Abstract
Background: Accumulating evidence has suggested that there is a positive association between asthma and cardiovascular diseases (CVDs), implying a common architecture between them. However, the shared genetic architecture and causality of asthma and CVDs remain unclear. Methods: Based on the genome-wide association study (GWAS) summary statistics of recently published studies, our study examined the genetic correlation, shared genetic variants, and causal relationship between asthma (N = 127,669) and CVDs (N = 86,995–521,612). Statistical methods included high-definition likelihood (HDL), cross-trait meta-analyses of large-scale GWAS, transcriptome-wide association studies (TWAS), and Mendelian randomization (MR). Results: First, we observed a significant genetic correlation between asthma and heart failure (HF) (Rg = 0.278, P = 5 × 10−4). Through cross-trait analyses, we identified a total of 145 shared loci between asthma and HF. Fifteen novel loci were not previously reported for association with either asthma or HF. Second, we mapped these 145 loci to a total of 99 genes whose expressions are enriched in a broad spectrum of tissues, including the seminal vesicle, tonsil, appendix, spleen, skin, lymph nodes, breast, cervix and uterus, skeletal muscle, small intestine, lung, prostate, cardiac muscle, and liver. TWAS analysis identified five significant genes shared between asthma and HF in tissues from the hemic and immune system, digestive system, integumentary system, and nervous system. GSDMA, GSDMB, and ORMDL3 are statistically independent genetic effects from all shared TWAS genes between asthma and HF. Third, through MR analysis, genetic liability to asthma was significantly associated with heart failure at the Bonferroni-corrected significance level. The odds ratio (OR) is 1.07 [95% confidence interval (CI): 1.03–1.12; p = 1.31 × 10−3] per one-unit increase in loge odds of asthma. Conclusion: These findings provide strong evidence of genetic correlations and causal relationship between asthma and HF, suggesting a shared genetic architecture for these two diseases.
Highlights
Asthma is a heterogeneous disease with a strong genetic basis and is a major global public health problem worldwide due to its high prevalence and inadequate disease control (Barnes, 2011; Yang et al, 2017)
Estimates of genetic correlation using genome-wide association study (GWAS) summary statistics data are shown in Table 1 (SNP-based heritability estimated by high-definition likelihood (HDL) is shown in Supplementary Table S2)
Previous studies reported that GSDMB and ORMDL3 are associated with asthma (Zhao et al, 2015), but their association with heart failure (HF) was not reported
Summary
Asthma is a heterogeneous disease with a strong genetic basis and is a major global public health problem worldwide due to its high prevalence and inadequate disease control (Barnes, 2011; Yang et al, 2017). Cardiovascular diseases (CVDs) including heart failure (HF) are a rapidly growing public health threat globally (Roth et al, 2017) and confer a substantial burden to the healthcare system (Ziaeian and Fonarow, 2016). Both asthma and CVDs have increased over the past several decades, measured by disease incidence rate (for asthma) or prevalence (for CVDs) (Gottdiener, 2017). The shared genetic architecture and causality of asthma and CVDs remain unclear
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