Figure 1 Evolution of genetic concepts underlying risk of cardiovascular disease Figure 1 | Evolution of genetic concepts underlying risk of cardiovascular disease. The number of chromosomal loci known to affect cardiovascular disease (CVD) risk with genome-wide significance almost doubled in 2017. Likewise, the implications of genetic variations on their expression levels have become more transparent through large-scale RNA sequencing studies. Even more genetic variants will be found to affect CVD risk in the foreseeable future, given that thousands of genes have a role in one of the cell types involved in the pathogenesis of CVD, most of these genes carry variants that affect their expression level, and respective gene products interact at the protein level. These variants might include somatic mutations (those occurring in stem cells causing clonal expansion). Some of the genetic variants will have immediate mechanistic implications and, therefore, larger effects on CVD risk, whereas others might have less functional relevance. Conversely, the complete loss of a gene (knockout) can be compensated for in an individual, without an obvious phenotype. A crucial task for the future will be to unravel the mechanisms of how genetic variations propagate risk factors or lead to CVD. Schunkert, H. (2017) Expanding the spectrum of CVD genetics Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.209