ORCID Profile
0000-0001-6645-6164
Current Organisations
CNRS
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Queensland University of Technology
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Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: 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. In iduals 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. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. In iduals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.ADDBEH.2016.05.008
Abstract: Impulsivity predicts alcohol misuse and risk for alcohol use disorder. Cognition mediates much of this association. Genes also account for a large amount of variance in alcohol misuse, with dopamine and serotonin receptor genes of particular interest, because of their role in motivated behavior. The precise psychological mechanisms through which such genes confer risk is unclear. Trait impulsivity conveys risk for alcohol misuse by influencing two distinct domains of cognition: beliefs about the reinforcing effects of alcohol consumption (positive alcohol expectancy) and the perceived ability to resist it (drinking refusal self-efficacy). This study investigated the effect of the dopamine-related polymorphism in the DRD2/ANKK1 gene (rs1800497) and a serotonin-related polymorphism in the HTR2A gene (rs6313) on associations between impulsivity, cognition, and alcohol misuse in 120 emerging adults (18-21years). HTR2A predicted lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse. However, neither polymorphism moderated the linkages between impulsivity, cognition, and alcohol misuse. This is the first report of an association between HTR2A and alcohol-related cognition. Theoretically-driven biopsychosocial models have potential to elucidate the specific cognitive mechanisms through which distal risk factors like genes and temperament affect alcohol misuse in emerging adulthood.
Publisher: Elsevier BV
Date: 07-2004
DOI: 10.1016/J.CLINDERMATOL.2004.01.004
Abstract: Insights into the etiology of human obesity have arisen from the study of animal models. Animal models of obesity are also important for the development of future treatments of obesity. An agouti mouse mutation resulting in obese, yellow mice was described over a century ago and in 1992 agouti was cloned, making it the first obesity gene characterized at the molecular level. The lethal yellow mouse mutation is one of five dominant agouti mutations and is an excellent model for human obesity. The molecular categorization of agouti was responsible for the elucidation of the melanocortin system's involvement in hypothalamic weight regulation. As genetic knowledge increases many transgenic mice have been created with genes either over-expressed or deleted, models which further enhance the understanding of obesity.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2010
Abstract: 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. In iduals diagnosed with schizophrenia were nearly three times as likely to carry the CC genotype compared to the AA genotype. To investigate the importance of this SNP in the function of DTNBP1 , a number of psychiatric conditions including addictive behaviours and anxiety disorders were analysed for association with rs9370822. The DTNBP1 polymorphism was significantly associated with post-traumatic stress disorder (PTSD) as well as nicotine and opiate dependence but not alcohol dependence. In iduals suffering PTSD were more than three times as likely to carry the CC genotype compared to the AA genotype. In iduals with nicotine or opiate dependence were more than twice as likely to carry the CC genotype compared to the AA genotype. This study provides further support for the importance of DTNBP1 in psychiatric conditions and suggests that there is a common underlying molecular defect involving DTNBP1 that contributes to the development of several anxiety and addictive disorders that are generally recognised as separate clinical conditions. These disorders may actually be different expressions of a single metabolic pathway perturbation. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.
Publisher: Frontiers Media SA
Date: 23-06-2021
DOI: 10.3389/FNINS.2021.678503
Abstract: 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 in idual 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 in iduals of European ( n = 70,870) and African ( n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p & 1E-20 DBP: β = 1.32, SE = 0.04, p & 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study – United Kingdom Biobank – PTSD symptoms were negatively associated with SBP levels (β = −1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01) no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.
Publisher: Oxford University Press (OUP)
Date: 03-07-2014
Abstract: 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. Two BDNF SNPs rs6265 and a nearby SNP rs7103411 were genotyped in a total of 848 in iduals. These included a schizophrenia group (n = 157) and a second schizophrenia replication group (n = 235), an alcohol-dependent group (n = 231) that had no schizophrenia diagnosis and a group of healthy controls (n = 225). Allelic association between rs7103411 and comorbid alcohol dependence was identified (P = 0.044) in the primary schizophrenia s le. In the replication study, we were able to detect allelic associations between both BDNF SNPs and comorbid alcohol dependence (rs6265, P = 0.006 rs7103411, P = 0.014). Moreover, we detected association between both SNPs and risk-taking behaviour after drinking (rs6265, P = 0.005 rs7103411, P = 0.009) and we detected strong association between both SNPs and alcohol dependence in males (rs6265, P = 0.009 rs7103411, P = 0.013) while females showed association with multiple behavioural measures reflecting repetitive alcohol consumption. Haplotype analysis revealed the rs6265-rs7103411 A/C haplotype is associated with comorbid alcohol dependence (P = 0.002). When these SNPs were tested in the non-schizophrenia alcohol-dependent group we were unable to detect association. We conclude that these BDNF SNPs play a role in development of comorbid alcohol dependence in schizophrenia while our data do not indicate that they play a role in alcohol-dependent patients who do not have schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2015
DOI: 10.1038/TP.2015.177
Abstract: Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) s les from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with in idual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post-mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3 , DPPA5 , PRDM9, DDX43, REC8 , LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.BBI.2016.12.006
Abstract: 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. Using RNA-Seq we analysed gene expression in the frontal cortex of 24 in iduals with schizophrenia and 25 unaffected controls. We identified 1146 genes that were differentially expressed in schizophrenia, approximately 60% of which were up-regulated and 366 of 1146 (32%) also have aberrant DNA methylation (p=2.46×10 Our results identified biological functional genes that are differentially expressed in schizophrenia. A subset of these genes are clinically proven drug targets. We also found a strong pattern of differentially expressed immune response genes that may reflect an underlying defect in schizophrenia.
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/6979435
Abstract: Posttraumatic stress disorder (PTSD) is a debilitating condition that develops in some people after exposure to a traumatic event. Brain-derived neurotrophic factor ( BDNF ) is highly expressed in the mammalian brain and is thought to be involved in learning and memory processes. A nonsynonymous polymorphism in the BDNF gene, rs6265 (Val66Met), has been hypothesised to be associated with PTSD. Association studies examining the Val66Met polymorphism and PTSD have been inconclusive, likely due to the variability in type of trauma exposure analysed. Vietnam veterans ( n = 257 ) screened for PTSD and controlled for trauma exposure were genotyped for BDNF Val66Met. The association was not significant so we incorporated our data into a meta-analysis to obtain greater statistical power. A comprehensive search of more than 1237 articles revealed eight additional studies suitable for meta-analysis ( n = 3625 ). A random-effects meta-analysis observed a potential protective factor of the Val/Val genotype. After removing two studies with violation of Hardy-Weinberg equilibrium, findings for the Val/Val genotype reached significance. Subgroup analyses confirmed a trend for this finding. Limitations of some studies that inform this meta-analysis include poorly screened controls and a lack of examination of population stratification. Effectively designed studies should inform this line of research in the future.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.PSYCHRES.2017.11.069
Abstract: Posttraumatic Stress Disorder (PTSD) is a debilitating psychiatric disorder with decreased general health prognosis and increased mortality. Inflammation has been hypothesised to be a link between PTSD and the most common co-morbid medical disorders. However, the relationship between inflammation and PTSD is not clear. In idual inflammatory markers have shown variable associations with PTSD. This study investigates the correlations between serum cytokines, PTSD and resilience in a cohort of Caucasian Vietnam combat veterans (n = 299). After correction for multiple testing, PTSD severity was correlated with small but significant decreases in interleukin 6 and interferon γ (p = 0.004, p = 0.013, respectively) whereas resilience was correlated with increased levels of interleukin 6 and interferon γ (p = 0.023 p = 0.007, respectively). Analyses of sub-symptoms of PTSD revealed that mood and arousal symptoms showed the most significant effect on interleukin 6 and interferon γ. More research is needed to further elucidate the mechanisms underlying the relationship between cytokine levels, PTSD sub-symptoms and trauma outcomes to improve the knowledge base of differences in trauma response and the biological system.
