Phenome-wide association network demonstrates close connection with individual disease trajectories from the HUNT study

Disease networks offer a potential road map of connections between diseases. Several studies have created disease networks where diseases are connected either based on shared genes or Single Nucleotide Polymorphism (SNP) associations. However, it is still unclear to which degree SNP-based networks map to empirical, co-observed diseases within a different, general, adult study population spanning over a long time period. We created a SNP-based phenome-wide association network (PheNet) from a large population using the UK biobank phenome-wide association studies. Importantly, the SNP-associations are unbiased towards much studied diseases, adjusted for linkage disequilibrium, case/control imbalances, as well as relatedness. We map the PheNet to significantly co-occurring diseases in the Norwegian HUNT study population, and further, identify consecutively occurring diseases with significant ordering in occurrence, independent of age and gender in the PheNet. Our analysis reveals an overlap far larger than expected by chance between the two disease networks, with diseases typically connecting within their own category. Upon examining the sequential occurrence of diseases in the HUNT dataset, we find a giant component consisting of mostly cardiovascular disorders. This allows us to identify sequentially occurring diseases that are genetically linked and co-occur frequently, while also highlighting non-sequential diseases. Furthermore, we observe that survivors of severe cardiovascular diseases subsequently often face less severe conditions, but with a reduced time until their next fatal illness. The HUNT sub-PheNet showing both genetically and co-observed diseases offers an interesting framework to study groups of diseases and examine if they, in fact, are comorbidities. We find that the HUNT sub-PheNet offers the possibility to pinpoint exactly which mutation(s) constitute shared cause of the diseases. This could be of great benefit to both researchers and clinicians studying relationships between diseases.