| 1 | J Mol Psychiatry 2014 -1 2: 6 |
|---|---|
| PMID | 25713723 |
| Title | Mitochondrial complex I and III gene mRNA levels in schizophrenia, and their relationship with clinical features. |
| Abstract | The etiology of schizophrenia is not precisely known; however, mitochondrial function and cerebral energy metabolism abnormalities were determined to be possible factors associated with the etiology of schizophrenia. Impaired mitochondrial function negatively affects neuronal plasticity, and can cause cognitive deficits and behavioral abnormalities observed during the clinical course of schizophrenia. The present study aimed to investigate the relationship between the clinical features of schizophrenia, and mitochondrial complex activation, based on measurement of mRNA levels in the NDUFV1, NDUFV2, NDUFS1, and UQCR10 genes involved in the peripheral mitochondrial complex. The study included 138 schizophrenia patients and 42 healthy controls. The schizophrenia group was divided into a chronic schizophrenia subgroup (n?=?84) and a first-episode schizophrenia subgroup (n?=?54). The symptoms profile and severity of disorder were evaluated using the Scale for the Assessment of Negative Symptoms (SANS), Scale for the Assessment of Positive Symptoms (SAPS), and Brief Psychiatric Rating Scale (BPRS). The level of mRNA expression of NDUFV1, NDUFV2, and NDUFS1 was significantly higher in the schizophrenia group than in the control group. The mRNA level of NDUFV2 was positively correlated with BPRS and SAPS scores in the first-episode schizophrenia subgroup. The findings showed that there was a positive correlation between gene mRNA levels and psychotic symptomatology, especially positive symptoms. Our results suggest that mRNA levels of the NDUFV1, NUDFV2, and NDUFS1 genes of complex I of the mitochondrial electron transport chain might become a possible peripheral marker for the diagnosis of schizophrenia. |
| SCZ Keywords | schizophrenia |
| 2 | Neuropsychopharmacology 2014 May 39: 1347-54 |
| PMID | 24196945 |
| Title | A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. |
| Abstract | Mitochondria are the main source of energy for neurons and have a role in many vital neuronal functions. Mitochondrial dysfunction has been described in schizophrenia, and antipsychotics such as clozapine and olanzapine have been associated with differences in gene expression in mitochondria. We investigated the hypothesis that nuclear-encoded mitochondrial genes, particularly those involved in oxidative phosphorylation or involved in oxidative stress, mitochondrial biogenesis, inflammation, and apoptosis, would be associated with antipsychotic-induced weight gain (AIWG). In total, we selected 28 genes and analyzed 60 SNPs (50 are functional), in 283 schizophrenia subjects, treated with atypical medications for up to 14 weeks. Association between AIWG (as measured by the % of weight gain from baseline) and SNP genotypes were tested using linear regression with treatment duration, baseline body weight, and medication type as covariates. We observed a significant association between rs6435326 in the NDUFS1 gene and AIWG in the subset of European patients (N=150, Pcorrected=0.02). The haplotype carrying the risk alleles of rs6435326 and two other SNPs (rs1053517 and rs1801318) in NDUFS1 was also nominally associated with percentage of weight gain (T-C-G vs A-T-A, P=0.005). In addition, stepwise linear regression was performed to select important variables predictive of the outcome, and a gene-gene interaction analysis was carried out. We observed a significant interaction between the TT risk genotype of rs6435326 in NDUFS1 and AG genotype of rs3762883 in COX18 (Pcorrected=0.001). A permutation-based test of all 60 SNPs jointly showed significant association with weight gain (P=0.02). Finally, our replication study of rs6435326, rs1053517 and rs1801318 in NDUFS1 using samples from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed that rs1801318 was significantly associated with AIWG (N=200, Pcorrected=0.04), and the three SNPs were collectively associated with AIWG (P=0.04). In conclusion, our findings suggest an association between NDUFS1 and AIWG in schizophrenia subjects. To the best of our knowledge, this is the first study to explore genetic variation in the mitochondrial genes in the context of AIWG. |
| SCZ Keywords | schizophrenia |
| 3 | Sci Rep 2015 -1 5: 11076 |
| PMID | 26053550 |
| Title | Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations? |
| Abstract | schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia. |
| SCZ Keywords | schizophrenia |
| 4 | J. Hum. Genet. 2015 Jan 60: 11-6 |
| PMID | 25354934 |
| Title | Genetic variant in NDUFS1 gene is associated with schizophrenia and negative symptoms in Han Chinese. |
| Abstract | Abnormalities in mitochondrial complex I, which is responsible for controlling mitochondrial function, have been implicated in a variety of diseases associated with mitochondrial dysfunction, potentially including schizophrenia. The NADH dehydrogenase Fe-S protein 1 (NDUFS1) is the largest subunit of complex I. To explore whether the encoding NDUFS1 gene confers susceptibility to schizophrenia or is associated with the severity of typical symptoms of schizophrenia, we recruited 519 stable schizophrenia patients receiving clozapine treatment and 594 healthy controls for genotyping to investigate the association of four selected tagging single-nucleotide polymorphisms (SNPs) of NDUFS1 and both schizophrenia risk and symptom severity. The severity of psychotic symptoms was evaluated using the Positive and Negative Syndrome Scale and then tested for association with the four SNPs. The SNP rs1044120 showed significant association with schizophrenia (adjusted P=0.032). The frequency of the G allele of rs1044120 was significantly higher in patients than among the healthy controls (adjusted P=0.008). Stratification by sex revealed a significant association between the rs1044120 polymorphism and schizophrenia among males (adjusted P=0.036 and 0.008 in genotypic and allelic comparisons, respectively). We also observed a significant difference in the negative symptom scores among the three genotypes among these males (adjusted P=0.036). Post hoc comparisons showed that rs1044120 G/G carriers had higher negative symptom scores than those with G/T and T/T carriers (raw P=0.035 and 0.005, respectively). Our findings suggest that NDUFS1 may confer susceptibility to schizophrenia in male subjects, acting as a causative factor for the severity of negative symptoms in schizophrenia. |
| SCZ Keywords | schizophrenia |