Rare copy number variation in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a heritable (h = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry.

Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European ( = 70,870) and African ( = 1,354) ancestry.

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex.

Epigenetic analysis confirms no accelerated brain aging in schizophrenia.

Epigenetic aging is associated with several biological mechanisms and diseases. We assessed two brain data sets, one small (n = 48) and one large (n = 392), to test epigenetic aging in schizophrenia. DNA methylation age from frontal cortex was significantly correlated with chronological age but no significant differences in DNA methylation age acceleration between schizophrenia cases and controls were observed in both data sets.

Physical comorbidities of post-traumatic stress disorder in Australian Vietnam War veterans.

Objective: To determine whether the prevalence of physical comorbidities in Australian Vietnam War veterans with post-traumatic stress disorder (PTSD) is higher than in trauma-exposed veterans without PTSD.

Design, Setting And Participants: Cross-sectional analysis of the health status (based on self-reported and objective clinical assessments) of 298 Australian Vietnam War veterans enrolled by the Gallipoli Medical Research Institute (Brisbane) during February 2014 - July 2015, of whom 108 were confirmed as having had PTSD and 106 served as trauma-exposed control participants.Main outcomes and measures: Diagnostic psychiatric interview and psychological assessments determined PTSD status, trauma exposure, and comorbid psychological symptoms.

mRNA Expression and DNA Methylation Analysis of Serotonin Receptor 2A (HTR2A) in the Human Schizophrenic Brain.

Serotonin receptor 2A () is an important signalling factor implicated in cognitive functions and known to be associated with schizophrenia. The biological significance of in schizophrenia remains unclear as molecular analyses including genetic association, mRNA expression and methylation studies have reported inconsistent results. In this study, we examine expression and methylation and the interaction with polymorphisms to identify their biological significance in schizophrenia.

Clinically proven drug targets differentially expressed in the prefrontal cortex of schizophrenia patients.

Background: Due to the heterogeneous nature of schizophrenia, understanding the genetic risk for the disease is a complex task. Gene expression studies have proven to be more reliable than association studies as they are consistently replicated in a tissue specific manner.

Methods: Using RNA-Seq we analysed gene expression in the frontal cortex of 24 individuals with schizophrenia and 25 unaffected controls.

Interaction of multiple gene variants and their effects on schizophrenia phenotypes.

Background: Schizophrenia is a clinically heterogeneous disorder and may be explained by its complex genetic architecture. Many schizophrenia susceptibility genes were identified but the picture remains unclear due to inconsistent or contradictory genetic association studies. This confusion may, in part, be because symptoms result from the combined interaction of many genes and these interacting genes are associated with specific sub-phenotypes of schizophrenia rather than schizophrenia as a whole.

Expression and methylation of BDNF in the human brain in schizophrenia.

Objectives: To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene.

Methods: DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing.

Dopamine 2 Receptor Genes Are Associated with Raised Blood Glucose in Schizophrenia.

Objective: Type 2 diabetes is commonly found in schizophrenia and is an important contributor to mortality and morbidity in this condition. Dopamine has been implicated in the aetiology of both diabetes and schizophrenia. It is possible that both disorders share a common genetic susceptibility.

Association of NOS1AP variants and depression phenotypes in schizophrenia.

Background: The nitric oxide synthase 1 adaptor protein gene (NOS1AP) has previously been recognised as a schizophrenia susceptibility gene due to its role in glutamate neurotransmission. The gene is believed to inhibit nitric oxide (NO) production activated by the N-methyl-d-aspartate (NMDA) receptor and reduced NO levels have been observed in schizophrenia patients. However, association studies investigating NOS1AP and schizophrenia have produced inconsistent results, most likely because schizophrenia is a clinically heterogeneous disorder.

Progress towards understanding the genetics of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a complex syndrome that occurs following exposure to a potentially life threatening traumatic event. This review summarises the literature on the genetics of PTSD including gene-environment interactions (GxE), epigenetics and genetics of treatment response. Numerous genes have been shown to be associated with PTSD using candidate gene approaches.

BDNF SNPs are implicated in comorbid alcohol dependence in schizophrenia but not in alcohol-dependent patients without schizophrenia.

Aims: The functional BDNF single nucleotide polymorphism (SNP) rs6265 has been associated with many disorders including schizophrenia and alcohol dependence. However, studies have been inconsistent, reporting both positive and negative associations. Comorbid alcohol dependence has a high prevalence in schizophrenia so we investigated the role of rs6265 in alcohol dependence in Australian populations of schizophrenia and alcohol-dependent patients.

KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence.

KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts.

DRD2 C957T and TaqIA genotyping reveals gender effects and unique low-risk and high-risk genotypes in alcohol dependence.

Aims: As recent conflicting reports describe a genetic association between both the C- and the T-alleles of the dopamine D2 receptor (DRD2) C957T polymorphism (rs6277) in alcohol-dependent subjects, our aim was to examine this polymorphism and TaqIA (rs1800497) in Australian alcohol-dependent subjects.

Methods: The C957T polymorphism was genotyped in 228 patients with alcohol dependence (72 females and 156 males) and 228 healthy controls.

Results: The C-allele and C/C genotype of C957T was associated with alcohol dependence, whereas the TaqIA polymorphism was not.

A DRD2 and ANKK1 haplotype is associated with nicotine dependence.

To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.

A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study.

Background: It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset: HapMap tag-single-nucleotide polymorphism analysis.

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain; levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression.

Alcohol Use Disorders Identification Test (AUDIT) scores are elevated in antipsychotic-induced hyperprolactinaemia.

Hyperprolactinaemia in antipsychotic treated patients with schizophrenia is a consequence of D2 receptor (DRD2) blockade. Alcohol use disorder is commonly comorbid with schizophrenia and low availability of striatal DRD2 may predispose individuals to alcohol use. In this pilot study we investigated whether hyperprolactinaemia secondary to pharmacological DRD2 blockade was associated with alcohol use disorder in 219 (178 males and 41 females) patients with schizophrenia.

Cigarette smoking in young adults: the influence of the HTR2A T102C polymorphism and punishment sensitivity.

Background: The C allele of a common polymorphism of the serotonin 2A receptor (HTR2A) gene, T102C, results in reduced synthesis of 5-HT2A receptors and has been associated with current smoking status in adults. The -1438A/G polymorphism, located in the regulatory region of this gene, is in linkage disequilibrium with T102C, and the A allele is associated with increased promoter activity and with smoking in adult males. We investigated the contributions of the HTR2A gene, chronic psychological stress, and impulsivity to the prediction of cigarette smoking status and dependence in young adults.

A polymorphism in the dysbindin gene (DTNBP1) associated with multiple psychiatric disorders including schizophrenia.

Background: A number of studies have found associations between dysbindin (DTNBP1) polymorphisms and schizophrenia. Recently we identified a DTNBP1 SNP (rs9370822) that is strongly associated with schizophrenia. Individuals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype.