Bipolar patients display stoichiometric imbalance of gene expression in post-mortem brain samples.

Bipolar disorder is a severe neuro-psychiatric condition where genome-wide association and sequencing studies have pointed to dysregulated gene expression as likely to be causal. We observed strong correlation in expression between GWAS-associated genes and hypothesised that healthy function depends on balance in the relative expression levels of the associated genes and that patients display stoichiometric imbalance. We developed a method for quantifying stoichiometric imbalance and used this to predict each sample's diagnosis probability in four cortical brain RNAseq datasets. The percentage of phenotypic variance on the liability-scale explained by these probabilities ranged from 10.0 to 17.4% (AUC: 69.4-76.4%) which is a multiple of the classification performance achieved using absolute expression levels or GWAS-based polygenic risk scores. Most patients display stoichiometric imbalance in three to ten genes, suggesting that dysregulation of only a small fraction of associated genes can trigger the disorder, with the identity of these genes varying between individuals.

The Potential Role of Regulatory Genes (DNMT3A, HDAC5, and HDAC9) in Antipsychotic Treatment Response in South African Schizophrenia Patients.

Despite advances in pharmacogenetics, the majority of heritability for treatment response cannot be explained by common variation, suggesting that factors such as epigenetics may play a key role. Regulatory genes, such as those involved in DNA methylation and transcriptional repression, are therefore excellent candidates for investigating antipsychotic treatment response. This study explored the differential expression of regulatory genes between patients with schizophrenia (chronic and antipsychotic-naïve first-episode patients) and healthy controls in order to identify candidate genes for association with antipsychotic treatment response. Seven candidate differentially expressed genes were identified, and four variants within these genes were found to be significantly associated with treatment response (DNMT3A rs2304429, HDAC5 rs11079983, and HDAC9 rs1178119 and rs11764843). Further analyses revealed that two of these variants (rs2304429 and rs11079983) are predicted to alter the expression of specific genes (DNMT3A, ASB16, and ASB16-AS1) in brain regions previously implicated in schizophrenia and treatment response. These results may aid in the development of biomarkers for antipsychotic treatment response, as well as novel drug targets.

Modification of the association between antipsychotic treatment response and childhood adversity by MMP9 gene variants in a first-episode schizophrenia cohort.

Antipsychotics remain the most effective, and wide used option for ameliorating the symptoms of schizophrenia. However, inter-individual differences in treatment outcome are vast and suggest a role for genetic and environmental factors in affording favourable outcomes. A notable epigenetic relationship which has gained considerable traction in recent literature is the way in which the severity of childhood trauma can modify associations seen between genetic variation and antipsychotic treatment response. A potential mechanism of action which may facilitate this relationship is synaptic plasticity. This study investigated the role of variants in matrix metallopeptidase 9 (MMP9), a gene involved in synaptic plasticity, with treatment outcome considering the severity of childhood trauma as an interacting variable. The cohort comprised South African first episode schizophrenia patients treated with a single injectable antipsychotic, flupenthixol decanoate, monitored over 12 months. Relationships between novel and previously described variants, and haplotypes, with antipsychotic treatment response were found to be modified when considering childhood trauma as an interacting variable. This study provides the first evidence for the involvement of polymorphisms within MMP9 and the severity of childhood trauma in antipsychotic treatment response, and warrants further investigation into the role gene-environment interactions may play in the betterment of antipsychotic treatment strategies.