Unraveling shared genetics across asthma subtypes and 81 asthma-related traits

Asthma presents clinical and biological heterogeneity.

We sought to better understand asthma heterogeneity by investigating the shared genetics between various asthma subtypes and a large number of biological and physiologic traits involved in asthma pathophysiology.

We built a harmonized comprehensive database of 254 full genome-wide association study summary statistics datasets on asthma, asthma subtypes and 81 asthma-related traits (blood cells and molecular, anthropometric, and lung function traits). We enriched this database by performing meta-analyses for asthma-related traits reported in ≥2 studies. Then we identified shared genome-wide significant loci and estimated genetic overlaps and correlations (r_g) between asthma subtypes and asthma-related traits by MiXeR software and linkage disequilibrium score regression.

Overall, asthma-associated loci were more pleiotropic than non-asthma-associated loci (median of shared traits, 4 vs 1, P = 1.3 × 10^-36). Childhood-onset and moderate-to-severe asthma had higher SNP heritability (h²_SNP ± standard error [SE], 0.27 ± 0.004 and 0.16 ± 0.02, respectively) than adult-onset asthma (0.08 ± 0.002) and asthma ever (0.06 ± 0.001). All asthma subtypes showed significant r_g with eosinophils and IgE levels (0.24 ≤ r_g ≤ 0.40, 5.1 × 10^-14 ≤ P ≤ .04), with childhood-onset asthma sharing 94% of "causal" variants with IgE, whereas other asthma subtypes shared <60%. Adult-onset asthma showed significant r_g and shared a substantial amount of causal variants with adult body mass index (r_g = 0.26, P < .007; shared variants, 84%) and forced expiratory volume in 1 second (r_g = -0.36, P < 7.7 × 10^-10; shared variants, 95%). Finally, moderate-to-severe asthma was characterized by a significant r_g with hepatocyte growth factor levels (r_g = 0.38, P = 6 × 10^-4), a potential biomarker of lung injury.

Common and specific genetic architectures underlie different asthma subtypes and can help us understand the pathophysiologic mechanisms underlying asthma heterogeneity.