Genome-wide association studies of late-onset cardiovascular disease

Abstract

Human genetics is a powerful tool for discovering causal mediators of human disease and physiology. Cardiovascular diseases with late onset in the lifecourse have historically not been considered genetic diseases, but in recent years the contribution of a heritable factor has been established. More importantly, over the last decade genome-wide association studies (GWASs) have identified many loci associated with late-onset cardiovascular diseases including coronary artery disease, carotid artery disease, ischemic stroke, aortic aneurysm, peripheral vascular disease, atrial fibrillation, valvular disease and correlates of myocardial function. Here we review findings from GWASs considered statistically robust with regard to multiple testing (p<5×10−8) for late-onset cardiovascular diseases and traits. Although for only a handful of the 92 genetic loci described here have the mechanisms underlying disease association been established, new and previously unsuspected pathways have been implicated for several conditions. Examples include a role for NO signaling in myocardial repolarization and sudden cardiac death and a role for the protein sortilin in lipid metabolism and coronary artery disease. Genetic loci with multiple trait associations have also provided novel biological insights. For example, of the 46 genetic loci associated with coronary artery disease, only 16 are also associated with conventional risk factors for cardiovascular disease whereas the remaining two thirds may reflect novel pathways. Much work remains to functionally characterize genetic loci and for clinical utility, but accruing insights into the biological basis of cardiovascular aging in human populations promise to point to novel therapeutic and preventive strategies.

Genomic structural variations for cardiovascular and metabolic comorbidity

“…We observed no candidate genes overlap between CNVs identified in our study and SNPs associated with coronary artery disease on a genome-wide level24. This result confirms the idea that CNVs could be new genetic markers to uncover susceptibility loci for future disease association studies.…”

Genetic Variation in Cardiomyopathy and Cardiovascular Disorders

“…This common variant/common disease hypothesis formed the basis of many genomewide association studies (GWAS), and consistent with this, many genetic loci have been identified through GWAS studies for cardiovascular traits including hypertension, infarction, EKG intervals, heart failure and sudden death 11 . The contribution of any given GWAS-identified locus to the phenotype in the population is relatively small.…”

Endocardial Notch Signaling in Cardiac Development and Disease

“…68,77 Thus, animal model studies shed light into how Notch2 and Jag1 mutations interact to create a more representative mouse model of AGS and provided an explanation of the variable phenotypic expression observed in patients with AGS. 73 The advent of next-generation sequencing technology 146 coupled with efficient DNA capture 147 has enabled the use of exome sequencing as a new approach to study the genetic basis of human disease that combined with genome-wide association studies, 148 is a powerful tool to identify the basis of complex genetic traits. Genomic editing technologies such as Crispr/Cas9 opens the door for the relatively rapid generation of inactivating mutations in new disease-candidate genes identified by genome-wide association studies 149,150 and the generation of potentially pathogenic mutations identified by exome sequencing 150 or by any other next-generation sequencing-related approach.…”