Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank

doi:10.1016/j.jaci.2019.09.035

Journal of Allergy and Clinical Immunology

Volume 145, Issue 2, February 2020, Pages 537-549

https://doi.org/10.1016/j.jaci.2019.09.035 Get rights and content

Background

Clinical and epidemiologic studies have shown that obesity is associated with asthma and that these associations differ by asthma subtype. Little is known about the shared genetic components between obesity and asthma.

Objective

We sought to identify shared genetic associations between obesity-related traits and asthma subtypes in adults.

Methods

A cross-trait genome-wide association study (GWAS) was performed using 457,822 subjects of European ancestry from the UK Biobank. Experimental evidence to support the role of genes significantly associated with both obesity-related traits and asthma through a GWAS was sought by using results from obese versus lean mouse RNA sequencing and RT-PCR experiments.

Results

We found a substantial positive genetic correlation between body mass index and later-onset asthma defined by asthma age of onset at 16 years or greater (Rg = 0.25, P = 9.56 × 10⁻²²). Mendelian randomization analysis provided strong evidence in support of body mass index causally increasing asthma risk. Cross-trait meta-analysis identified 34 shared loci among 3 obesity-related traits and 2 asthma subtypes. GWAS functional analyses identified potential causal relationships between the shared loci and Genotype-Tissue Expression (GTEx) quantitative trait loci and shared immune- and cell differentiation–related pathways between obesity and asthma. Finally, RNA sequencing data from lungs of obese versus control mice found that 2 genes (acyl-coenzyme A oxidase-like [ACOXL] and myosin light chain 6 [MYL6]) from the cross-trait meta-analysis were differentially expressed, and these findings were validated by using RT-PCR in an independent set of mice.

Conclusions

Our work identified shared genetic components between obesity-related traits and specific asthma subtypes, reinforcing the hypothesis that obesity causally increases the risk of asthma and identifying molecular pathways that might underlie both obesity and asthma.

Graphical abstract

Section snippets

Study population and design

The UK Biobank study has been previously described in detail.¹¹^,²⁰ All participants provided informed consent to the UK Biobank. Our overall study design is shown in Fig 1. To identify genetic variants that contributed to self-reported obesity traits and doctor-diagnosed asthma, we performed a GWAS using phenotype data provided for UK Biobank participants (n = 487,409). We restricted the population to 457,822 subjects of European ancestry (457,822 with BMI measures, 457,690 with WHR and WC

Single-trait GWAS results

We identified 1636 genome-wide significant independent loci associated with BMI, 1074 associated with WHRadjBMI, 1260 associated with WCadjBMI, 77 associated with later-onset asthma, 219 associated with early-onset asthma, 101 associated with nonatopic asthma, and 198 associated with atopic asthma (see Tables E2-E8 and Figs E1-E7 in this article’s Online Repository at www.jacionline.org). The genomic inflation factor intercepts from LDSC were 1.12 for BMI, 1.19 for WHRadjBMI, 1.17 for WCadjBMI,

Discussion

In the present study we found a positive genetic correlation between obesity traits and glycemic traits with later-onset and nonatopic asthma but not with early-onset and atopic asthma. Sensitivity analysis showed a significantly higher genetic correlation between later-onset asthma and WHRadjBMI in male than female subjects, but not for BMI and WCadjBMI, suggesting differences in genetic background of obesity traits in relation to asthma. A cross-trait meta-analysis identified independent

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: Supported by the National Heart, Lung, and Blood Institute, R01HL139496 (to Q.L.). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work.

View full text

Asthma and lower airway diseaseShared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank

Background

Objective

Methods

Results

Conclusions

Graphical abstract

Section snippets

Study population and design

Single-trait GWAS results

Discussion

Lancet

J Allergy Clin Immunol

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Hum Genet

Am J Hum Genet

J Biol Chem

Respir Med

J Acad Nutr Diet

Chest

J Allergy Clin Immunol

Cell Signal

Cell Metab

Ann Allergy Asthma Immunol

FEBS Lett

Biochim Biophys Acta

J Allergy Clin Immunol

J Biol Chem

Obesity and diabetes in the developing world—a growing challenge

N Engl J Med

The epidemiology of obesity and asthma

J Allergy Clin Immunol

Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

Am J Respir Crit Care Med

Adult-onset asthma: is it really different?

Eur Respir Rev

Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits

Nat Genet

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Nat Genet

A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases

Nat Genet

Shared genetic architecture between metabolic traits and Alzheimer's disease: a large-scale genome-wide cross-trait analysis

Hum Genet

Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis

Respir Res

Shared genetic variants between serum levels of high-density lipoprotein cholesterol and wheezing in a cohort of children from Cyprus

Ital J Pediatr

Analyses of shared genetic factors between asthma and obesity in children

J Allergy Clin Immunol

An expanded genome-wide association study of type 2 diabetes in Europeans

Diabetes

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Nat Genet

The impact of low-frequency and rare variants on lipid levels

Nat Genet

UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age

PLoS Med

Mixed-model association for biobank-scale data sets

Nat Genet

A reference panel of 64,976 haplotypes for genotype imputation

Nat Genet

Schizophrenia Working Group of the Psychiatric Genomics Consortium, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

Nat Genet

Sex differences: implications for the obesity-asthma association

Exerc Sport Sci Rev

Asthma and lower airway disease
Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank