Revisiting antipsychotic drug actions through gene networks associated with schizophrenia. Kauppi, K., Rosenthal, S. B., Lo, M., Sanyal, N., Jiang, M., Abagyan, R., McEvoy, L. K, Andreassen, O. A, & Chen, C. The American journal of psychiatry, 175(7):674–682, July, 2018. ZSCC: 0000010
Revisiting antipsychotic drug actions through gene networks associated with schizophrenia [link]Paper  doi  abstract   bibtex   
Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel druggable pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated. However, the specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation, but in combination with other genes. Thus, we utilized protein-protein interaction networks (interactome) to map antipsychotic drug targets (n=88) to networks of schizophrenia risk genes (n=328). Our results showed that schizophrenia risk genes were significantly localized in the interactome (p=0.0015), forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Intriguingly, antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH and HCN families were not connected to existing antipsychotics, but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia such as cognitive dysfunction and negative symptoms. This network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multi-target anti-schizophrenia drugs. This approach is transferable to other diseases.
@article{kauppi_revisiting_2018,
	title = {Revisiting antipsychotic drug actions through gene networks associated with schizophrenia},
	volume = {175},
	issn = {0002-953X},
	url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028303/},
	doi = {10.1176/appi.ajp.2017.17040410},
	abstract = {Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel druggable pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated. However, the specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation, but in combination with other genes. Thus, we utilized protein-protein interaction networks (interactome) to map antipsychotic drug targets (n=88) to networks of schizophrenia risk genes (n=328). Our results showed that schizophrenia risk genes were significantly localized in the interactome (p=0.0015), forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Intriguingly, antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH and HCN families were not connected to existing antipsychotics, but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia such as cognitive dysfunction and negative symptoms. This network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multi-target anti-schizophrenia drugs. This approach is transferable to other diseases.},
	number = {7},
	urldate = {2021-03-19},
	journal = {The American journal of psychiatry},
	author = {Kauppi, Karolina and Rosenthal, Sara Brin and Lo, Min-Tzu and Sanyal, Nilotpal and Jiang, Mian and Abagyan, Ruben and McEvoy, Linda K and Andreassen, Ole A and Chen, Chi-Hua},
	month = jul,
	year = {2018},
	pmid = {29495895},
	pmcid = {PMC6028303},
	note = {ZSCC: 0000010 },
	pages = {674--682},
}
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