Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Discovery of 95 PTSD loci provides insight into genetic architecture and neurobiology of trauma and stress-related disorders.

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E ), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC ), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B ), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK ). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Post-traumatic stress disorder in the Canadian Longitudinal Study on Aging: A genome-wide association study.

OBJECTIVE: Canada exhibits one of highest lifetime prevalence for post-traumatic stress disorder (PTSD), but the etiology of this debilitating mental health condition still remains largely unknown. This study aims to examine the genetics of PTSD in the Canadian Longitudinal Study on Aging (CLSA) to identify potential genetic factors involved in the development of PTSD. METHOD: The CLSA sample was screened for primary (PTSD status) and secondary outcomes (avoidance, detachment, guardedness, and nightmares) based on the Primary Care PTSD Screen Scale (PC-PTSD). After GWAS quality control and whole-genome imputation, single-marker, gene-based, and polygenic risk score (PRS) analyses were performed. RESULTS: Based on available genotype and phenotype data, N = 16,535 individuals were selected for the analyses. While genome-wide analyses did not show significant findings for our primary and secondary outcomes, PRS analyses showed variable levels of association between PC-PTSD items with trauma, major depressive disorder, schizophrenia, bipolar disorder, educational attainment, and insomnia (p < 5e-4). CONCLUSION: This is the first GWAS of PTSD status and individual PC-PTSD items in a population sample of older adults from Canada. This study was also able to replicate findings from previous studies. Genetic investigations into individual symptom components of PTSD may help untangle the complex genetic architecture of PTSD.

Liver enzyme CYP2D6 gene and tardive dyskinesia.

Background: Tardive dyskinesia (TD) is an iatrogenic involuntary movement disorder occurring after extended antipsychotic use with unclear pathogenesis. CYP2D6 is a liver enzyme involved in antipsychotic metabolism and a well-studied gene candidate for TD. Materials & methods: We tested predicted CYP2D6 metabolizer phenotype with TD occurrence and severity in our two samples of European chronic schizophrenia patients (total n = 198, of which 82 had TD). Results: TD occurrence were associated with extreme metabolizer phenotype, controlling for age and sex (p = 0.012). In other words, individuals with either increased and no CYP2D6 activity were at higher risk of having TD. Conclusion: Unlike most previous findings, TD occurrence may be associated with both extremes of CYP2D6 metabolic activity rather than solely for poor metabolizers.

Association Study of the Complement Component C4 Gene in Tardive Dyskinesia.

Tardive dyskinesia (TD) is a movement disorder that may develop in schizophrenia patients being treated long-term with antipsychotic medication. TD interferes with voluntary movements and leads to stigma, and can be associated with treatment non-adherence. The etiology of TD is unclear, but it appears to have a genetic component. There is emerging evidence of immune dysregulation in TD. In the current study, we set out to investigate the complex schizophrenia-associated complement component 4 (C4) gene for possible association with TD occurrence and TD severity as assessed by the Abnormal Involuntary Movement Scale (AIMS) in a sample of 129 schizophrenia patients of European ancestry. We have genotyped the copy numbers of long and short forms of C4A and C4B gene variants in 129 European ancestry patients with schizophrenia or schizoaffective disorder. We did not find predicted C4A or C4B expression to be nominally associated with TD risk or severity. However, we found the number of copies of C4BL to be nominally associated with TD severity (p = 0.020).

An examination of genes, stress and suicidal behavior in two First Nations communities: The role of the brain-derived neurotropic factor gene.

Suicide claims over 800,000 lives each year worldwide. Suicide rates in indigenous populations in Canada are about double that of the national average, making it a serious public health issue. Numerous factors are involved in suicide risk, including genetic factors, as well as various psychosocial stressors, such as historical experience with the Indian Residential School system for Indigenous populations, as well as protective variables such as social support. Here, we report the first genetic study of suicidal behaviors that includes multiple measures of stress and social supports. We investigated the role of the functional Val66Met marker (rs6265) in the Brain-Derived Neurotropic Factor (BDNF) gene in suicidal ideation and suicide attempt in a First Nations community sample (N = 278). We did not find a significant association between the BDNF rs6265 marker and suicidal behaviors. We found childhood adversities, recent life stress, chronic stress, perceived stress, difficulties, and hazardous alcohol use to be associated with both suicidal ideation and suicide attempt. Thus, while additional studies with larger samples are required to elucidate the genetic component of suicide, addressing environmental stressors may be important for suicide prevention.

