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.
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Gonçalves
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Clement C
authors.initials: CC
authors.lastname: Zai
authors.affiliation: Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Tiwari
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Eva J
authors.initials: EJ
authors.lastname: Brandl
authors.affiliation: Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Andriy
authors.initials: A
authors.lastname: Derkach
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York City, NY, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieberman
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Müller
authors.affiliation: 1] Department of Statistical Sciences, University of Toronto, Toronto, ON, Canada [2] Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1] Department of Psychiatry, University of Toronto, Toronto, ON, Canada [2] Neuroscience Section, Centre for Addiction and Mental Health, Toronto, ON, Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000009:adverse effects / Q000627:therapeutic use; D001835:Body Weight; D003024:Clozapine / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D050259:Genes, Mitochondrial; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D008954:Models, Biological; D009245:NADH Dehydrogenase / Q000235:genetics; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects* / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; C506210:COX18 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C487793:NDUFS1 protein, human; D001569:Benzodiazepines; D009245:NADH Dehydrogenase; D003024:Clozapine; D000077152:Olanzapine