Nathaniel W. McGregor

Symmetry symptoms in obsessive-compulsive disorder: clinical and genetic correlates

Objective: In obsessive-compulsive disorder (OCD), symmetry-related symptoms may be important. Although clinical correlates of symmetry-related symptoms have been identified in OCD, few data exist on genetic associations. Animal studies indicate involvement of dopamine in symmetry-related behavior, suggesting this may be relevant to analogous symptoms in OCD. Alterations in dopamine may also reflect environmental influences. However, the association of symmetry-related symptomatology, early adversity, and polymorphisms in dopaminergic genes has not been investigated in OCD. Methods: Clinical information and polymorphisms in key dopaminergic genes were compared between OCD patients with primary symmetry symptoms and those without. Results: OCD patients with primary symmetry symptoms comprised 46.6% (n=210) of the sample (n=451), and were older (p < 0.01), had longer illness duration (p < 0.01), higher OCD severity scores (p = 0.01), and greater comorbidity (p < 0.01) than those without. In Caucasians (n=343), genotype frequency differed significantly between groups for ANKK1 rs1800497, with more OCD patients with symmetry symptoms being homozygous for the A2 (CC) genotype (χ2 = 7.296; p = 0.026). Conclusion: Symmetry symptoms have some distinct clinical features and may represent a marker of severity in OCD. However, clinical associations, in combination with the association found with the ANKK1 rs1800497 A2 variant, suggest that primary symmetry symptoms may represent a distinctive clinical and psychobiological profile.

Selected Rapporteur Summaries From the XX World Congress of Psychiatric Genetics, Hamburg, Germany, October 14-18, 2012

The XXth World Congress of Psychiatric Genetics (WCPG), sponsored by The International Society of Psychiatric Genetics (ISPG) took place in Hamburg, Germany on October 14–18, 2012. Approximately 600 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned sessions as rapporteurs. This manuscript represents topics covered in most, but not all, oral presentations during the conference, and some of the major notable new findings reported at this 2012 WCPG.

DNA methylation and antipsychotic treatment mechanisms in schizophrenia: Progress and future directions

&NA; Antipsychotic response in schizophrenia is a complex, multifactorial trait influenced by pharmacogenetic factors. With genetic studies thus far providing little biological insight or clinical utility, the field of pharmacoepigenomics has emerged to tackle the so‐called “missing heritability” of drug response in disease. Research on psychiatric disorders has only recently started to assess the link between epigenetic alterations and treatment outcomes. DNA methylation, the best characterised epigenetic mechanism to date, is discussed here in the context of schizophrenia and antipsychotic treatment outcomes. The majority of published studies have assessed the influence of antipsychotics on methylation levels in specific neurotransmitter‐associated candidate genes or at the genome‐wide level. While these studies illustrate the epigenetic modifications associated with antipsychotics, very few have assessed clinical outcomes and the potential of differential DNA methylation profiles as predictors of antipsychotic response. Results from other psychiatric disorder studies, such as depression and bipolar disorder, provide insight into what may be achieved by schizophrenia pharmacoepigenomics. Other aspects that should be addressed in future research include methodological challenges, such as tissue specificity, and the influence of genetic variation on differential methylation patterns. HighlightsAntipsychotics both act upon and are influenced by DNA methylation in schizophrenia.Studies have focused on the serotonergic, dopaminergic, and GABAergic systems.Many complex factors, including genetic variation, influence DNA methylation.DNA methylation shows promise as an antipsychotic response biomarker.Recommended epigenetic studies could point to targets for epidrug development.

