Accumulated wisdom cautions against dismissing the potential clinical relevance of loci that are associated with small effects as they may provide flags for potential therapeutic targets. Perhaps the most convincing example of how genetic associations with small or modest effect sizes can have great treatment potential comes when considering statins, the first line drug of choice for the treatment of high cholesterol. Statins, developed in the 1970s, work by competitively inhibiting HMG-CoA reductase within the cholesterol synthesis pathway. Subsequent candidate genetic and GWAS-based investigations linked common genetic variation within the HMG-CoA reductase gene (HMGCR) to cholesterol. However, the effect sizes of such common genetic variation on cholesterol and cardiovascular risk are miniscule (i.e., < 20×) when compared to the effect of statins (Willer and Mohlke, 2012, Barrett et al., 2015). For example, the HMGCR SNP rs12916 reduces LDL cholesterol levels by 2.5 mg/dl for each copy of the protective allele, with even smaller associations with coronary artery disease, while statins typically decrease LDL by 14–70 mg/dL. This example is not unique. Similar observations of large medication effects targeting proteins in
