Cardiovascular Disease: From Genetics to Therapeutics

Dear Colleagues,

Human genetic studies, including common and rare variant association studies (GWAS, RVAS), phenotypic analyses in large biobanks (PheWAS) and other “omics” approaches (QTL, TWAS, and single cell studies), have identified thousands of genetic risk signals associated with cardiovascular disease and related phenotypes. These genetic data hold great potential for the discovery of novel disease mechanisms, drug targets, and therapeutic approaches. For example, most of the over 200 loci associated with coronary artery disease are not associated with circulating cholesterol or blood pressure (the two major risk factors for which we have effective therapeutics), suggesting the presence of additional disease mechanisms that are not currently being therapeutically targeted.

Discovering these new disease mechanisms, however, remains challenging because ~80% of likely causal disease variants are in non-coding regions of the genome. These variants likely modify the activities of regulatory elements, such as enhancers, that can each regulate multiple target genes, at great distances, and which can be highly cell type-specific. Moreover, determining the causal noncoding variant within a linkage disequilibrium block is difficult, relative to coding variants, because of limitations in our predictive tools. Even for coding variants, it remains non-trivial to understand their connections to disease. Accordingly, it has been extremely difficult to determine the target gene, relevant cell type, and mechanism for the vast majority of disease-associated loci.

Cardiovascular disease remains the leading cause of death worldwide, and there is a great unmet need for novel classes of therapeutics that might be discovered if we could unlock the ever-increasing wealth of information from human genetic studies. The challenge for the field, then, is to find ways to accelerate variant-to-function discovery for cardiovascular disease. This will require the development of better computational models to predict variant functions and higher throughput approaches to link variants to molecular and cellular phenotypes, together with an intensified effort to discover disease mechanisms for individual causal genes and pathways and to develop new therapeutics to target them.

This Special Issue cordially invites novel studies and review articles that address all aspects of genetics-to-therapeutics discovery for cardiovascular disease, including new genetic analyses/meta-analyses, predictive modeling, high-throughput variant-to-function approaches, single cell studies that identify pathogenic cell types or transcriptomic signatures, dissection of variant-to-disease mechanisms at individual loci, and efforts to develop new therapeutics targeting known or novel causal genes and pathways.

Dr. Gavin Schnitzler
Guest Editor

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• cardiovascular disease
• genetics
• variant to function
• causal genes
• disease mechanism
• drug discovery