Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation.

Matthew J Bown ,Caroline J Bull ,Christopher Kabrhel,L.c Tsoi ,E Louise Thomas ,Richard S Houlston ,James T Elder ,Emma E Vincent ,Susan Martin,Hanieh Yaghootkar,Robin N Beaumont,Philip Law,Andrew R Wood ,Naveed Sattar,Jessica Tyrrell,Ian Tomlinson ,Timothy M Frayling ,Marc J Gunter ,Malcolm Dunlop ,Nikos Papadimitriou,Joshua A Bell ,Jimmy D Bell ,Philip E Stuart

doi:10.7554/elife.72452

Abstract

Some individuals living with obesity may be relatively metabolically healthy, whilst others suffer from multiple conditions that may be linked to adverse metabolic effects or other factors. The extent to which the adverse metabolic component of obesity contributes to disease compared to the non-metabolic components is often uncertain. We aimed to use Mendelian randomisation (MR) and specific genetic variants to separately test the causal roles of higher adiposity with and without its adverse metabolic effects on diseases. We selected 37 chronic diseases associated with obesity and genetic variants associated with different aspects of excess weight. These genetic variants included those associated with metabolically 'favourable adiposity' (FA) and 'unfavourable adiposity' (UFA) that are both associated with higher adiposity but with opposite effects on metabolic risk. We used these variants and two sample MR to test the effects on the chronic diseases. MR identified two sets of diseases. First, 11 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here, MR with the FA and UFA genetics showed opposing effects on risk of disease: coronary artery disease, peripheral artery disease, hypertension, stroke, type 2 diabetes, polycystic ovary syndrome, heart failure, atrial fibrillation, chronic kidney disease, renal cancer, and gout. Second, 9 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) are likely a cause. Here, MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, both indicated higher disease risk: osteoarthritis, rheumatoid arthritis, osteoporosis, gastro-oesophageal reflux disease, gallstones, adult-onset asthma, psoriasis, deep vein thrombosis, and venous thromboembolism. Our results assist in understanding the consequences of higher adiposity uncoupled from its adverse metabolic effects, including the risks to individuals with high body mass index who may be relatively metabolically healthy. Diabetes UK, UK Medical Research Council, World Cancer Research Fund, National Cancer Institute.

Highlights

Obesity is associated with a higher risk of many diseases, notably metabolic conditions such as type 2 diabetes, but many individuals are often relatively metabolically healthy compared to others of similar body mass index (BMI)
Of these 37, 5 metabolic conditions were part of our previous study that validated the use of favourable adiposity” (FA) and unfavourable adiposity’ (UFA) genetic variants as a way of partially separating the metabolic from non- metabolic components of higher adiposity (Martin et al, 2021)
Mendelian randomisation (MR) using the UFA genetic variants indicated that higher adiposity with its adverse metabolic consequences was causal to disease, whilst MR using the FA genetic variants indicated that higher adiposity with favourable metabolic effects was protective. (ii) Diseases with evidence that there is a non-metabolic causal effect

Summary

Introduction

Obesity is associated with a higher risk of many diseases, notably metabolic conditions such as type 2 diabetes, but many individuals are often relatively metabolically healthy compared to others of similar body mass index (BMI). Whilst these metabolically healthier individuals may be at lower risk of some obesity-related conditions, they may be at risk of conditions that are linked to other aspects of obesity, such as the load-b earing effects. To better understand the disease consequences of obesity, many previous studies have used the approach of Mendelian randomisation (MR) (Smith and Ebrahim, 2004) These studies used common genetic variants robustly associated with BMI as proxies for obesity to assess the causal effects of higher BMI on many diseases.

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