Publisher: American Academy of Sleep Medicine (AASM)
Date: 15-05-2018
DOI: 10.5664/JCSM.7096
Publisher: MDPI AG
Date: 04-01-2017
DOI: 10.3390/GENES8010014
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.GENE.2017.04.048
Abstract: The nitric oxide pathway in the hippoc us is involved in the biological stress response with detrimental consequences to cells and HPA axis feedback. Hippoc al atrophy and HPA axis feedback dysfunction are associated with posttraumatic stress disorder (PTSD). This study systematically investigates two genes of the nitric oxide pathway NOS1AP and NOS1 for a potential involvement in PTSD, comorbidities and resilience. A cohort of age and gender matched Vietnam veterans including trauma-exposed cases and controls was recruited and comprehensively assessed (n=299). A total of 49 NOS1AP and 16 NOS1 polymorphisms were analysed and genotypes correlated with gold standard clinical measures to assess PTSD severity and related phenotypes (depression, anxiety, stress, resilience) based on diagnostic status. Multiple NOS1AP polymorphisms were associated across all measures, and NOS1 polymorphisms were associated with PTSD severity, stress and resilience. The GG genotype of NOS1 polymorphism rs10744891 was associated with PTSD severity (surviving multiple correction) while the combined TT-TG genotypes were associated with resilience (p=0.005 p=0.033, respectively). This study indicates that NOS1AP and NOS1 from the nitric oxide pathway are likely to play a key role in PTSD, its comorbidities and resilience. Given the essential role of NOS1AP and NOS1 in stress response they may be reliable targets for screening and intervention strategies.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.JAD.2015.08.069
Abstract: 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. This study aims to investigate the association between NOS1AP variants and defined depression phenotypes of schizophrenia. Nine NOS1AP SNPs, rs1415259, rs1415263, rs1858232, rs386231, rs4531275, rs4656355, rs4657178, rs6683968 and rs6704393 were genotyped in 235 schizophrenia subjects screened for various phenotypes of depression. One NOS1AP SNP (rs1858232) was associated with the broad diagnosis of schizophrenia and eight SNPs were associated with depression related phenotypes within schizophrenia. The rs1415259 SNP showed strong association with sleep dysregulation phenotypes of depression. Results suggest that NOS1AP variants are associated with various forms of depression in schizophrenia and are more prevalent in males. Schizophrenia is a clinically heterogeneous disease that can vary greatly between different ethnic and geographic populations so our observations should be viewed with caution until they are independently replicated, particularly in larger patient cohorts.
Publisher: University of Toronto Press Inc. (UTPress)
Date: 05-2020
Abstract: Introduction: The Diagnostic and Statistical Manual of Mental Disorders (5th ed. DSM–5) brought a change to the symptom clusters of posttraumatic stress disorder (PTSD). In line with the DSM–5 changes, an updated version of the Clinician-Administered PTSD Scale (CAPS–5) was released. The CAPS–5 is considered to be the gold-standard measure of PTSD however, examinations of the psychometric properties and optimal factor structure of this scale are underrepresented in PTSD studies. Methods: This study used confirmatory factor analysis (CFA) to assess the factor structure of the CAPS–5 using a s le of 267 male Australian Vietnam Veterans. Models drawn from the PTSD CFA literature were used to test the underlying dimensions of PTSD: the four-factor DSM–5 model, six-factor externalizing behaviour and anhedonia models, and seven-factor hybrid model. Results: The results found that the DSM–5 model showed slightly less than adequate fit (comparative fit index [CFI] = 0.90, Tucker–Lewis index [TLI] = 0.88, root mean square error of approximation [RMSEA] = 0.064), however, other models showed acceptable fit. The anhedonia model provided a significantly better fit than the other models (CFI = 0.92, TLI = 0.90, RMSEA = 0.059). Discussion: Overall, the results supported the anhedonia model. This result may indicate that the underlying dimensions of PTSD in Australian Vietnam Veterans may best be represented by six distinct factors.
Publisher: Wiley
Date: 09-01-2003
DOI: 10.1034/J.1600-0749.2003.00007.X
Abstract: Production of the pigment eumelanin is controlled by alpha-melanocyte stimulating hormone (alpha-MSH) stimulation of melanocortin 1 receptor (Mc1r), whereas production of pheomelanin results from agouti antagonism of alpha-MSH signalling through Mc1r. The role of agouti in mouse pigmentation has been extensively investigated but a role for agouti signalling protein (ASIP) in human pigmentation has not been determined. To determine whether ASIP regulates known melanogenic genes in humans, ASIP was over-expressed in a human melanoma cell line. Levels of mRNA and protein were measured in genes known to be up or down-regulated by agouti in the mouse, namely microphthalmia (Mitf), tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), dopachrome tautomerase (Dct), Mc1r, silver, initiation transcription factor 2 (Itf2) and mini chromosome maintenance protein 6 (Mcm6). These melanogenic genes were not found to be significantly up or down-regulated by ASIP at the transcriptional level in human melanoma cells. However, ASIP down-regulation of tyrp1 was observed at the translational level. To identify novel genes that may be regulated by ASIP in melanoma cells, microarrays were used to determine differences in gene expression between the control and ASIP transfected melanoma cells. The expression level of human RNAs were determined by microarray analysis using a 19,200 cDNA and a 19,200 oligonucleotide array representing 13,000 and 18,864 in idual genes, respectively. Genes observed to be modulated by ASIP were confirmed by quantitative real-time polymerase chain reaction. Results identify five genes, namely PPARbeta, eIF-4B, RRM2, MINOR and EVI2B that are down-regulated by ASIP, indicating a likely role for ASIP in human melanogenesis.
Publisher: Mary Ann Liebert Inc
Date: 02-2012
Abstract: 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. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach so, the entire DRD2 gene was represented. One polymorphism, rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. In iduals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls. Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset.