The genetic architecture of schizophrenia, bipolar disorder, obsessive-compulsive disorder and autism spectrum disorder

&NA; Considerable evidence suggests that autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and obsessive‐compulsive disorder (OCD) share a common molecular aetiology, despite their unique clinical diagnostic criteria. The aim of this study was therefore to determine and characterise the common and unique molecular architecture of ASD, SCZ, BD and OCD. Gene lists were obtained from previously published studies for ASD, BD, SCZ and for OCD. Genes identified to be common to all disorders, or unique to one specific disorder, were included for enrichment analyses using the web‐server tool Enrichr. Ten genes were identified to be commonly associated with the aetiology of ASD, SCZ, BD and OCD. Enrichment analyses determined that these genes are predominantly involved in the dopaminergic and serotonergic pathways, the voltage‐gated calcium ion channel gene network, folate metabolism, regulation of the hippo signaling pathway, and the regulation of gene silencing and expression. In addition to well‐characterised and previously described pathways, regulation of the hippo signaling pathway was commonly associated with ASD, SCZ, BD and OCD, implicating neural development and neuronal maintenance as key in neuropsychiatric disorders. In contrast, a large number of previously associated genes were shown to be disorder‐specific. And unique disorder‐specific pathways and biological processes were presented for ASD, BD, SCZ and OCD aetiology. Considering the current global incidence and prevalence rates of mental health disorders, focus should be placed on cross‐disorder commonalities in order to realise actionable and translatable results to combat mental health disorders. Highlights10 common genes were identified for the aetiology of ASD, SCZ, BD and OCD.The majority of genes investigated were disorder‐specific.Neural development and neuronal maintenance are key in neuropsychiatric disorders.Cross‐disorder results provide good candidates to combat mental health disorders.

Modification of the association between early adversity and obsessive-compulsive disorder by polymorphisms in the MAOA, MAOB and COMT genes

The monoamine oxidases (MAOA/B) and catechol-O-methyltransferase (COMT) enzymes break down regulatory components within serotonin and dopamine pathways, and polymorphisms within these genes are candidates for OCD susceptibility. Childhood trauma has been linked OCD psychopathology, but little attention has been paid to the interactions between genes and environment in OCD aetiology. This pilot study investigated gene-by-environment interactions between childhood trauma and polymorphisms in the MAOA, MAOB and COMT genes in OCD. Ten polymorphisms (MAOA: 3 variants, MAOB: 4 variants, COMT: 3 variants) were genotyped in a cohort of OCD patients and controls. Early-life trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Gene-by-gene (GxG) and gene-by-environment interactions (GxE) of the variants and childhood trauma were assessed using logistic regression models. Significant GxG interactions were found between rs362204 (COMT) and two independent polymorphisms in the MAOB gene (rs1799836 and rs6651806). Haplotype associations for OCD susceptibility were found for MAOB. Investigation of GxE interactions indicated that the sexual abuse sub-category was significantly associated with all three genes in haplotype x environment interaction analyses. Preliminary findings indicate that polymorphisms within the MAOB and COMT genes interact resulting in risk for OCD. Childhood trauma interacts with haplotypes in COMT, MAOA and MAOB, increasing risk for OCD.

Posttraumatic Stress Disorder, Overweight, and Obesity: A Systematic Review and Meta-analysis.

AbstractPrevious reports have suggested a high prevalence of overweight and obesity among individuals with posttraumatic stress disorder (PTSD). Few studies, however, systematically analyze the relationship between PTSD and body mass index (BMI). We conducted a systematic review and meta-analysis aimed at estimating the association between PTSD and BMI. Fifty-four articles were reviewed, 30 of which (with 191,948 individuals with PTSD and 418,690 trauma-exposed individuals or healthy controls) were eligible for inclusion in the meta-analysis. The pooled standard mean difference, based on a random-effects model, was 0.41 (95% confidence interval, 0.28–0.54; z = 6.26; p < .001). Statistical heterogeneity between the included studies was high (p < .001; I2 = 99%). Despite limitations, the findings of this systematic review and meta-analysis suggest an association between PTSD and BMI. Furthermore, longitudinal studies tentatively indicate that PTSD may lead to an increase in BMI and, as such, to the development of overweight/obesity, particularly in women. Further prospective studies and research elaborating the nature and etiology of the association are required.

