Genetics 100 for Cardiologists: Basics of Genome-Wide Association Studies

Abstract The spring of 2012 marked the fifth anniversary of the widespread appearance in the biomedical literature of genome-wide association studies (GWAS) of diseases of adulthood. Articles reporting GWAS results now regularly appear in dozens of general medicine and cardiology journals. As of August 2012, more than 1700 published GWAS have reported findings across a range of human diseases. Many of these reported new genetic determinants of cardiovascular disease, including coronary artery disease and its risk factors such as diabetes, dyslipidemia, and hypertension. Though GWAS reports follow a standard format, superficially they can appear intimidating to most nongeneticists, whom we suspect often skip over them. Considering the importance of GWAS in cardiovascular science and medicine, and because they show no signs of fading, it is important for cardiovascular medical personnel and scientists to understand GWAS fundamentals. In this article, we provide a roadmap for the nonexpert reader to navigate through GWAS of cardiovascular disease. We cover the basic essentials needed to understand GWAS: underlying theory, mechanics, analysis and display, interpretation, and relevance. Areas covered include the relationship between GWAS and standard epidemiologic study design, the concepts of DNA sequence variation and linkage disequilibrium, the particular statistical considerations in studies involving many independent variables and large sample sizes, the meaning and interpretation of Manhattan plots, and the biologic and clinical significance of GWAS-based discoveries. We conclude with comments about the limitations of GWAS and about what to look for in the “post-GWAS era.”