Examining the Role of Neuroticism Polygenic Risk in Late Life Cognitive Change: A UK Biobank Study.

Cognitive decline is a public health concern affecting about 50 million individuals worldwide. Neuroticism, defined as the trait disposition to experience intense and frequent negative emotions, has been associated with an increased risk of late-life cognitive decline. However, the underlying biological mechanisms of this association remain unknown. This study investigated the relationship between genetic predisposition to neuroticism, computed by polygenic risk score (PRS), and performance in cognitive domains of reasoning, processing speed, visual attention, and memory in individuals over age 60. The sample consisted of UK Biobank participants with genetic and cognitive data available (N = 10,737, 4686 females; mean age = 63.4 ± 2.71). The cognitive domains were assessed at baseline for all participants and seven years later for a subset (N = 645, 262 females; mean age = 62.9 ± 2.44). Neuroticism PRS was not associated cross-sectionally with cognitive measures (p > 0.05). However, the trajectory of change for processing speed (ß = 0.020; 95% CI = [0.006, 0.035], adjusted p = 0.0148), visual attention (ß = -0.077; 95% CI = [-0.0985, -0.0553], adjusted p = 1.412 × 10-11), and memory (ß = -0.033; 95% CI = [-0.0535, -0.0131], adjusted p = 0.005) was significantly associated with neuroticism PRS. Specifically, a higher genetic predisposition to neuroticism was associated with less decline in these cognitive domains. This trend persisted after sensitivity analysis using complete cases, although it only remained nominally significant for visual attention.

Sex-dependent association study of complement C4 gene with treatment-resistant schizophrenia and hospitalization frequency.

The complement component 4 (C4) gene, codes for two isotypes, C4A and C4B, and can exist in long or short forms (C4L and C4S). The C4AL variant has been associated with elevated schizophrenia (SCZ) risk. Here, we investigated the relationship between C4 variation and clinical outcomes in SCZ. N = 434 adults with SCZ or schizoaffective disorder were included in this retrospective study. A three-step genotyping workflow was performed to determine C4 copy number variants. These variants were tested for association with clinical outcome measures, including treatment-resistant SCZ (TRS), number of hospitalizations (NOH), and symptom severity (PANSS). Sex and ancestry stratified analyses were performed. We observed a marginally significant association between C4S and TRS in males only, and a negative association between C4S and NOH in the total sample. C4AS had negative association with NOH in males and non-Europeans. Lastly, C4A copy numbers and C4A predicted brain expression showed negative association with NOH in males only. Our study provides further support for sex-specific effect of C4 on SCZ clinical outcomes, and also suggests that C4S and C4AS might have a protective effect against increased severity. C4 could potentially serve as a genetic biomarker in the future, however, more research is required.

Dopamine mediates a directionally opposite correlation between empathy and the reinforcing effects of amphetamine and gambling in people with gambling disorder vs. healthy controls.

Understanding the relationship between empathy, subjective effects of addictive reinforcers and dopamine function in people with gambling disorder (PGD) vs. healthy controls (HCs) may inform GD treatment. The current investigation addressed this issue via retrospective analysis of data from three studies using amphetamine and a slot machine (SLOTS) as reinforcers in PGD and HCs. The Empathy scale of Eysenck's Impulsiveness Questionnaire assessed trait Empathy. The Gamblers Beliefs Questionnaire assessed cognitive distortions. The Eysenck Lie scale assessed socially desirable responding. PET scans quantified dopamine receptor expression and amphetamine-induced dopamine release in Study 1. Pre-treatment with the D2-receptor (D2R)-preferring antagonist, haloperidol or D1R-D2R antagonist, fluphenazine before SLOTS tested the role of D2 autoreceptors and post-synaptic D2R in Study 2. Pre-treatment with the multi-system indirect dopamine agonist, modafinil before SLOTS assessed the reliability of correlations in PGD. Striatal D2R expression predicted greater Empathy and lower amphetamine 'Liking' in HCs, and predicted greater symptom severity in PGD. Empathy predicted lower 'Exciting' effects of SLOTS under placebo in HCs; no correlation emerged under either antagonist. Relative to placebo, haloperidol decreased, whereas fluphenazine increased, the positive correlation between Empathy and Exciting effects of SLOTS in PGD. Modafinil markedly reduced the positive correlation between Empathy and Exciting effects of SLOTS seen under placebo in PGD. Empathy predicted greater cognitive distortions in PGD in all studies. Lie scale variance influenced several primary effects. Prior research linking the insula with Empathy, reactivity to interoceptive signals for risky rewards (uncertainty), and cognitive distortions, provides a parsimonious account for these results.

