Most diseases are the consequence of the breakdown of cellular processes, but the relationships among genetic/epigenetic defects, the molecular interaction networks underlying them, and the disease phenotypes remain poorly understood. To gain insights into such relationships, here we constructed a bipartite human disease association network in which nodes are diseases and two diseases are linked if mutated enzymes associated with them catalyze adjacent metabolic reactions. We find that connected disease pairs display higher correlated reaction flux rate, corresponding enzyme-encoding gene coexpression, and higher comorbidity than those that have no metabolic link between them. Furthermore, the more connected a disease is to other diseases, the higher is its prevalence and associated mortality rate. The network topology-based approach also helps to uncover potential mechanisms that contribute to their shared pathophysiology. Thus, the structure and modeled function of the human metabolic network can provide insights into disease comorbidity, with potentially important consequences for disease diagnosis and prevention.

We investigate the avalanche dynamics of the Bak-Tang-Wiesenfeld sandpile model on scale-free (SF) networks, where the threshold height of each node is distributed heterogeneously, given as its own degree. We find that the avalanche size distribution follows a power law with an exponent tau. Applying the theory of the multiplicative branching process, we obtain the exponent tau and the dynamic exponent z as a function of the degree exponent gamma of SF networks as tau=gamma divided by (gamma-1) and z=(gamma-1) divided by (gamma-2) in the range 23, with a logarithmic correction at gamma=3. The analytic solution supports our numerical simulation results. We also consider the case of a uniform threshold, finding that the two exponents reduce to the mean-field ones.

The impact of disease-causing defects is often not limited to the products of a mutated gene but, thanks to interactions between the molecular components, may also affect other cellular functions, resulting in potential comorbidity effects. By combining information on cellular interactions, disease-gene associations, and population-level disease patterns extracted from Medicare data, we find statistically significant correlations between the underlying structure of cellular networks and disease comorbidity patterns in the human population. Our results indicate that such a combination of population-level data and cellular network information could help build novel hypotheses about disease mechanisms.