Heart-lung connections: Phenotypic and genetic insights from a large-scale genome-wide cross-trait analysis

Abstract Background Extensive comorbidity between cardiovascular (CVD) and respiratory (RT) diseases is well-documented, yet the shared genetic mechanisms remain elusive. Genetic pleiotropy may play a pivotal role in understanding the intricate comorbidity patterns associated with cardiovascular and respiratory conditions. Methods Our comprehensive analysis encompasses the largest available GWAS dataset of European ancestry covering six major CVDs (atrial fibrillation, coronary artery disease, venous thromboembolism, heart failure, peripheral arterial disease, and stroke) and four prevalent RTs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and sleep apnea). Initially, we aimed to unveil the common genetic basis of major CVDs, through genome-wide and local genetic correlations and polygenic overlap. Subsequently, the shared genetic mechanisms between RTs and CVDs was investigated in terms of both horizontal and vertical pleiotropy. From a horizontal pleiotropy perspective, cross-trait analysis was utilized to identify pleiotropic genetic determinants including genomic loci, single nucleotide polymorphisms (SNPs), genes, biological pathways, and protein targets. From a vertical pleiotropic perspective, Mendelian randomization was employed to evaluate potential causal relationships between CVDs and RTs. Results Our study confirmed the significant existence of genetic correlations and overlaps between CVDs and RTs. Pleiotropy analysis under the composite null hypothesis identified 17,964 significant potential pleiotropic SNPs in 24 trait pairs, with 73 pleiotropic loci and 69 colocalized loci detected. Gene-based analysis revealed 59 candidate pleiotropic genes, highly enriched in unsaturated fatty acid biosynthetic processes and MHC class I-mediated antigen processing and presentation. Mendelian randomization analysis demonstrated a positive causal relationship only between chronic obstructive pulmonary disease and heart failure. Overall, the genetic basis between CVDs and RTs was inconsistent with vertical pleiotropy, suggesting the dramatic impact of horizontal pleiotropy. Conclusions Our findings indicate widely distributed pleiotropic genetic determinants between RTs and CVDs across the genome. These results support a common genetic basis for RTs and CVDs and are important for intervention and therapeutic targets in comorbidities. Clinical Perspective What Is New? A common genetic underpinning for CVDs and RTs has been identified using a variety of approaches and further explained as a shared genetic mechanism mediated by pleiotropy. The systematic atlas of horizontal pleiotropy addressed key questions about pleiotropic SNPs, genomic loci, genes, functional features, and protein targets contributing to comorbidity between CVDs and RTs. The systematic atlas of vertical pleiotropy highlighted causal associations between CVDs and RTs beyond the observed correlations. What Are the Clinical Implications? This study may help to elucidate the shared genetic mechanism between respiratory and cardiovascular diseases and further prioritize shared drug targets between RTs and CVDs.