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

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.

Figure 1.

Overall study design. UKBB: UK Biobank; LDSC: LD score regression. GSMR: generalized summary data-based Mendelian Randomization; LCV: Latent Causal Variable model

Figure 2.

Genome-wide genetic correlation between 4 types of asthma and metabolic traits The color of each box scales with the magnitude of the genetic correlation. Pairs of traits with nominal significant genetic correlation (p < 0.05) are marked by 1 star, and pairs of traits with significant genetic correlation after correcting for multiple testing (p < 0.05/40) are marked by 2 stars.

Figure 3:

ACOXL and MYL6 expression in lean and obese mice (A) RNA-seq detected ACOXL differential expression in lung tissue from wild-type (WT)(C57BL/6J) and db/db mice (n = 4 mice/group) (B) RNA-seq detected MYL6 differential expression in lung tissue from low fat diet (LFD) and high fat diet (HFD) mice (n = 4 mice/group). (C) RT-PCR detected ACOXL differential expression in lung tissue from WT and db/db mice (n = 6 mice/group). (D) RT-PCR detected MYL6 differential expression in lung tissue from LFD and HFD mice (n = 4 mice/group). (E) RT-PCR detected MYL6 expression in lung tissue from HFD mice at different time points (n = 4 mice/time point).