Our findings indicate that, in addition to the blood pressure variants now identified, large numbers of common genetic variants affecting blood pressure remain to be identified, and that these variants explain a significant part of the variance in blood pressure in adults and children. These non-significant, unidentified SNPs together explain a larger part of the variance than the genome wide significant SNPs only. We also showed that adult based genetic risk scores explained variance in blood pressure in children. This indicates not only that there is a polygenic effect on blood pressure in children, but more importantly, it indicates that there is overlap in variants involved with blood pressure maintenance in adults and children and that these variants act in throughout life.
In this study, we did not remove any SNPs that are in high linkage disequilibrium with each other. Pruned analyses, as presented in the Supplemental Material
, do not change our conclusion that adding more non-genome wide significant SNPs to genetic risk scores increases the variance explained by these scores. However, as expected, removing SNPs by LD pruning results in a reduction of the variance explained. Since SNPs in LD are removed randomly, in many cases informative SNPs are taken out of the analyses. Therefore a pruned analysis is expected to underestimate the true effect on the explained variance by the genetic risk scores.
The additive explained variance of genetic risk scores on blood pressure is maximizing around the Pdiscovery-threshold of 0.3 and does not increase with more liberal thresholds. This genetic risk score includes over 550k SNPs. This result suggests that SNPs with a Pdiscovery-value lower than 0.3 in the discovery sample add to the explained variance of blood pressure and that many common variants associated with blood pressure regulation have not been identified yet. SNPs with a Pdiscovery higher than 0.3 are unlikely to be associated with blood pressure. Genetic risk scores of a similar size, consisting of randomly selected SNPs, still resulted in a significant increase in explained variance when added to the baseline model without a genetic risk score. The increase in explained variance based on the random genetic risk scores was lower than the increase based on the original genetic risk score models, although this difference was small and statistically significant in only half of the presented phenotypes. This result suggests that a sufficiently large number of SNPs tags many genes throughout the genome which influence blood pressure regulation. These findings are in line with our hypothesis that blood pressure is polygenic trait and that there are many more genes involved with blood pressure than are found so far in genome wide association studies. Currently, the advantage of using genetic risk scores based on SNPs selected on their P-value in a GWAS discovery sample, as compared to genetic risk scores based on a random set of SNPs, seems to be limited. Larger GWAS discovery samples with identification of new common and rare SNPs might lead to higher explained variance.
Although there have been several mutations described causing dominant, monogenic, forms of hypertension and more of such rare variants may still be undiscovered 6
, our results support the hypothesis that hypertension is a polygenic disease, which is in part explained by a large number of genes regulating blood pressure. In our adult population, genetic risk scores including large numbers of SNPs, explain the largest proportion of variance in blood pressure, indicating the involvement of multiple genes in blood pressure regulation.
Risk scores containing highly significant SNPs, identified in large scale genome wide association meta-analyses in adults 7–8
, were significantly associated with in blood pressure in adults, but not in children. There are several explanations possible for this finding, including a smaller number of subjects and lower power in the children cohort. However, this finding might also indicate that the genome wide significant SNPs found so far are related to late-onset pathology. It has been long hypothesized that there is a common polygenic regulation of blood pressure in adults and children. This is the first study showing evidence of such a mechanism.
It has been shown in literature that blood pressure tracks from childhood to adulthood 15
. This study indicates that genes are explaining a part of the blood pressure tracking over life. We show that the same set of genes, based on an adult discovery sample, explain part of the variation in blood pressure in both adults and children. We also showed that these SNP sets explain variation in hypertension in adults, indicating also a polygenic origin of hypertension. It has been shown that high blood pressure in childhood predisposes to hypertension in adulthood 16
. Adult based genetic risk scores do not explain variance in childhood hypertension in children significantly. This fits with the common view that causes of juvenile hypertension are different from adult hypertension 11
The percentage of explained variance by genetic risk scores is still low, although the heritability has been shown to be substantial 4
, yet compared to the variance explained by the genome wide significant SNPs on blood pressure found so far, there is a 4–5 fold increase in explained variance of blood pressure in our target samples.
In the coming years the variance explained by polygenic models may be improved further, using technology, such as whole genome sequencing, which can be used to identify low frequency variants. We used common variants only (MAF >0.01) to create genetic risk scores. Low frequency variants may add to the variance explained by these genetic risk scores. Also, we assumed an additive model, similar to the discovery analysis. We have to recognize that the biology of the genes involved in blood pressure regulation and possible interactions between these genes are unknown. Another possibility would be to construct genetic risk scores based on SNPs included in candidate biological pathways. A genetic risk score including SNPs from the FGF signaling pathway 14
seemed to explain a larger proportion explained variance in hypertension as compared to a genetic risk score including a similar number of SNPs, based on the previous top SNPs from the GWAS. This indicates that prior knowledge on biological models and underlying mechanisms might improve the explained variance by genetic risk scores. Alternative methods of constructing genetic risk scores may be better when further research reveals more of the underlying genetic biology of blood pressure regulation.
Specific common variants that are associated with blood pressure still need to be identified. Much research is still needed to identify more and specific genes associated with blood pressure regulation in adults. If these common variants overlap with blood pressure regulation in children, they could provide clues for early etiology of hypertension.