Contribution of Regulatory-Gene Networks to Heritability of Coronary Artery Disease

Central Illustration. Environmentally triggered eSNPs of cellular gene networks contribute to CAD heritability. ( A ) Schematics of the macro- and micro levels of gene-environmental interactions. Macro-environmental factors (e.g., lifestyle, food intake and smoking) interact with genetic variants in organs to change the micro-environment in cellular networks leading to CAD. ( B )Schematics of environmental and genetic risk for complex diseases over a lifetime. One fraction (10–25%) of inherited risk for complex diseases (H 2 ) with the strongest penetrance is characterized by genetic variants promoting disease development independent of parallel environmental risk factors and thus, likely influence disease development already from early stages in life (“G”, upper life span axis). Similarly, there may also be a smaller fraction (10–25%) of penetrant environmental risk factors driving disease independently of the genetic makeup of an individual (“E”, lower life span axis). However, research in cell cultures has shown that a large fraction of SNPs affecting gene expression (eSNPs) in genetically identical cells is altered depending on parallel environmental perturbations.( 47 ) Accordingly, it is feasible that the largest fraction (50–80%) of inherited risk (H 2 ) for complex diseases constitutes SNPs which disease-driving effects only transpire at stages in a life when triggering environmental factors are present (“GxE”, middle life span axis). An example of a triggering environmental factor can be that of fatty diet or smoking, but also a certain age. ( C ) Fractions of genetic factors contributing to the heritability (H 2 ) of CAD. Coronary artery disease (CAD), the cause of myocardial infarction, is partly inherited. Yet less than 25% of CAD heritability has thus far been accounted for by genome-wide association studies (GWAS). Using two recent genetics of gene expression studies, we sought additional heritability contributions from regulatory gene networks (RGNs) active in CAD. Genetic variants of the RGNs contribute to additional 10 % of CAD heritability beyond the 25% previously identified by GWAS. This novel fraction of genetic variants should help to improve clinical risk predictions of CAD and myocardial infarction, and the RGNs provide new mechanistic insights into the etiology of CAD.