Genetic testing for CYP2D6 and CYP2C19 suggests improved outcome for antidepressant and antipsychotic medication.

Individuals carrying genetic variants that result in non-extensive CYP2D6 and CYP2C19 enzyme activity seem to be more prone to non-response and side-effects of psychotropic medications. Therefore, tailoring prescriptions using genetic information may improve patient outcomes. This study examined treatment outcome in psychiatric care after CYP2D6 and CYP2C19 genetic information was provided to patients and physicians. CYP2D6 and CYP2C19 genotyping, assessment of side effects and medical histories were obtained from 80 subjects who were prescribed either antidepressant or antipsychotic medications. Our measure of outcome was mainly physicians' opinions however UKU side effects scores were also used. For CYP2D6, we calculated an activity score based on genotype and psychiatric medications. Correlation analysis was performed for CYP2D6 activity scores and UKU scores. Overall, we received supportive responses from physicians who enrolled patients in our study. Notably, while almost every fourth physician reported improvement in patient outcome, not a single physician indicated that their patient's symptoms worsened after they had used a pharmacogenetic report to guide treatment. We did not observe statistically significant differences in side effects. Overall, our results suggest improved patient outcome following pharmacogenetic testing; nonetheless, more research is required to assess the exact benefit of pharmacogenetics in clinical practice.

Investigation of the HSPG2 Gene in Tardive Dyskinesia - New Data and Meta-Analysis.

Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD.

Genetic testing as a supporting tool in prescribing psychiatric medication: Design and protocol of the IMPACT study.

OBJECTIVE: Pharmacotherapy is one of the primary treatments for psychiatric disorders. Given the variation in individual response, a more personalized approach is needed. This paper will discuss methods for user-friendly referrals, recruitment criteria, data storage and dissemination, biological sample and clinical questionnaire collection, and advertising. METHODS: The Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT) study is one of the first to use pharmacogenetic testing on a large scale in psychiatry as a tool to predict individual drug response and tolerability. As IMPACT's eligibility criteria includes all diagnoses and comorbidities, the participant population will reflect the diversity amongst mental health consumers. IMPACT's innovative study design will demonstrate the utility of this testing within the health care system. RESULTS: IMPACT has successfully implemented pharmacogenetic testing on a relatively large scale, and in both tertiary level and primary care settings. It represents a novel approach to psychiatric care and from its initial stages the design has evolved to accommodate the nature and needs of the health care community. CONCLUSION: It is anticipated that IMPACT will continue to demonstrate the feasibility of pharmacogenetic testing and facilitate its introduction and implementation in routine healthcare practice.

The Role of the Catechol-o-Methyltransferase (COMT) GeneVal158Met in Aggressive Behavior, a Review of Genetic Studies.

Aggressive behaviors have become a major public health problem, and early-onset aggression can lead to outcomes such as substance abuse, antisocial personality disorder among other issues. In recent years, there has been an increase in research in the molecular and genetic underpinnings of aggressive behavior, and one of the candidate genes codes for the catechol-O-methyltransferase (COMT). COMT is involved in catabolizing catecholamines such as dopamine. These neurotransmitters appear to be involved in regulating mood which can contribute to aggression. The most common gene variant studied in the COMT gene is the Valine (Val) to Methionine (Met) substitution at codon 158. We will be reviewing the current literature on this gene variant in aggressive behavior.

Physicians' opinions following pharmacogenetic testing for psychotropic medication.

Pharmacogenetics seeks to improve patient drug response and decrease side effects by personalizing prescriptions using genetic information. Since 2012, by one estimate, the number of patients who have had pharmacogenetic testing has doubled and this number is expected to double again by 2015. Given the increasing evidence for genetic influences on treatment response, we deemed it important to study physicians' opinions of pharmacogenetic testing. Surveys were completed by 168 Canadian physicians who had ordered at least one pharmacogenetic test (in particular for CYP2D6 or CYP2C19) for the prescription of psychiatric medication. Our results indicated that 80% of respondents believe genetic testing would become common standard in psychiatric drug treatment and 76% of respondents reported satisfactory or higher than satisfactory understanding of the pharmacogenetic report provided. Significantly more male physicians believed they had a higher understanding of the pharmacogenetic report compared to female physicians. To our knowledge, this is the only study that has assessed physicians' opinions of pharmacogenetic testing for psychotropic medication after they had received a pharmacogenetic report. Our results demonstrate a positive opinion of physicians on pharmacogenetics and indicate great potential for future clinical application.