Shared Genetic Architecture and Causal Relationship Between Asthma and Cardiovascular Diseases: A Large-Scale Cross-Trait Analysis

Yi Zhou; Zhi-Sheng Liang; Yinzi Jin; Jiayuan Ding; Tao Huang; Jason H Moore; Zhi-Jie Zheng; Jie Huang

doi:10.3389/fgene.2021.775591

Shared Genetic Architecture and Causal Relationship Between Asthma and Cardiovascular Diseases: A Large-Scale Cross-Trait Analysis

Front Genet. 2022 Jan 20:12:775591. doi: 10.3389/fgene.2021.775591. eCollection 2021.

Authors

Yi Zhou¹, Zhi-Sheng Liang¹, Yinzi Jin¹, Jiayuan Ding², Tao Huang^{1

3}, Jason H Moore⁴, Zhi-Jie Zheng^{1

5}, Jie Huang^{1

5}

Affiliations

¹ Department of Global Health, School of Public Health, Peking University, Beijing, China.
² College of Arts and Sciences, Boston University, Boston, MA, United States.
³ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
⁴ Department of Biostatistics, Epidemiology and Informatics, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, United States.
⁵ Institute for Global Health and Development, Peking University, Beijing, China.

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 log_e 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.

Keywords: Mendelian randomization; asthma; genetic correlation; heart failure; shared genetics.