Mapping disease connections

Bipolar linked to HSP. HSP and Bipolar disorder may share some common underlying molecular mechanism.

Bipolar disorder is linked to Alzheimer’s disease and Schizophrenia; all three of which are Mental Disorders. But it is also linked to Hereditary Spastic Paraplegia (HSP) which is not a Mental Disorder, but regarded as a neuromuscular disease. Indeed, our disease network also links HSP to a number of muscular diseases such as Dermatomyositis and Muscular Dystrophies (Table 1 and Supplementary Table S6 online).

The novel gene expression connection between HSP and Bipolar disorder indicates that they may share some common underlying molecular mechanism.

BACKGROUND: Drug repositioning offers the possibility of faster development times and reduced risks in drug discovery. With the rapid development of high-throughput technologies and ever-increasing accumulation of whole genome-level datasets, an increasing number of diseases and drugs can be comprehensively characterized by the changes they induce in gene expression, protein, metabolites and phenotypes.

METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic, large-scale analysis of genomic expression profiles of human diseases and drugs to create a disease-drug network. A network of 170,027 significant interactions was extracted from the approximately 24.5 million comparisons between approximately 7,000 publicly available transcriptomic profiles. The network includes 645 disease-disease, 5,008 disease-drug, and 164,374 drug-drug relationships. At least 60% of the disease-disease pairs were in the same disease area as determined by the Medical Subject Headings (MeSH) disease classification tree. The remaining can drive a molecular level nosology by discovering relationships between seemingly unrelated diseases, such as a connection between bipolar disorder and hereditary spastic paraplegia, and a connection between actinic keratosis and cancer. Among the 5,008 disease-drug links, connections with negative scores suggest new indications for existing drugs, such as the use of some antimalaria drugs for Crohn’s disease, and a variety of existing drugs for Huntington’s disease; while the positive scoring connections can aid in drug side effect identification, such as tamoxifen’s undesired carcinogenic property. From the approximately 37K drug-drug relationships, we discover relationships that aid in target and pathway deconvolution, such as 1) KCNMA1 as a potential molecular target of lobeline, and 2) both apoptotic DNA fragmentation and G2/M DNA damage checkpoint regulation as potential pathway targets of daunorubicin.

CONCLUSIONS/SIGNIFICANCE: We have automatically generated thousands of disease and drug expression profiles using GEO datasets, and constructed a large scale disease-drug network for effective and efficient drug repositioning as well as drug target/pathway identification.

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PLoS One. 2009 Aug 6;4(8):e6536Human disease-drug network based on genomic expression profiles.
Hu G, Agarwal P.
Computational Biology, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America. [email protected]

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