The impact of cellular networks on disease comorbidity

Abstract

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.

Figure 1

(A) The fraction of patients in the Medicare database diagnosed with ICD-9-CM codes mapped to OMIM diseases. Although they represent fewer than 6% of all ICD-9-CM codes, 90% of the patients were diagnosed with at least one. (B) Breast cancer and cancer of bone and cartilage offer an example of a disease pair linked on the cellular-network level. They share two genes (CHEK2 and TP53), and their proteins interact through 13 protein–protein interactions (green lines). The average coexpression ρ̄ between the genes of each disease is 0.103. Their comorbidity between the two diseases are RR = 8.69, indicating that the number of patients who simultaneously develop both diseases shows a seven-fold increase compared with random expectation, and φ = 0.00813 (P≈6 × 10⁻⁷¹). (C) The functional domains of the TP53 protein. Breast cancer and cancer of bone and cartilage shown also constitute a domain-sharing disease pair: mutations on the TP53 protein associated with breast cancer and cancer of bone and cartilage take place on the same P53 domain.

Figure 2

(A) The Pearson correlation between comorbidity and the three quantities (n^g, n^p, ρ̄) that capture cellular-level links between diseases. See also Table I. (B) Average comorbidity for disease pairs satisfying the cellular constraints discussed in the text. See also Table II. (C–E) Average comorbidity for disease pairs with increasing values of n^g, n^p, and ρ̄.

Figure 3

Two examples of disease (disorder) pairs with significant comorbidity that are connected at the cellular level through either shared genes (A) or protein–protein interactions (A and B). (A) Alzheimer's disease and myocardial infarction (P≈10⁻⁵). (B) Autonomic nervous system disorder and carpal tunnel syndrome (P≈10⁻¹⁴⁸).