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.

Association study of the complement component C4 gene and suicide risk in schizophrenia.

Schizophrenia is a severe mental illness and a major risk factor for suicide, with approximately 50% of schizophrenia patients attempting and 10% dying from suicide. Although genetic components play a significant role in schizophrenia risk, the underlying genetic risk factors for suicide are poorly understood. The complement component C4 gene, an immune gene involved in the innate immune system and located in the major histocompatibility complex (MHC) region, has been identified to be strongly associated with schizophrenia risk. In addition, recent findings have also suggested that the MHC region has been associated with suicide risk across disorders, making C4 a potential candidate of interest for studying suicidality in schizophrenia patients. Despite growing interest in investigating the association between the C4 gene and schizophrenia, to our knowledge, no work has been done to examine the potential of C4 variants as suicide risk factors in patients with schizophrenia. In this study, we investigated the association between different C4 copy number variants and predicted C4 brain expression with suicidal outcomes (suicide attempts/suicidal ideation). We directly genotyped 434 schizophrenia patients to determine their C4A and C4B copy number variants. We found the C4AS copy number to be marginally and negatively associated with suicide risk, potentially being protective against suicide attempts (OR = 0.49; p = 0.05) and suicidal ideation (OR = 0.65; p = 0.07). Furthermore, sex-stratified analyses revealed that there are no significant differences between males and females. Our preliminary findings encourage additional studies of C4 and potential immune dysregulation in suicide.

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.

A potential paradigm shift in opioid crisis management: The role of pharmacogenomics.

Pharmacogenetic investigations into the opioid crisis suggest genetic variation could be a significant cause of opioid-related morbidity and mortality. Variability in opioid system genes, including single nucleotide polymorphisms, manifest after pharmacogenetic testing, as previously invisible risk factors for addiction and overdose. Pharmacodynamic genes regulate opioid-sensitive brain networks and neural reward circuitry. Pharmacokinetic genes expressed in drug metabolic pathways regulate blood levels of active vs. inactive opioid metabolites. Elucidating the complex interplay of genetic variations in pharmacokinetic and pharmacodynamic pathways will shed new light on the addictive and toxic properties of opioids. This narrative review serves to promote understanding of key genetic mechanisms affecting the metabolism and actions of opioids, and to explore causes of the recent surge in opioid-related mortality associated with COVID-19. Personalised treatment plans centred around an individual's genetic makeup could make opioid-based pain management and opioid use disorder (OUD) treatments safer and more effective at both the individual and system levels.

Barriers to clinical adoption of pharmacogenomic testing in psychiatry: a critical analysis.

Pharmacogenomics (PGx) is the study of genetic influences on an individual's response to medications. Improvements in the quality and quantity of PGx research over the past two decades have enabled the establishment of commercial markets for PGx tests. Nevertheless, PGx testing has yet to be adopted as a routine practice in clinical care. Accordingly, policy regulating the commercialization and reimbursement of PGx testing is in its infancy. Several papers have been published on the topic of challenges, or 'barriers' to clinical adoption of this healthcare innovation. However, many do not include recent evidence from randomized controlled trials, economic utility studies, and qualitative assessments of stakeholder opinions. The present paper revisits the most cited barriers to adoption of PGx testing: evidence for clinical utility, evidence for economic effectiveness, and stakeholder awareness. We consider these barriers in the context of reviewing PGx literature published over the past two decades and emphasize data from commercial PGx testing companies, since they have published the largest datasets. We conclude with a discussion of existing limitations to PGx testing and recommendations for progress.

Supporting pharmacogenetic-guided opioid prescriptions for post-operative pain: The design, protocol and preliminary results of the OTP study.

The interindividual variability in opioid response is an issue that contributes to the ongoing opioid crisis. Current evidence suggests this variability can be attributed to genetic factors. The pharmacogenetics of Opioid Treatment for acute post-operative Pain (OTP) project was a prospective study that aimed to identify genetic markers associated with opioid treatment outcomes. Healthy patients undergoing third-molar extractions were recruited from dental offices located within the Greater Toronto Area. Participants were evaluated using the Brief Pain Inventory Short Form, the Opioid Related Symptom Distress Scale, and the Leeds Dependence Questionnaire. Seventy-two participants had an active opioid prescription. Participants were prescribed one of the following opioids: codeine, morphine, hydromorphone, tramadol, or oxycodone. The majority of participants were female (57%), ranging from 16 to 44 years of age. Pain severity, pain interference, and side effects declined over the seven-day post-operative period. Additionally, 4% of participants displayed medium to high risk of dependence. It is anticipated that OTP will enable the development of a genetic test for opioid use and facilitate the introduction of this test into routine healthcare practice. The OTP study represents a novel approach to opioid treatment and has significant implications for future interventions targeting the ongoing opioid crisis. Employing a pharmacogenomic-guided strategy for prescribing opioids may improve patients' response to this treatment and, in so doing, increase adherence to the target treatment plan. Optimized prescriptions may also provide public healthcare systems with beneficial savings and reduce the risks associated with opioid use.

The pharmacogenetics of opioid treatment for pain management.

BACKGROUND: Opioids are widely used as an analgesic for the treatment of moderate to severe pain. However, there are interindividual variabilities in opioid response. Current evidence suggests that these variabilities can be attributed to single nucleotide polymorphisms in genes involved in opioid pharmacodynamics and pharmacokinetics. Knowledge of these genetic factors through pharamacogenetic (PGx) testing can help clinicians to more consistently prescribe opioids that can provide patients with maximal clinical benefit and minimal risk of adverse effects. AIM: The research outlined in this literature review identifies variants involved in opioid PGx, which may be an important tool to achieving the goal of personalized pain management. RESULTS: Cytochrome P450 (CYP) 2D6, CYP3A4, CYP3A5, catechol-o-methyltransferase (COMT), adenosine triphosphate binding cassette transporter B1 (ABCB1), opioid receptor mu 1 (OPRM1), and opioid receptor delta 1 (OPRD1) are all important genes involved in opioid drug response, side effect profile and risk of dependence; these are important genetic factors that should be included in potential opioid PGx tests for pain management. CONCLUSIONS: Employing a PGx-guided strategy for prescribing opioids can improve response rate, reduce side effects and increase adherence to treatment plans for pain; more research is needed to explore opioid-related PGx factors for the development and validation of an opioid genetic panel. Optimal prescriptions could also provide healthcare payers with beneficial savings, while reducing the risk of propagating the current opioid crisis.