Publisher: Springer Science and Business Media LLC
Date: 04-09-2017
DOI: 10.1038/S41537-017-0026-4
Abstract: 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. Our results were consistent with a previous study investigating schizophrenia and epigenetic aging in superior temporal gyrus. Future studies targeting different brain regions and defined cell types are warranted to further investigate accelerated brain aging in schizophrenia.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.COMPPSYCH.2016.08.015
Abstract: 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. This study investigates the relationship between schizophrenia susceptibility genes and schizophrenia sub-phenotypes by identifying multiple gene variant interactions. Fifty SNPs from 21 genes were genotyped in 235 Australian participants with schizophrenia screened for various phenotypes. Schizophrenia participants were grouped into relevant phenotype clusters using cluster analysis and normalized phenotype cluster scores were calculated for each patient. The relationship between genotypes and normalized phenotype cluster scores were analyzed by linear regression analysis. Three phenotype clusters were identified. There was some overlap in symptoms between phenotype clusters, particularly for depression. However, cluster 1 appears to be characterized by speech disorder and affective behavior symptoms, cluster 2 has predominantly hallucination symptoms and cluster 3 has mainly delusion symptoms. Interaction of five SNPs was found to have an effect on cluster 1 symptoms ten SNPs on cluster 2 symptoms and eight SNPs on cluster 3 symptoms. The interaction of specific susceptibility genes is likely to lead to specific clinical sub-phenotypes of schizophrenia. Larger patient cohorts with more extensive clinical data will improve the detection of gene interactions and the resultant schizophrenia clinical phenotypes.
Publisher: Cambridge University Press (CUP)
Date: 10-2010
DOI: 10.1016/J.EURPSY.2009.11.011
Abstract: Dystrobrevin binding protein 1 ( DTNBP1 ), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.BRAT.2017.07.003
Abstract: Impulsivity is a core characteristic of externalizing problems and a robust predictor of alcohol use in adolescence. There is little evidence on the causal mechanisms through which impulsivity influences drinking or how they are affected by key social factors (peer influence). This study reports the development of the first comprehensive laboratory model of adolescent impulsivity and alcohol use. One-hundred and twenty adolescents (50% female) of legal drinking age (M = 19.47 years, SD = 1.12) in Australia (18+ years) were subjected to 1 of 3 experimental manipulations to increase impulsive behavior (reward cue exposure, negative mood induction, ego depletion). Changes in disinhibition (stop-signal task) and reward-seeking (BAS-Fun Seeking) were measured before completing a laboratory drinking task alone or with a heavy-drinking confederate. Reward cue exposure increased alcohol consumption, with the effect mediated by increased reward-seeking. Negative mood induction increased disinhibition, but not drinking. The presence of a heavy-drinking peer directly increased alcohol consumption in an additive fashion. Findings provide causal evidence that extends survey-based research by highlighting the role of reward-related impulsivity in adolescent alcohol use. The new laboratory model can provide novel insights into the psychological processes underlying adolescent impulsivity and impulsivity-related drinking.
Publisher: SAGE Publications
Date: 16-08-2018
Abstract: There are some psychosocial factors that have similar importance to biological factors in the genesis of coronary diseases. However, reasons for high rates of coronary heart disease in in iduals with post-traumatic stress disorder (PTSD) are yet to be fully elucidated. Using a meta-analysis, we investigated the longitudinal relationship between PTSD and coronary heart disease (CHD) as an independent factor in the aetiology of CHD. The databases of Medline, EBSCOhost and Psychoinfo were electronically searched for relevant articles. The pooled hazard ratio (HR) for the magnitude of the relationship between PTSD and CHD was an HR of 1.61, and p-value of p 0.0005, 95% confidence interval (CI) [1.46–1.77] before adjustment for depression in nine studies ( N = 151,144) that met inclusion criteria. The HR estimates for the seven depression-adjusted estimates was 1.46, and a p-value of p 0.0005, 95% CI[0.26–1.69]. This study demonstrates an association between CHD and PTSD.
Publisher: Wiley
Date: 02-06-2023
DOI: 10.1111/WRR.13100
Abstract: MicroRNAs are small, non‐coding RNAs that regulate gene expression, and consequently protein synthesis. Downregulation and upregulation of miRNAs and their corresponding genes can alter cell apoptosis, proliferation, migration and fibroproliferative responses following a thermal injury. This review summarises the evidence for altered human miRNA expression post‐burn, and during wound healing and scarring. In addition, the most relevant miRNA targets and their roles in potential pathways are described. Previous studies using molecular techniques have identified 197 miRNAs associated with human wound healing, burn wound healing and scarring. Five miRNAs alter the expression of fibroproliferative markers, proliferation and migration of fibroblasts and keratinocytes post‐burn: hsa‐miR‐21 and hsa‐miR‐31 are increased after wounding, and hsa‐miR‐23b, hsa‐miR‐200b and hsa‐let‐7c are decreased. Four of these five miRNAs are associated with the TGF‐β pathway. In the future, large scale, in vivo, longitudinal human studies utilising a range of cell types, ethnicity and clinical healing outcomes are fundamental to identify burn wound healing and scarring specific markers. A comprehensive understanding of the underlying pathways will facilitate the development of clinical diagnostic or prognostic tools for better scar management and the identification of novel treatment targets for improved healing outcomes in burn patients.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 07-01-2014
DOI: 10.1038/TP.2013.111
Abstract: Recent studies suggest that genetic and environmental factors do not account for all the schizophrenia risk, and epigenetics also has a role in disease susceptibility. DNA methylation is a heritable epigenetic modification that can regulate gene expression. Genome-wide DNA methylation analysis was performed on post-mortem human brain tissue from 24 patients with schizophrenia and 24 unaffected controls. DNA methylation was assessed at over 485 000 CpG sites using the Illumina Infinium HumanMethylation450 Bead Chip. After adjusting for age and post-mortem interval, 4641 probes corresponding to 2929 unique genes were found to be differentially methylated. Of those genes, 1291 were located in a CpG island and 817 were in a promoter region. These include NOS1 , AKT1 , DTNBP1 , DNMT1 , PPP3CC and SOX10 , which have previously been associated with schizophrenia. More than 100 of these genes overlap with a previous DNA methylation study of peripheral blood from schizophrenia patients in which 27 000 CpG sites were analysed. Unsupervised clustering analysis of the top 3000 most variable probes revealed two distinct groups with significantly more people with schizophrenia in cluster one compared with controls ( P =1.74 × 10 −4 ). The first cluster composed of 88% of patients with schizophrenia and only 12% controls, whereas the second cluster composed of 27% of patients with schizophrenia and 73% controls. These results strongly suggest that differential DNA methylation is important in schizophrenia etiology and add support for the use of DNA methylation profiles as a future prognostic indicator of schizophrenia.
