A new method for identifying causal genes of schizophrenia and anti-tuberculosis drug-induced hepatotoxicity

Abstract

Schizophrenia (SCZ) may cause tuberculosis, the treatments for which can induce anti-tuberculosis drug-induced hepatotoxicity (ATDH) and SCZ-like disorders. To date, the causal genes of both SCZ and ATDH are unknown. To identify them, we proposed a new network-based method by integrating network random walk with restart algorithm, gene set enrichment analysis, and hypergeometric test; using this method, we identified 500 common causal genes. For gene validation, we created a regularly updated online database ATDH-SCZgenes and conducted a systematic meta-analysis of the association of each gene with either disease. Till now, only GSTM1 and GSTT1 have been well studied with respect to both diseases; and a total of 23 high-quality association studies were collected for the current meta-analysis validation. Finally, the GSTM1 present genotype was confirmed to be significantly associated with both ATDH [Odds Ratio (OR): 0.71, 95% confidence interval (CI): 0.56-0.90, P = 0.005] and SCZ (OR: 0.78, 95% CI: 0.66-0.92, P = 0.004) according to the random-effect model. Furthermore, these significant results were supported by "moderate" evidence according to the Venice criteria. Our findings indicate that GSTM1 may be a causal gene of both ATDH and SCZ, although further validation pertaining to other genes, such as CYP2E1 or DRD2, is necessary.

Figure 1. Forest plots from meta-analysis of GSTM1/GSTT1 polymorphisms and ATDH.

(A) Summary of the ORs and corresponding 95% CIs for the GSTM1 present genotype; (B) summary of the ORs and 95% CIs for the GSTT1 present genotype.

Figure 2. Forest plots from meta-analysis of GSTM1/GSTT1 polymorphisms and SCZ.

(A) Summary of the ORs and corresponding 95% CIs for the GSTM1 present genotype; (B) summary of ORs and 95% CIs for the GSTT1 present genotype.

Figure 3. Schematic illustration of the roles of GSTM1 in liver and brain.

INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; NAT2, arylamine N-acetyltransferase2; CYP2E1, cytochrome P450 2E1.

Figure 4. Identification of the key drivers of both ATDH and SCZ.

(A) Known ATDH and SCZ genes were mapped onto the STRING network. (B) ATDH genes were expanded using RWR and the known ADTH genes as seed genes. The stop point was determined using a running sum curve reflective of the overlap between the top expanded ATDH genes and known SCZ genes. SCZ genes were expanded in a similar manner. (C) Common genes between ATDH and SCZ were highlighted for further key driver evaluation. (D) The neighbor genes of candidate key drivers were tested for overlap significance with common disease genes. These neighbors of key drivers should significantly affect the more common disease genes.