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

Zhaozhong Zhu; Yanjun Guo; Huwenbo Shi; Cong-Lin Liu; Ronald Allan Panganiban; Wonil Chung; Luke J O'Connor; Blanca E Himes; Steven Gazal; Kohei Hasegawa; Carlos A Camargo Jr; Lu Qi; Miriam F Moffatt; Frank B Hu; Quan Lu; William O C Cookson; Liming Liang

doi:10.1016/j.jaci.2019.09.035

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

J Allergy Clin Immunol. 2020 Feb;145(2):537-549. doi: 10.1016/j.jaci.2019.09.035. Epub 2019 Oct 24.

Authors

Zhaozhong Zhu¹, Yanjun Guo², Huwenbo Shi³, Cong-Lin Liu⁴, Ronald Allan Panganiban⁵, Wonil Chung³, Luke J O'Connor³, Blanca E Himes⁶, Steven Gazal³, Kohei Hasegawa⁷, Carlos A Camargo Jr⁸, Lu Qi⁹, Miriam F Moffatt¹⁰, Frank B Hu¹¹, Quan Lu⁵, William O C Cookson¹⁰, Liming Liang¹²

Affiliations

¹ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Boston, Mass; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Mass; Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass. Electronic address: zhz586@mail.harvard.edu.
² Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Boston, Mass; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Boston, Mass.
⁴ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.
⁵ Program in Molecular and Integrative Physiological Sciences, Departments of Environmental Health and Genetics & Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, Mass.
⁶ Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pa.
⁷ Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
⁸ Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Boston, Mass; Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
⁹ Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, La.
¹⁰ Section of Genomic Medicine, National Heart and Lung Institute, London, United Kingdom.
¹¹ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Mass.
¹² Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Boston, Mass; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Mass. Electronic address: lliang@hsph.harvard.edu.

Abstract

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.

Keywords: Obesity; RNA sequencing; RT-PCR; asthma subtypes; genome-wide association study; metabolic disorder; shared genetics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adult
Animals
Asthma / genetics*
Biological Specimen Banks
Body Mass Index
Female
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study
Humans
Male
Mice
Obesity / genetics*
United Kingdom

Abstract

Publication types

MeSH terms

Grants and funding