Publisher: Wiley
Date: 04-2017
DOI: 10.5694/MJA16.00935
Abstract: 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. 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. Demographic data, and medical and sleep history were collected comprehensive clinical examination, electrocardiography, spirometry, liver transient elastography, and selected pathology assessments and diagnostic imaging were performed. Outcomes associated with PTSD were identified regression analysis excluded the effects of potentially confounding demographic and risk factors and comorbid symptoms of depression and anxiety. The mean total number of comorbidities was higher among those with PTSD (17.7 SD, 6.1) than in trauma-exposed controls (14.1 SD, 5.2 P < 0.001). For 24 of 171 assessed clinical outcomes, morbidity was greater in the PTSD group, including for conditions of the gastrointestinal, hepatic, cardiovascular, and respiratory systems, sleep disorders, and laboratory pathology measures. In regression analyses including demographic factors, PTSD remained positively associated with 17 adverse outcomes after adjusting for the severity of depressive symptoms, it remained significantly associated with ten. PTSD in Australian Vietnam veterans is associated with comorbidities in several organ systems, independent of trauma exposure. A comprehensive approach to the health care of veterans with PTSD is needed.
Publisher: Wiley
Date: 21-01-2002
DOI: 10.1034/J.1600-0749.2002.00039.X
Abstract: The agouti protein regulates pigmentation in the mouse hair follicle producing a black hair with a subapical yellow band. Its effect on pigmentation is achieved by antagonizing the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (Mc1r), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). Dominant mutations in the non-coding region of mouse agouti cause yellow coat colour and ectopic expression also results in obesity, type 11 diabetes, increased somatic growth and tumourigenesis. At least some of these pleiotropic effects can be explained by antagonism of other members of the melanocortin receptor family by agouti protein. The yellow coat colour is the result of agouti chronically antagonizing the binding of alpha-MSH to Mc1r and the obese phenotype results from agouti protein antagonizing the binding of alpha-MSH to Mc3r and/or Mc4r. Despite the existence of a highly homologous agouti protein in humans, agouti signal protein (ASIP), its role has yet to be defined. However it is known that human ASIP is expressed at highest levels in adipose tissue where it may antagonize one of the melanocortin receptors. The conserved nature of the agouti protein combined with the erse phenotypic effects of agouti mutations in mouse and the different expression patterns of human and mouse agouti, suggest ASIP may play a role in human energy homeostasis and possibly human pigmentation.
Publisher: American Academy of Sleep Medicine (AASM)
Date: 15-05-2019
DOI: 10.5664/JCSM.7762
Publisher: Wiley
Date: 09-08-2017
DOI: 10.1111/ACPS.12778
Abstract: Epigenetic modifications such as DNA methylation may play a key role in the aetiology and serve as biomarkers for post-traumatic stress disorder (PTSD). We performed a genomewide analysis to identify genes whose DNA methylation levels are associated with PTSD. A total of 211 in iduals comprising Australian male Vietnam War veterans (n = 96) and males from a general population belonging to the Grady Trauma Project (n = 115) were included. Genomewide DNA methylation was performed from peripheral blood using the Illumina arrays. Data analysis was performed using generalized linear regression models. Differential DNA methylation of 17 previously reported PTSD candidate genes was associated with PTSD symptom severity. Genomewide analyses revealed CpG sites spanning BRSK1, LCN8, NFG and DOCK2 genes were associated with PTSD symptom severity. We replicated the findings of DOCK2 in an independent cohort. Pathway analysis revealed that among the associated genes, genes within actin cytoskeleton and focal adhesion molecular pathways were enriched. These data highlight the role of DNA methylation as biomarkers of PTSD. The results support the role of previous candidates and uncover novel genes associated with PTSD, such as DOCK2. This study contributes to our understanding of the biological underpinnings of PTSD.
Publisher: Cambridge University Press (CUP)
Date: 07-2012
DOI: 10.1016/J.EURPSY.2010.08.004
Abstract: Catechol-O-methyl transferase ( COMT ) encodes an enzyme involved in the metabolism of dopamine and maps to a commonly deleted region that increases schizophrenia risk. A non-synonymous polymorphism (rs4680) in COMT has been previously found to be associated with schizophrenia and results in altered activity levels of COMT . Using a haplotype block-based gene-tagging approach we conducted an association study of seven COMT single nucleotide polymorphisms (SNPs) in 160 patients with a DSM-IV diagnosis of schizophrenia and 250 controls in an Australian population. Two polymorphisms including rs4680 and rs165774 were found to be significantly associated with schizophrenia. The rs4680 results in a Val/Met substitution but the strongest association was shown by the novel SNP, rs165774, which may still be functional even though it is located in intron five. In iduals 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. This association was slightly improved when males were analysed separately possibly indicating a degree of sexual dimorphism. Our results confirm that COMT is a good candidate for schizophrenia risk, by replicating the association with rs4680 and identifying a novel SNP association.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Future Medicine Ltd
Date: 04-2022
Abstract: Chronic lung allograft dysfunction (CLAD) affects approximately 50% of all lung transplant recipients by 5 post-operative years and is the leading cause of death in lung transplant recipients. Early CLAD diagnosis or ideally prediction of CLAD is essential to enable early intervention before significant lung injury occurs. New technologies have emerged to facilitate biomarker discovery, including epigenetic modification and single-cell RNA sequencing. This review examines new and existing technologies for biomarker discovery and the current state of research on biomarkers for identifying lung transplant rejection.
Publisher: Informa UK Limited
Date: 09-11-2017
DOI: 10.1080/15622975.2016.1245443
Abstract: To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene. DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex s les from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing. Expression, methylation and genotype data were correlated and examined for association with schizophrenia. There was 43% more of the BDNF V-VIII-IX transcript in schizophrenia s les. BDNF mRNA expression and DNA methylation of seven CpG sites were not associated with schizophrenia after accounting for age and PMI effects. BDNF mRNA expression and DNA methylation were not altered by Val66Met after accounting for age and PMI effects. DNA methylation of one CpG site had a marginally significant positive correlation with mRNA expression in schizophrenia subjects. Schizophrenia risk was not associated with differential BDNF mRNA expression and DNA methylation. A larger age-matched cohort with comprehensive clinical history is required to accurately identify the effects of genotype, mRNA expression and DNA methylation on schizophrenia risk.
Publisher: Mary Ann Liebert Inc
Date: 10-2014
Abstract: Stress has been identified as a common trigger for psychosis. Dopamine pathways are suggested to be affected by chronic and severe stress and to play an important role in psychosis. This pilot study investigates the potential relationship of stress and psychosis in subclinical psychotic experiences. It was hypothesized that single-nucleotide polymorphisms (SNPs) previously found to be associated with psychiatric disorders would be associated with both stress and subclinical psychotic experiences. University students (N=182) were genotyped for 17 SNPs across 11 genes. Higher stress reporting was associated with rs4680 COMT, rs13211507 HLA region, and rs13107325 SLC39A8. Reports of higher subclinical psychotic experiences were associated with DRD2 SNPs rs17601612 and rs658986 and an AKT1 SNP rs2494732. Replication studies are recommended to further pursue this line of research for identification of markers of psychosis for early diagnosis and intervention.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.PSYCHRES.2011.09.024
Abstract: 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 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P=0.003). Analysis of the combined genotypes of both SNPs revealed that in iduals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P=0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.