A translational approach to the genetics of anxiety disorders

HighlightsVariants within matrix metallopeptidase 9 (MMP9) and brain‐derived neurotrophic factor (BDNF) are associated with risk to anxiety disorders.The relationship between childhood trauma and risk for anxiety disorders diagnoses is modified by variants in synaptic plasticity genes.The severity of childhood trauma is associated with an anxiety disorders diagnoses. Abstract There have been important advances in our understanding of the genetic architecture of anxiety disorders. At the same time, relatively few genes have reached genome wide significance in anxiety disorders, and there is relatively little work on how exposure to an adverse environment impacts on gene expression in either animal models or human clinical populations. Here we assessed differential expression of genes of the dorsal striatum involved in synaptic transmission in an animal models of early adversity (maternal separation followed by restraint stress), and investigated whether variants in these genes were associated with risk for anxiety disorders, particularly in the presence of environmental stressors. Fifty‐two male Sprague Dawley rats underwent maternal separation, and gene expression was studied using array technology. The human homologues of the differentially expressed genes were screened and analysed in a DSM‐IV anxiety disorders cohort, and healthy controls (patients, n = 92; controls, n = 194), using blood. Two candidate genes (Mmp9 and Bdnf) were aberrantly expressed in the experimental rodent group relative to controls. Four single nucleotide polymorphisms (SNPs) in the human homologues of these genes were significantly associated with susceptibility for anxiety disorders (MMP9: rs3918242 and BDNF: rs6265, rs10835210 and rs11030107). Three of these (BDNF: rs6265, rs10835210, rs11030107) were found to interact significantly with childhood trauma severity resulting in increased likelihood of an anxiety disorder diagnosis. This study provides insights into the utility of rat models for identifying molecular candidates for anxiety disorders in humans.

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

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

Variation within voltage-gated calcium channel genes and antipsychotic treatment response in a South African first episode schizophrenia cohort

Voltage-gated calcium channels have been implicated in schizophrenia aetiology; however, little is known about their involvement in antipsychotic treatment response. This study investigated variants within the calcium channel subunit genes for association with antipsychotic treatment response in a first episode schizophrenia cohort. Twelve regulatory variants within seven genes were shown to be significantly associated with treatment outcome. Most notably, the CACNA1B rs2229949 CC genotype was associated with improved negative symptomology, where the C allele was predicted to abolish a miRNA-binding site (has-mir-5002-3p), suggesting a possible mechanism of action through which this variant may have an effect. These results implicate the calcium channel subunits in antipsychotic treatment response and suggest that increased activation of these channels may be explored to enhance or predict antipsychotic treatment outcome.

Pharmacogenetics of Antiretroviral Drug Response and Pharmacokinetic Variations in Indigenous South African Populations

Interindividual and interethnic differences in response to antiretroviral drugs (ARVs) are influenced by genetic variation. The few genomic studies conducted among African-Americans and African ethnic groups do not reflect the extensive genetic diversity within African populations. ARVs are widely used in Africa. Therefore, genomic characterization of African populations is required before genotype-guided dosing becomes possible. The aim of this study was to determine and report on the frequency of genetic variants in genes implicated in metabolism and transport of ARVs in South African populations. The study comprised 48 self-reported South African Colored (SAC) and 296 self-reported Black African (BA) individuals. Allele and genotype frequency distributions for 93 variants contributing to metabolism and transport of ARVs were compared between groups, and other global populations. Fifty-three variants had significant differences in allele and genotype frequencies when comparing SAC and BA groups. Thirteen of these have strong clinical annotations, affecting efavirenz and tenofovir pharmacokinetics. This study provides a summary of the genetic variation within genes implicated in metabolism and transport of ARVs in indigenous South African populations. The observed differences between indigenous population groups, and between these groups and global populations, demonstrate that data generated from specific African populations cannot be used to infer genetic diversity within other populations on the continent. These results highlight the need for comprehensive characterization of genetic variation within indigenous African populations, and the clinical utility of these variants in ARV dosing for global precision medicine. Population pharmacogenetics is a nascent field of global health and warrants further research and education.