Dataset Information

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.

SUBMITTER: Fall T

PROVIDER: S-EPMC3692470 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

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

Fall Tove T Hägg Sara S Mägi Reedik R Ploner Alexander A Fischer Krista K Horikoshi Momoko M Sarin Antti-Pekka AP Thorleifsson Gudmar G Ladenvall Claes C Kals Mart M Kuningas Maris M Draisma Harmen H M HH Ried Janina S JS van Zuydam Natalie R NR Huikari Ville V Mangino Massimo M Sonestedt Emily E Benyamin Beben B Nelson Christopher P CP Rivera Natalia V NV Kristiansson Kati K Shen Huei-Yi HY Havulinna Aki S AS Dehghan Abbas A Donnelly Louise A LA Kaakinen Marika M Nuotio Marja-Liisa ML Robertson Neil N de Bruijn Renée F A G RF Ikram M Arfan MA Amin Najaf N Balmforth Anthony J AJ Braund Peter S PS Doney Alexander S F AS Döring Angela A Elliott Paul P Esko Tõnu T Franco Oscar H OH Gretarsdottir Solveig S Hartikainen Anna-Liisa AL Heikkilä Kauko K Herzig Karl-Heinz KH Holm Hilma H Hottenga Jouke Jan JJ Hyppönen Elina E Illig Thomas T Isaacs Aaron A Isomaa Bo B Karssen Lennart C LC Kettunen Johannes J Koenig Wolfgang W Kuulasmaa Kari K Laatikainen Tiina T Laitinen Jaana J Lindgren Cecilia C Lyssenko Valeriya V Läärä Esa E Rayner Nigel W NW Männistö Satu S Pouta Anneli A Rathmann Wolfgang W Rivadeneira Fernando F Ruokonen Aimo A Savolainen Markku J MJ Sijbrands Eric J G EJ Small Kerrin S KS Smit Jan H JH Steinthorsdottir Valgerdur V Syvänen Ann-Christine AC Taanila Anja A Tobin Martin D MD Uitterlinden Andre G AG Willems Sara M SM Willemsen Gonneke G Witteman Jacqueline J Perola Markus M Evans Alun A Ferrières Jean J Virtamo Jarmo J Kee Frank F Tregouet David-Alexandre DA Arveiler Dominique D Amouyel Philippe P Ferrario Marco M MM Brambilla Paolo P Hall Alistair S AS Heath Andrew C AC Madden Pamela A F PA Martin Nicholas G NG Montgomery Grant W GW Whitfield John B JB Jula Antti A Knekt Paul P Oostra Ben B van Duijn Cornelia M CM Penninx Brenda W J H BW Smith George Davey GD Kaprio Jaakko J Samani Nilesh J NJ Gieger Christian C Peters Annette A Wichmann H Erich HE Boomsma Dorret I DI de Geus Eco J C EJ Tuomi TiinaMaija T Power Chris C Hammond Christopher J CJ Spector Tim D TD Lind Lars L Orho-Melander Marju M Palmer Colin Neil Alexander CN Morris Andrew D AD Groop Leif L Järvelin Marjo-Riitta MR Salomaa Veikko V Vartiainen Erkki E Hofman Albert A Ripatti Samuli S Metspalu Andres A Thorsteinsdottir Unnur U Stefansson Kari K Pedersen Nancy L NL McCarthy Mark I MI Ingelsson Erik E Prokopenko Inga I

PLoS medicine 20130625 6

<h4>Background</h4>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.<h4>Methods and findings</h4>We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index ( ...[more]

PMID: 23824655

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Project description:BackgroundMendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear.ObjectiveWe aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization.MethodsWe constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y.ResultsWHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal.ConclusionsAbdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Project description:BackgroundEarlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.Methods and findingsOne-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with -1.38 kg/m2 of BMI at age 18 y (or -0.34 SD units, 95% CI -0.46, -0.23; P = 9.77 × 10-09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI -0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or -0.39 SDs, 95% CI -0.50, -0.29; P = 6.28 × 10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26 y, 95% CI -0.37, -0.16; P = 1.16 × 10-06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI -0.21, -0.12; P = 4.00 × 10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10-15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.ConclusionsOur results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.

Project description:Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10-8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.

Dataset Information

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

Background

Methods and findings

Conclusions

Publications

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

Similar Datasets

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