Publisher: Elsevier BV
Date: 05-2001
Publisher: Oxford University Press (OUP)
Date: 11-05-2012
Abstract: 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. The C957T polymorphism was genotyped in 228 patients with alcohol dependence (72 females and 156 males) and 228 healthy controls. The C-allele and C/C genotype of C957T was associated with alcohol dependence, whereas the TaqIA polymorphism was not. When analysed separately for C957T, males showed an even stronger association with the C-allele and females showed no association. The C957T and TaqIA haplotyping revealed a strong association with alcohol dependence and a double-genotype analysis (combining C957T and TaqIA genotypes) revealed that the relative risk of different genotypes varied by up to 27-fold with the TT/A1A2 having an 8.5-fold lower risk of alcohol dependence than other genotypes. Decreased DRD2 binding associated with the C-allele of the DRD2 C957T polymorphism is likely to be important in the underlying pathophysiology of at least some forms of alcohol dependence, and this effect appears to be limited to males only.
Publisher: Bentham Science Publishers Ltd.
Date: 09-2008
DOI: 10.2174/157016308785739811
Abstract: Single nucleotide polymorphisms (SNPs) are unique genetic differences between in iduals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of s les for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable in idualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2003
Abstract: The melanocortins are a group of small protein hormones derived by post-translational cleavage of the proopiomelanocortin (POMC) gene product. The known melanocortin hormones include alpha-melanocyte stimulating hormone (MSH), beta-MSH, gamma-MSH and adrenocorticotropic hormone (ACTH). Five melanocortin receptors (MCIR through to MC5R) have been identified and most of these show tissue-specific expression patterns, as well as different binding affinities for each of the melanocortin hormones. The central melanocortin system consists of alpha-MSH, agouti-related protein (AGRP), MC3R and MC4R. AGRP and alpha-MSH are believed to be the natural antagonist and agonist respectively of MC3R and MC4R. This central melanocortin system is thought to play a fundamental role in the control of feeding and body weight. Knock-out mice models and genetic studies have pointed to the importance of the melanocortins in complex human pathways such as pigmentation, lipolysis, food intake, thermogenesis, sexual behaviour, memory and inflammatory response. Recently the melanocortins and their receptors have been the target for drug-based treatment of human physiological processes. MC3R and MC4R are likely targets for controlling body weight MCIR may be used in the treatment of inflammation and MC2R for the treatment of glucocortical deficiency. A role for MCSR still remains unclear, but the evidence suggests an exocrine gland function.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JANXDIS.2014.09.014
Abstract: 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. Genome-wide association studies have been limited due to the large s le size required to reach statistical power. Studies have shown that GxE interactions are important for PTSD susceptibility. Epigenetics plays an important role in PTSD susceptibility and some of the most promising studies show stress and child abuse trigger epigenetic changes. Much of the molecular genetics of PTSD remains to be elucidated. However, it is clear that identifying genetic markers and environmental triggers has the potential to advance early PTSD diagnosis and therapeutic interventions and ultimately ease the personal and financial burden of this debilitating disorder.
Publisher: Hindawi Limited
Date: 07-2007
DOI: 10.1002/HUMU.20504
Abstract: Human pigmentation is a complex physical trait in which the membrane-associated transporter protein (MATP) plays an important role as it is involved in intracellular processing and trafficking of melanosomal proteins. Recently, pathogenic mutations in MATP have been shown to cause oculocutaneous albinism type 4, while other polymorphisms are known to have a role in normal pigmentation variation. We previously reported significant associations of two coding region polymorphisms with hair, skin, and eye color in Caucasians. Here we characterize the promoter region of MATP identifying two new transcription start sites and a novel duplication (c.-1176_-1174dupAAT). A total of 700 in iduals from five different population groups (529 Caucasians, 38 Asians, 46 African Americans, 47 Australian Aborigines, and 40 Spanish Basques) were genotyped for known promoter polymorphisms c.-1721C>G (rs13289) and c.-1169G>A (rs6867641), as well as c.-1176_-1174dupAAT. Allele frequencies of all three polymorphisms were significantly different between population groups. In Caucasians, the -1721G, +dup, and -1169A alleles were significantly associated with olive skin color. The three promoter polymorphisms were found to be in linkage disequilibrium with each other but not with the two previously reported coding region polymorphisms. Functional analyses in a melanoma cell line showed that the promoter haplotype -1721G, +dup, -1169A significantly decreased MATP transcription. This report provides further evidence for the involvement of MATP in normal pigmentation variation by identifying associations between MATP alleles and skin color variation in Caucasians and demonstrating a functional significance of these polymorphisms.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.PSYCHRES.2018.10.051
Abstract: Several studies have established that Major depressive disorder is associated with excess inflammation with an elevation of both pro and anti-inflammatory cytokines in major depressive disorder. In addition, in iduals with major depressive disorder are at higher risk of developing coronary artery disease. The role of innate immunity and NFκB-mediated inflammation in depression and its increased association with coronary artery disease is yet to be fully elucidated. Polymorphisms in the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat and Pyrin Domain Containing 12 (NLRP12), are associated with depression and coronary artery disease in trauma exposed in iduals. In a cohort of Vietnam War veterans (n = 299) NLRP12 polymorphisms were analysed for association with depression and coronary calcium scores. The NLRP12 polymorphism, rs34436714 was associated with a higher DASS21 Score for depression (p = 0.037). NLRP12 polymorphisms rs34971363 and rs6509825 (p = 0.022 and p = 0.020) were associated with raised coronary calcium score. To our knowledge, this is the first time rs34436714 has been investigated in Vietnam veterans identifying AC as a risk genotype for depression in Caucasian cohorts. It is also the first time the rs34971363 (CG) and rs6509825 (CT) genotype have been associated with raised coronary calcium score.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2022
DOI: 10.1038/S41380-022-01776-4
Abstract: Posttraumatic stress disorder (PTSD) is a heritable (h
Publisher: Springer Science and Business Media LLC
Date: 08-10-2019
DOI: 10.1038/S41467-019-12576-W
Abstract: 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. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2 , is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.
Publisher: SAGE Publications
Date: 10-10-2018
Abstract: Several studies have demonstrated a link between post-traumatic stress disorder and myocardial infarction. We aim to determine what phenotypic features or symptom profile associated with cardiovascular disease may help with early detection and intervention. This is a cross-sectional study. The study population comprises trauma-exposed Vietnam War veterans. Variables significantly associated with myocardial infarction from the bivariate analysis were avoidance memories, avoidance reminders and sleep disturbance. These variables were put into a logistic regression with known risk factors for myocardial infarction. Only sleep disturbance retained its effect, with a p-value of 0.015. It is concluded that sleep disturbance may be a modifiable risk factor in the treatment and prevention of myocardial infarction.
