Genome-wide association studies of late-onset cardiovascular disease

Highlights

• A genetic component to late-onset cardiovascular diseases has been established.

• GWAS has identified many loci contributing to risk of late-onset CVD.

• We summarize loci identified with a stringent statistical significance threshold.

• Only for a few loci have mechanisms explaining CVD association been described.

• Mechanistic insights hold promise for novel therapeutic and preventive strategies.

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 vascular and 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. This article is part of a Special Issue entitled ‘SI:CV Aging’.

Introduction

Over the 20th century, cardiovascular diseases have replaced infectious and nutritional disease as the leading cause of death globally [1], and are leading causes of hospitalization in western countries. Such diseases typically display a late onset in the lifecourse, and are associated with both mortality and greatly impaired quality of life in the elderly.

Much effort has been invested in the development of preventive as well as novel therapeutic strategies for cardiovascular disease, notably for coronary artery disease, stroke, aortic aneurysmal disease, heart failure, atrial fibrillation and valvular disease, to facilitate healthful aging. Unfortunately, more than 90% of compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval, in large part due to limited predictive value of preclinical models of disease [2], [3]. For aging-related disease, it is particularly difficult to create animal models that faithfully recapitulate human aging, as assessment of aging in animal models over extended time is often not feasible, as in studies of the degeneration of aortic valves or development of impaired myocardial relaxation with aging.

Recently, human genetics has emerged as an unbiased tool to identify novel molecular targets in late-onset human diseases, as inherited differences in protein abundance or function can identify potential therapeutic effects that may respond favorably to pharmacological modulation [2]. Recent examples of the success of this strategy within the cardiovascular field have been the rise of PCSK9 and APOC3 inhibitors, potent cholesterol- and triglyceride-lowering medications developed after loss-of-function mutations in these genes were shown to confer lowering of cholesterol and triglycerides, respectively, and protection against coronary artery disease [4], [5].

The recent progress and reduced costs of genotyping methods with arrays and next generation resequencing technologies have facilitated studies of genetic variation on a genome-wide scale. Particular success in terms of number of identified genetic loci has been observed with studies of common variants across the entire genome, termed genome-wide association studies (GWASs) [6].

The major cardiovascular diseases with a late onset in life have not traditionally been considered to be heritable, in contrast to diseases with early onset such as familial hypercholesterolemia, long QT syndrome or hypertrophic cardiomyopathy where familial aggregation was noted as early as in the 19th century. However, in recent years population-based studies have established a modest heritable component to the major cardiovascular diseases as well as many intermediate traits, motivating molecular genetic analyses of these diseases [7], [8], [9], [10], [11], [12], [13]. Genetic methods used to study early-onset Mendelian diseases, notably linkage analysis, have largely been unsuccessful in identifying variants associated with common disease, whereas GWAS has been highly successful. Importantly, even though large sample sizes are required in GWAS to detect comparatively modest genetic effects, the identification of novel genetic associations can improve our understanding of the pathophysiology of human disease and provide novel drug targets, with potentially much stronger effects on the fundamental molecular process. Therefore, GWAS has been applied to all the major cardiovascular diseases as well as for longevity and a multitude of intermediate phenotypes for cardiovascular disease, such as plasma lipids, blood pressure and myocardial repolarization [14], [15].

Importantly, GWAS has highlighted the importance of cardiovascular disease for aging and death. For example, the genetic locus most robustly associated with longevity is located at the ApoE gene. This locus has been associated both with coronary artery disease and dementia, highlighting among other things the importance of cardiovascular health for longevity [16], [17], [18], [19]. In addition, polygenic scores based on genetic variants associated with cardiovascular disease are associated with longevity (Smith JG, unpublished).

In this overview, we outline the central concepts of genome-wide association studies, describe findings from GWAS of aging-related cardiovascular phenotypes and diseases, and close with a discussion about the next steps to drawing biologic insights and potential drug targets from identified genetic loci. Most important to the cardiovascular disease spectrum at the population-level are atherosclerotic changes in the coronary and carotid circulations, as well as myocardial disease including heart failure and cardiac arrhythmia, each of which is discussed in a separate section. The clinical utility of genetic loci established as determinants of cardiovascular disease is currently limited due to comparatively modest effects and the multifactorial nature of these diseases, and is briefly discussed in a final section.