| Abstrakt: |
Genome-wide association studies (GWAS) have been valuable for the identification of genetic factors associated with complex diseases or traits. GWAS findings can be enhanced if analysed in the context of protein-protein interaction (PPI) networks, as the related pathophysiology results from dysfunction of interacting polyprotein pathways. In a recent study, we reconstructed the PPI network of blood pressure regulation (BP) based on a systematically-curated GWAS meta-database and network extension principles. Our meta-database enables the selection of GWAS-data of different ancestries and/or different Ensembl-defined transcript consequence severities. Thus, this study aimed at investigating any differences in the BP PPI network, due to (a) ancestry, by comparing the most-abundant European and Asian ancestry GWAS datasets, and (b) variant consequence severity, by excluding single nucleotide polymorphisms (SNPs) involved only in “modifier” categories, of difficult to predict impact. We identified that 82% of the collected BP-SNPs are from European-specific studies, with only 11% from Asian-specific, validating the need to augment the GWAS-data from other than European ancestries. Thus, only 7% vs 83% of the 1170 BP GWAS-proteins originate from Asian- and European-specific studies, respectively, with 2% (24) identified as Asian-specific vs ∼45% (524) as European-specific GWAS-proteins. In the second part of the study, we found that the vast majority (85%) of the BP-SNPs with protein-coding transcript consequences are only intron variants (‘modifier’ category). Hence, the PPI network based on the SNPs in other than “modifier” categories included 142 proteins, with 12 in the largest connected component. However, while the relevant interactome is much smaller than the full, when extended based on our shortest-path approach, it revealed the same BP-significant pathways. This result supports the need to upgrade the information content of GWAS-data through network analysis. |