Publisher: SAGE Publications
Date: 31-10-2013
Abstract: Although the advent of atypical, second-generation antipsychotics (SGAs) has resulted in reduced likelihood of akathisia, this adverse effect remains a problem. It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. The aim of this study was to identify whether the A1(T) allele of DRD2/ANKK1 was associated with akathisia (as measured by Barnes Akathisia Rating Scale) in a clinical s le of 234 patients who were treated with antipsychotic drugs. Definite akathisia (a score ≥ 2 in the global clinical assessment of akathisia) was significantly less common in subjects who were prescribed SGAs (16.8%) than those prescribed FGAs (47.6%), p 0.0001. Overall, 24.1% of A1+ patients (A1A2/A1A1) who were treated with SGAs had akathisia, compared to 10.8% of A1- (thus, A2A2) patients. A1+ patients who were administered SGAs also had higher global clinical assessment of akathisia scores than the A1- subjects ( p = 0.01). SGAs maintained their advantage over FGAs regarding akathisia, even in A1+ patients who were treated with SGAs. These results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs, and these variants may explain inconsistencies found across prior studies, when comparing FGAs and SGAs.
Publisher: MDPI AG
Date: 02-2023
DOI: 10.3390/IJMS24032712
Abstract: Redox imbalance or oxidative stress that results from both environmental and genetic factors is observed in patients with schizophrenia. Therefore, identifying markers of oxidative stress in the early stages of psychosis and using antioxidant treatments as an adjuvant to antipsychotics has important implications. The reaction of p-N,N-dimethylaminobenzaldehyde (DMAB) with pyrrole moieties has been well studied for well over a century for use as a marker of oxidative stress dysregulation. Throughout this time, pyrroles have been investigated with varying veracity in urine extracts to identify elevated levels in patients diagnosed with schizophrenia. Since the 1960’s, various claims have been made with respect to what causes the colour change when DMAB is added to urine extracts. Whilst the substances from this reaction have not been fully elucidated, an objective look at most studies indicates that urobilinogen is likely to be one them. Urobilinogen has also been identified as a major interferent in our results. Both pyrroles and urobilinogen condense the DMAB reaction system (form condensation products) and are quite different. The urobilinogen detected in urine forms when gut microflora chemically reduces the bilirubin content of bile acids. In comparison, evidence suggests that the pyrrole fraction originates from the fragmentation of regulatory haem by reactive oxygen species (ROS) such as hydrogen peroxide and super and nitrous oxides. Clinical studies in our laboratories have established that pyrroles as a urine biomarker have specificity in detecting schizophrenia however, caution must be applied as the readings are subject to interference by other DMAB active compounds that are present, such as urobilinogen. This review highlights the initial chemistry in isolating pyrroles and provides recommendations for standardised laboratory testing to ensure pyrroles are correctly measured and distinguished from other by-products.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.JAD.2012.10.013
Abstract: Posttraumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-d-aspartate (NMDA) activity, was investigated in combat veterans. A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control in iduals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p=0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p=0.002 F=6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p=0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p=0.001). The s le sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide.
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.COMPPSYCH.2017.01.015
Abstract: Posttraumatic stress disorder (PTSD) is associated with increased inflammation and comorbid medical conditions. However, study findings for in idual inflammatory marker levels have been inconsistent. Some research suggests that resilience may play a role in decreased inflammation. A polymorphism in the promoter region of the tumor necrosis factor α gene (TNFα), TNFA -308 (rs1800629) is associated with psychiatric illness but its role in PTSD is yet to be elucidated. This study investigates a key inflammatory marker, TNFα, for its role in PTSD severity. In a cohort of trauma-exposed Vietnam War veterans (n=299 159 cases, 140 controls) TNF α serum levels and TNFα polymorphism rs1800629 were correlated with PTSD severity and resilience scores. The polymorphism was associated with PTSD severity (p=0.045). There were significant group differences between cases and controls with regards to serum TNFα levels (p=0.036). Significant correlations were found between PTSD severity and elevated TNFα levels (r=0.153 p=0.009), and between resilience and decreased TNFα levels at a trend level (p=0.08) across the entire cohort. These relationships were non-significant after controlling for covariates. In the PTSD diagnostic group, a correlation of TNFα and PTSD severity was observed on a trend level (p=0.06), the relationship between TNFα and resilience remained non-significant. To our knowledge, this is the first time rs1800629 has been investigated in PTSD contributing to a growing body of literature that identifies the GG as a risk genotype for psychiatric disorders in Caucasian cohorts. However, more research is needed to replicate our results in larger, equally well-characterized cohorts. The relationship between serum TNFα levels and PTSD severity and resilience requires further investigation.
Publisher: SAGE Publications
Date: 06-04-2016
Abstract: 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. In a cross-sectional study, we examined 2 dopamine D2 receptor (DRD2) single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia (C939 T, rs6275 and C957 T, rs6277) along with fasting blood glucose and body mass index (BMI) in 207 antipsychotic-treated patients with schizophrenia. All participants met DSM-IV criteria for schizophrenia, and those with other psychiatric disorders were excluded. Analysis of covariance was used to compare fasting glucose results by DRD2 genotypes, after controlling for known confounds. For significant associations, follow-up Bonferroni post hoc tests examined differences in fasting glucose levels between genotypes. Specific comparisons were also made using analysis of variance and chi-square (Fisher’s exact test). The 2 DRD2 risk genotypes were associated with significant increases in blood glucose, after controlling for BMI, age, sex, dosage and type of antipsychotic medication, number of hospitalisations, and negative symptoms (rs6275, F(2, 182) = 5.901, P = 0.003 rs6277 SNP, F(2, 178) = 3.483, P = 0.033). These findings support the involvement of DRD2 not only in schizophrenia but also in elevated levels of blood glucose commonly found in antipsychotic-treated patients with schizophrenia. Our data support the notion that diabetes may not merely be a comorbid condition but could be fundamentally associated with the pathogenesis of schizophrenia itself.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.GENE.2019.02.067
Abstract: Brain-derived neurotrophic factor (BDNF) gene is associated with increased risk of posttraumatic stress disorder (PTSD) and plays a role in neuroplasticity, cognition and memory. BDNF has strong potential as a therapeutic target as studies have shown that antidepressants, electroconvulsive treatment and exercise modulate BDNF expression and methylation. In this study we examined the role of BDNF methylation and expression in PTSD and the implications of exercise in mediating these effects. BDNF DNA methylation and gene expression analysis was performed in a s le of 96 male Vietnam veterans. Cases were combat-exposed veterans with current PTSD (n = 48) and controls were combat exposed veterans with no past or current PTSD diagnosis (n = 48). No association between BDNF mRNA and PTSD was identified. PTSD was associated with decreased methylation at three BDNF CpG sites (cg01546433 P = 0.004835 cg24650785 P = 0.000259 and cg002298481 P = 0.000672). Differential BDNF methylation was associated with exercise, with active exercise associated with lower methylation levels at three CpG sites (cg04481212 P = 0.005 cg01546433 P = 0.025 and cg00298481 P = 0.035). Given that exercise mediates BDNF action on cognitive plasticity, exercise may be a non-invasive, drug free option in the treatment of PTSD.
