Our study replicates the association between CHD risk and rs1333049 close to the CDKN2A/2B gene, rs618675 in the GJA4 gene, and rs1376251 in the TAS2R50 gene, in Caucasians. However, the number of events (maximum of 137 for CHD) was small. Thus, we had limited power to detect association for each individual SNP and our study results need to be validated in different, large population-based studies.
We assessed here the impact of the known cardiovascular disease genes/loci on the population burden of CHD over time, based on data from the Framingham Heart Study Offspring Cohort. Static PAFs have been extensively used to rank risk factors and to assess the prospective gains in disease prevention. In this study, we extended the static estimation of PAFs and evaluated how the population impact of genetic variants changed over the life course of CHD, as shown in the PAF plot (Figure ). The unadjusted PAFs associated with genetic variants slightly decreased as age advanced, whereas adjusted PAFs showed a subtle increase with age, which may be due to the small number of events in these data, especially in the early and late age groups. For example, only six CHD events occurred before the age of 45, whereas eight events occurred after 75. However, we observed much higher PAFs for the risk score compared with each individual SNP, suggesting the importance of evaluating multiple genetic variants for the population impact analysis.
While the use of the risk score summary metric was useful in this population in which no single SNP achieved a large PAF, these estimates should be interpreted with caution because any time we combine SNP effects based on statistical significance and effect size, we will automatically obtain an improved effect estimate and p-value.