Genetic and polygenic investigation of heart rate variability to identify biomarkers associated with Anxiety disorders.

Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.

Analysis of schizophrenia-associated genetic markers in the HLA region as risk factors for tardive dyskinesia.

OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.

Investigating the association of anxiety disorders with heart rate variability measured using a wearable device.

BACKGROUND: Reduced vagally-mediated heart rate variability (HRV) has been associated with anxiety disorders (AD). The aim of this study was to use a wearable device and remote study design to re-evaluate the association of HRV with ADs, anxiety-related traits, and confounders. METHODS: 240 individuals (AD = 120, healthy controls = 120) completed an at-home assessment of their short-term resting vagally-mediated HRV using a wristband, monitored over videoconference. Following quality control, analyses were performed investigating differences in HRV between individuals with AD (n = 119) and healthy controls (n = 116), associations of HRV with anxiety-related traits and confounders, and antidepressants effects on HRV in patients, including analyses stratified by ancestry (i.e., European, East Asian, African). RESULTS: Among the confounders investigated, only age had a significant association with HRV. Patients with an AD had significantly lower vagally-mediated HRV than healthy controls in the European subsample, with a trend of significance in the whole sample. HRV was significantly associated with the Hamilton Anxiety Rating Scale (HAM-A) but not with antidepressant use in the European subsample. LIMITATIONS: The study measures occurred in a non-standardized at-home setting, and the three ancestry group sample sizes were unequal. CONCLUSIONS: This study demonstrates reduced vagally-mediated HRV among patients with ADs compared to healthy controls. Results also point to low HRV being related to more physical anxiety symptoms (measured via HAM-A), suggesting a possible anxiety subtype. Overall, this study highlights the feasibility of using wearables for patients and encourages exploration of the biological and clinical utility of HRV as a risk factor for ADs.

User Experiences of Pharmacogenomic Testing and Opinions among Psychiatry Patients.

Pharmacogenomic testing (PGx) is a tool used to guide physicians in selecting an optimal medication for clients based on their genetic profile. The objective of this qualitative study is to understand patients' experiences with PGx testing as well as their opinions regarding the clinical adoption of such tests in psychiatry. A focus group was conducted to assess the needs of clients who had experience using a PGx test. Participants were recruited from a large study on PGx testing that offered physicians an opportunity to use PGx reports to guide psychotropic prescriptions. The focus group discussions were recorded, transcribed, and coded using NVivo to identify core themes. A total of 11 people participated in the focus group. Our analysis revealed that many participants were in favour of implementing PGx testing in psychiatric practice, and all expressed important considerations for patient-centred optimization of PGx testing. The main themes captured were: education and awareness among clinicians, cost considerations, PGx results-sharing and accessibility, and prospective benefits. The results of this study suggest that patients are keen to see PGx testing in widespread clinical care, but they report important opportunities to improve knowledge mobilization of PGx testing.

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.

Genome-Wide Association Study of Sleep Disturbances in Depressive Disorders.

Sleep disturbance affects about 75% of depressed individuals and is associated with poorer patient outcomes. The genetics in this field is an emerging area of research. Thus far, only core circadian genes have been examined in this context. We expanded on this by performing a genome-wide association study (GWAS) followed by a preplanned hypothesis-driven analysis with 27 genes associated with the biology of sleep. All participants were diagnosed by their referring physician, completed the Beck Depression Inventory (BDI), and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale at baseline. Our phenotype consisted of replies to 3 questions from these questionnaires. From standard GWAS chip data, imputations were performed. Baseline total BDI scores (n = 364) differed significantly between those with and those without sleep problems. We were unable to find any significant GWAS hits although our top hit was for changes in sleep and an intergenic marker near SNX18 (p = 1.06 × 10-6). None of the markers in our hypothesis-driven analysis remained significant after applying Bonferroni corrections. Our top finding among these genes was for rs13019460 of Neuronal PAS Domain Protein 2 with changes in sleep (p = 0.0009). Overall, both analyses were unable to detect any significant associations in our modest sample though we did find some interesting preliminary associations worth further exploration.

The effect of polymorphisms in startle-related genes on anxiety symptom severity.

Given the limited effectiveness of treatments for pathological anxiety, there is a pressing need to identify genetic markers that can aid the precise selection of treatments and optimize treatment response. Anxiety and startle response levels demonstrate a direct relationship, and previous literature suggests that exaggerated startle reactivity may serve as an endophenotype of pathological anxiety. In addition, genetic variants related to startle reactivity may play a role in the etiology of pathological anxiety. In the current study, we selected 22 single nucleotide polymorphisms (SNPs) related to startle reactivity in the literature, and examined their association with anxiety symptom severity across psychiatric disorders (n = 508), and in a subset of patients with an anxiety disorder (n = 298). Overall, none of the SNPs pass correction for multiple independent tests. However, across psychiatric patients, rs6323 from the monoamine oxidase A (MAOA) gene and rs324981 from the neuropeptide S receptor 1 (NPSR1) gene were nominally associated with baseline anxiety symptom severity (p = 0.017, 0.023). These preliminary findings provide support for investigating startle-related genetic variants to identify biomarkers of anxiety symptom severity.

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).

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.

Combinatorial pharmacogenomics and improved patient outcomes in depression: Treatment by primary care physicians or psychiatrists.

Failed medication trials are common in the treatment of major depressive disorder (MDD); however, the use of combinatorial pharmacogenomics to guide medication selection has been previously associated with improved outcomes in the psychiatric care setting. The utility of combinatorial pharmacogenomics in patients with MDD in primary care and psychiatric care settings was evaluated here. Patients enrolled in a naturalistic, open-label, prospective study [Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT)] with MDD were evaluated (N = 1871). Pharmacogenomic testing was performed for all patients and medications were categorized based on gene-drug interactions. Beck's Depression Inventory (BDI) was evaluated at baseline and follow-up (weeks 8-12). Symptom improvement (percent decrease in BDI), response (≥50% decrease in BDI), and remission (BDI≤10) at follow-up were evaluated according to provider type and whether medications were genetically congruent (little/no gene-drug interactions). There was a 27.9% reduction in depression symptoms at follow-up, as well as response and remission rates of 25.7% and 15.2%, respectively. Outcomes were significantly better among patients treated by primary care providers versus psychiatrists (symptom improvement 31.7% versus 24.9%, p < 0.01; response rate 30.1% versus 22.3%, p < 0.01; remission rate 19.5% versus 12.0%, p < 0.01). There was a 31% relative improvement in response rate among patients taking congruent versus incongruent medications, with slightly higher congruence among primary care providers (87.6%) versus psychiatrists (85.2%). Following combinatorial pharmacogenomic testing, outcomes were significantly improved among patients treated by primary care providers compared to psychiatrists, which supports the use of pharmacogenomics in broader treatment settings.

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.