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JPSYCHIRES.2019.06.001
Abstract: In this study we investigated genome-wide sperm DNA methylation patterns in trauma-exposed Vietnam veterans. At the genome-wide level, we identified 3 CpG sites associated with PTSD in sperm including two intergenic and one CpG within the CCDC88C gene. Of those associated with PTSD in sperm at a nominal level, 1868 CpGs were also associated with PTSD in peripheral blood (5.6% overlap) including the RORA, CRHR1 and DOCK2 genes that have been previously implicated in PTSD. A total of 10 CpG sites were significantly associated with a reported history of a diagnosed mental health condition in children and reached genome-wide significance. CpGs associated with a history of a reported mental health condition in children were also enriched (90% of tested genes) for genes previously reported to be resistant to demethylation, making them strong candidates for transgenerational inheritance. In conclusion, our findings identify a unique sperm-specific DNA methylation pattern that is associated with PTSD.
Publisher: Elsevier BV
Date: 10-2005
DOI: 10.1016/J.PEPTIDES.2004.12.031
Abstract: In addition to its role in human pigmentation, components of the melanocortin system regulate appetite, energy homeostasis and hormone production. Recent studies have suggested possible roles of this system in immunity, transmission of pain signals, and reproductive potential. A number of polymorphisms have been identified in genes of the melanocortin system and are associated with pigmentation in humans, as well as being causative of disorders of adrenal hormone production and obesity. This review gives an outline of these polymorphisms, their functional significance and possible application to or impact on diagnosis and pharmacotherapy based on melanocortin pathways.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.GENE.2019.144163
Abstract: Previous studies have established that coronary artery disease is associated with excess inflammation. These studies have shown an elevation of both pro and anti-inflammatory cytokines in sufferers of coronary artery disease. There is increasing interest in the role played by the inflammasome Nod Like Receptor family pyrin domain containing 3 (NLRP3) in the aetiology of coronary artery disease. Increased severity of coronary artery disease correlates with higher levels of expression of NLRP3. Does NLRP3 polymorphisms play a role in the aetiology of coronary artery disease? In a cohort of Vietnam War (n-299) veterans who have been previously exposed to trauma, NLRP3 polymorphisms were analysed for association with coronary calcium scores using analyses of variance. Independent t-test was used to analyse genotypes. In s les with a small representation of minor homozygotes, genotypes were combined and analysed using independent t-test. If any of the genotype analysis suggested the potential for a dominant or a recessive model the model was further explored. Hardy-Weinberg Equilibrium was calculated using Hardy-Weinberg equilibrium calculator including analysis for ascertainment bias. The NLRP3 polymorphism, rs10159239 was significantly associated (p = 0.001) with a higher raised coronary calcium score. The Single Nucleotide Polymorphism rs10159239 was examined by logistic regression with known risk factors for Coronary artery disease and remained significant (0.035). This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. Further research is needed to replicate our results in larger well-characterised cohorts.
Publisher: Cambridge University Press (CUP)
Date: 06-2015
DOI: 10.1016/J.EURPSY.2015.01.008
Abstract: Dystrobrevin binding protein 1 ( DTNBP1 ) is a schizophrenia susceptibility gene involved with neurotransmission regulation (especially dopamine and glutamate) and neurodevelopment. The gene is known to be associated with cognitive deficit phenotypes within schizophrenia. In our previous studies, DTNBP1 was found associated not only with schizophrenia but with other psychiatric disorders including psychotic depression, post-traumatic stress disorder, nicotine dependence and opiate dependence. These findings suggest that DNTBP1 may be involved in pathways that lead to multiple psychiatric phenotypes. In this study, we explored the association between DTNBP1 SNPs (single nucleotide polymorphisms) and multiple psychiatric phenotypes included in the Diagnostic Interview of Psychosis (DIP). Five DTNBP1 SNPs, rs17470454, rs1997679, rs4236167, rs9370822 and rs9370823, were genotyped in 235 schizophrenia subjects screened for various phenotypes in the domains of depression, mania, hallucinations, delusions, subjective thought disorder, behaviour and affect, and speech disorder. SNP-phenotype association was determined with ANOVA under general, dominant/recessive and over-dominance models. Post hoc tests determined that SNP rs1997679 was associated with visual hallucination SNP rs4236167 was associated with general auditory hallucination as well as specific features including non-verbal, abusive and third-person form auditory hallucinations and SNP rs9370822 was associated with visual and olfactory hallucinations. SNPs that survived correction for multiple testing were rs4236167 for third-person and abusive form auditory hallucinations and rs9370822 for olfactory hallucinations. These data suggest that DTNBP1 is likely to play a role in development of auditory related, visual and olfactory hallucinations which is consistent with evidence of DTNBP1 activity in the auditory processing regions, in visual processing and in the regulation of glutamate and dopamine activity.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Mary Ann Liebert Inc
Date: 08-2016
Abstract: This exploratory study examined the association between exposure to stressful life events, polymorphisms (rs165774 and rs4680) in the catechol-O-methyltransferase (COMT) gene, and risk of depression in women. A cross-sectional design gathered information from 150 Australia women, aged 60-70 years, on sociodemographics, stressful life events, and depressive symptoms. Participants also provided buccal cell swabs for genetic analysis. Among women exposed to stressful life events, the odds of depressive symptoms increased by 18% with each additional exposure (95% confidence interval [95% CI] 1.04-1.33, p = 0.007). Women who carried at least one "A" allele (AA/AG) for both rs165774 and rs4680 single nucleotide polymorphisms were less likely to report depressive symptoms (compared with women with the GG genotype p = 0.019 and p = 0.037, respectively), although moderation analysis did not support the hypotheses of an interaction with stressful life events (rs165774: odds ratio [OR] = 1.13, 95% CI 0.87-1.46, p = 0.347 rs4680: OR = 1.15, 95% CI 0.91-1.44, p = 0.238). Our research suggests that women with polymorphisms in COMT were less susceptible to depressive symptoms but these polymorphisms do not appear to influence susceptibility to depression in those exposed to life stressors. Further research should consider other genetic variants in catecholamine pathways and their potential impact on women's mental health.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JPSYCHIRES.2010.09.014
Abstract: Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia. A s le of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi(2) test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF). Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion. In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.
