F Doney, Angela Döring, Paul Elliott, Tõnu Esko, Oscar H Franco, Solveig Gretarsdottir, Anna-Liisa Hartikainen, Kauko Heikkilä, Karl-Heinz Herzig, Hilma Holm, Jouke Jan Hottenga, Elina Hyppönen, Thomas Illig, Aaron Isaacs, Bo Isomaa, Lennart C Karssen, Johannes Kettunen, European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium

^*Corresponding author for this work

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

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 < 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: 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
Pages (from-to)	e1001474
Journal	PLOS Medicine
Volume	10
Issue number	6
DOIs	https://doi.org/10.1371/journal.pmed.1001474
Publication status	Published - 2013
Externally published	Yes

Keywords

Adiposity/genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Body Mass Index
Cardiovascular Diseases/genetics
Case-Control Studies
Confounding Factors, Epidemiologic
Genetic Association Studies
Humans
Mendelian Randomization Analysis
Meta-Analysis as Topic
Polymorphism, Single Nucleotide/genetics
Proteins/genetics
Quantitative Trait, Heritable

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Fall, T., Hägg, S., Mägi, 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., ... European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium (2013). The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. PLOS Medicine , 10(6), e1001474. https://doi.org/10.1371/journal.pmed.1001474

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

keywords = "Adiposity/genetics, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Mass Index, Cardiovascular Diseases/genetics, Case-Control Studies, Confounding Factors, Epidemiologic, Genetic Association Studies, Humans, Mendelian Randomization Analysis, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Proteins/genetics, Quantitative Trait, Heritable",

author = "Tove Fall and Sara H{\"a}gg and Reedik M{\"a}gi 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}, {Ren{\'e}e 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 D{\"o}ring and Paul Elliott and T{\~o}nu Esko and Franco, {Oscar H} and Solveig Gretarsdottir and Anna-Liisa Hartikainen and Kauko Heikkil{\"a} and Karl-Heinz Herzig and Hilma Holm and Hottenga, {Jouke Jan} and Elina Hypp{\"o}nen and Thomas Illig and Aaron Isaacs and Bo Isomaa and Karssen, {Lennart C} and Johannes Kettunen and {European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium}",

year = "2013",

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

language = "English",

volume = "10",

pages = "e1001474",

journal = "PLOS Medicine ",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "6",

}

Fall, T, Hägg, S, Mägi, 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-Y, 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, Döring, A, Elliott, P, Esko, T, Franco, OH, Gretarsdottir, S, Hartikainen, A-L, Heikkilä, K, Herzig, K-H, Holm, H, Hottenga, JJ, Hyppönen, E, Illig, T, Isaacs, A, Isomaa, B, Karssen, LC, Kettunen, J & European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium 2013, 'The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis', PLOS Medicine , vol. 10, no. 6, pp. e1001474. https://doi.org/10.1371/journal.pmed.1001474

TY - JOUR

T1 - The role of adiposity in cardiometabolic traits

T2 - a Mendelian randomization analysis

AU - Fall, Tove

AU - Hägg, Sara

AU - Mägi, 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, Renée F A G

AU - Ikram, M Arfan

AU - Amin, Najaf

AU - Balmforth, Anthony J

AU - Braund, Peter S

AU - Doney, Alexander S F

AU - Döring, Angela

AU - Elliott, Paul

AU - Esko, Tõnu

AU - Franco, Oscar H

AU - Gretarsdottir, Solveig

AU - Hartikainen, Anna-Liisa

AU - Heikkilä, Kauko

AU - Herzig, Karl-Heinz

AU - Holm, Hilma

AU - Hottenga, Jouke Jan

AU - Hyppönen, Elina

AU - Illig, Thomas

AU - Isaacs, Aaron

AU - Isomaa, Bo

AU - Karssen, Lennart C

AU - Kettunen, Johannes

AU - European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium

PY - 2013

Y1 - 2013

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

KW - Adiposity/genetics

KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO

KW - Body Mass Index

KW - Cardiovascular Diseases/genetics

KW - Case-Control Studies

KW - Confounding Factors, Epidemiologic

KW - Genetic Association Studies

KW - Humans

KW - Mendelian Randomization Analysis

KW - Meta-Analysis as Topic

KW - Polymorphism, Single Nucleotide/genetics

KW - Proteins/genetics

KW - Quantitative Trait, Heritable

U2 - 10.1371/journal.pmed.1001474

DO - 10.1371/journal.pmed.1001474

M3 - Article

C2 - 23824655

SN - 1549-1277

VL - 10

SP - e1001474

JO - PLOS Medicine

JF - PLOS Medicine

IS - 6

ER -

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis

Abstract

Keywords

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