Publisher: MDPI AG
Date: 22-09-2023
Publisher: Wiley
Date: 10-03-2006
DOI: 10.1111/J.1600-0749.2006.00301.X
Abstract: To date, a role for agouti signalling protein (ASIP) in human pigmentation has not been well characterized. It is known that agouti plays a pivotal role in the pigment switch from the dark eumelanin to the light pheomelanin in the mouse. However, because humans do not have an agouti banded hair pattern, its role in human pigmentation has been questioned. We previously identified a single polymorphism in the 3'-untranslated region (UTR) of ASIP that was found at a higher frequency in African-Americans compared with other population groups. To compare allele frequencies between European-Australians and indigenous Australians, the g.8818A --> G polymorphism was genotyped. Significant differences were seen in allele frequencies between these groups (P < 0.0001) with carriage of the G allele highest in Australian Aborigines. In the Caucasian s le set a strong association was observed between the G allele and dark hair colour (P = 0.004) (odds ratio 4.6 95% CI 1.4-15.27). The functional consequences of this polymorphism are not known but it was postulated that it might result in message instability and premature degradation of the transcript. To test this hypothesis, ASIP mRNA levels were quantified in melanocytes carrying the variant and non-variant alleles. Using quantitative real-time polymerase chain reaction the mean ASIP mRNA ratio of the AA genotype to the AG genotype was 12 (P < 0.05). This study suggests that the 3'-UTR polymorphism results in decreased levels of ASIP and therefore less pheomelanin production.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.BBI.2018.08.014
Abstract: Posttraumatic stress disorder (PTSD) is a serious condition that emerges following trauma exposure and involves long-lasting psychological suffering and health-issues. Uncovering critical genes and molecular networks is essential to understanding the biology of the disorder. We performed a genome-wide scan to identify transcriptome signatures of PTSD. Genome-wide peripheral blood transcriptomic data from 380 service personnel were investigated. This included a discovery s le of 96 Australian Vietnam War veterans and two independent pre and post-deployment replication s les of U.S. Marines (N = 188 and N = 96). A total of 60 transcripts were differentially expressed between veterans with and without PTSD, surviving Bonferroni multiple testing correction. Genes within the cytokine-cytokine receptor interaction, Jak-STAT signaling and Toll-like receptor signaling pathways were enriched. For 49% of the genes, gene expression changes were also accompanied by DNA methylation changes. Using replication data from two U.S. Marine cohorts, we observed that of the differentially expressed genes, 71% genes also showed significant gene expression changes between pre and post-deployment. Weighted gene co-expression networks revealed two modules of genes associated with PTSD. The first module (67 genes, p-value = 6e-4) was enriched for genes within the 11p13 locus including BDNF. The second module (266 genes, p-value = 0.01) was enriched for genes in 17q11 including SLC6A4, STAT5A and STAT5B. We identified novel transcriptomic loci and biological pathways for PTSD in service personnel. Network analysis revealed enrichment of loci harboring key candidate genes in PTSD. These findings highlight the role of transcriptional biomarkers in the molecular etiology of PTSD.
Publisher: Oxford University Press (OUP)
Date: 2021
Abstract: Biological markers that evaluate physical healing as well as psychological impact of a burn are essential for effective treatment of paediatric burns. The objective of this review is to summarize the evidence supporting the use of biomarkers in children with burns. An extensive review of the literature was performed using PubMed. A total of 59 biomarkers were identified relating to burn presence, specifically relating to processes involved in inflammation, wound healing, growth and metabolism. In addition, biomarkers involved in the stress response cascade following a burn trauma were also identified. Although many biomarkers have been identified that are potentially associated with burn-related physical and psychological trauma, an understanding of burn biology is still lacking in children. We propose that future research in the field of children’s burns should be conducted using broad screening methods for identifying potential biomarkers, examine the biological interactions of different biomarkers, utilize child-appropriate biological fluids such as urine or saliva, and include a range of different severity burns. Through further research, the biological response to burn injury may be fully realized and clinically relevant diagnostic tests and treatment therapies utilizing these biomarkers could be developed, for the improvement of healing outcomes in paediatric burn patients.
Publisher: Oxford University Press (OUP)
Date: 08-2013
DOI: 10.1017/S1461145711001659
Abstract: Dysfunction of dopamine D3 receptors, particularly in the mesocorticolimbic system, has been linked to the pathogenesis of major depression. Preclinical data show enhanced D3 receptor binding in the striatum upon antidepressant medication and electroconvulsive therapy (ECT). Thus, the potential impact of dopamine D3 receptor gene (DRD3) variation on ECT outcome in treatment-resistant major depression was evaluated by applying a combined molecular and imaging genetic approach. Altogether, 10 representative variants covering 95.4% of DRD3 gene variation were investigated for association with response to ECT in a s le of 104 (71 female, 33 male) Caucasian patients with pharmacorefractory major depression. Additionally, ventral striatum responsiveness to happy faces was assessed in two independent s les of depressed patients (total N=54) by means of functional magnetic resonance imaging at 3 T. Significant association of DRD3 rs3732790, rs3773679 and rs9817063 variants with response (uncorrected p=0.02–0.03) and remission (uncorrected p=0.01) after ECT was discerned. Logistic regression analyses revealed association of rs3732790 (uncorrected p=0.009 corrected p=0.045) and rs3773679 (uncorrected p=0.009 corrected p=0.045) with remission when applying a recessive model of inheritance. The rs3732790T allele conferring a more favourable treatment response was furthermore found to be associated with stronger striatal responsiveness to happy facial expressions (s le 1: cluster-corrected p=0.002 s le 2: p=0.023). In summary, the present study suggests some impact of DRD3 gene variation on ECT response, potentially mediated by alteration of striatal engagement during the processing of emotionally rewarding stimuli.
Publisher: Elsevier BV
Date: 05-2010
Publisher: Elsevier BV
Date: 02-2018
Publisher: Hindawi Limited
Date: 2009
DOI: 10.1002/DA.20517
Abstract: Variations in genes related to the dopaminergic pathway have been implicated in neuropsychiatric disorders such as schizophrenia, substance misuse, Alzheimer's disease and Post Traumatic Stress Disorder (PTSD). A single nucleotide polymorphism (SNP) (957C>T) and a deletion polymorphism (-141delC) in the DRD2 gene and a SNP (Taq1A) in a gene directly downstream of DRD2 have all been implicated in dopamine functioning in the brain. To test the importance of these three polymorphisms in PTSD susceptibility, a genetic screen was performed in 127 war veterans diagnosed with PTSD and 228 control in iduals without a history of PTSD. No significant association was found between PTSD and the Taq1A or -141delC polymorphisms. However, a significant association was observed with PTSD and the 957C>T polymorphism. PTSD in iduals were more likely to carry the C allele compared to the controls (P=0.021). Our findings suggest that the 957C>T polymorphism in the DRD2 gene is one of the genetic factors for susceptibility to PTSD.
Publisher: Public Library of Science (PLoS)
Date: 19-02-2014
Publisher: Elsevier BV
Date: 04-2022
No related grants have been discovered for Joanne Voisey.