Analysis of the complement component C4 gene with schizophrenia subphenotypes.

BACKGROUND: The complement component C4 gene has been identified as a strong marker for schizophrenia (SCZ) risk. The C4 gene has a complex genetic structure consisting of variable structural elements (C4A, C4B, C4L, and C4S) and compound structural forms (C4AL, C4BL, C4AS and C4BS). In addition, the variations in C4 structural forms may have a direct or indirect effect on the brain expression level of C4A and C4B proteins. Previous studies have associated C4AL with higher brain C4A expression and sex-dimorphism of C4 between males and females was observed. STUDY DESIGN: A total of 613 patients with DSM-IV SCZ or schizoaffective disorder (SCZ-AFF) were recruited to investigate the relationship between C4 gene variants and clinical characteristics of SCZ (age of onset, symptom severity, and global assessment of functioning (GAF)). This study also explored the effect of sex on the association of C4 with SCZ. 434 patients were included in the final analyses after genetic quality control. RESULTS: We observed associations between C4 and clinical characteristics of SCZ (age of onset, symptom severity, GAF) and found significant differences when males and females were examined separately. CONCLUSION: Overall, our preliminary findings encourage future investigations of C4 in SCZ-related phenotypes, including antipsychotic response and side effects. The study sample was of moderate size; therefore, further studies in larger samples are needed to extend and validate these results.

Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes.

Research demonstrates the important role of genetic factors in attention-deficit/hyperactivity disorder (ADHD). DNA sequencing of families provides a powerful approach for identifying de novo (spontaneous) variants, leading to the discovery of hundreds of clinically informative risk genes for other childhood neurodevelopmental disorders. This approach has yet to be extensively leveraged in ADHD. We conduct whole-exome DNA sequencing in 152 families, comprising a child with ADHD and both biological parents, and demonstrate a significant enrichment of rare and ultra-rare de novo gene-damaging mutations in ADHD cases compared to unaffected controls. Combining these results with a large independent case-control DNA sequencing cohort (3206 ADHD cases and 5002 controls), we identify lysine demethylase 5B (KDM5B) as a high-confidence risk gene for ADHD and estimate that 1057 genes contribute to ADHD risk. Using our list of genes harboring ultra-rare de novo damaging variants, we show that these genes overlap with previously reported risk genes for other neuropsychiatric conditions and are enriched in several canonical biological pathways, suggesting early neurodevelopmental underpinnings of ADHD. This work provides insight into the biology of ADHD and demonstrates the discovery potential of DNA sequencing in larger parent-child trio cohorts.

Neurophysiological and other features of working memory in older adults at risk for dementia.

Theta-gamma coupling (TGC) is a neurophysiological process that supports working memory. Working memory is associated with other clinical and biological features. The extent to which TGC is associated with these other features and whether it contributes to working memory beyond these features is unknown. Two-hundred-and-three older participants at risk for Alzheimer's dementia-98 with mild cognitive impairment (MCI), 39 with major depressive disorder (MDD) in remission, and 66 with MCI and MDD (MCI + MDD)-completed a clinical assessment, N-back-EEG, and brain MRI. Among them, 190 completed genetic testing, and 121 completed [11C] Pittsburgh Compound B ([11C] PIB) PET imaging. Hierarchical linear regressions were used to assess whether TGC is associated with demographic and clinical variables; Alzheimer's disease-related features (APOE ε4 carrier status and ß-amyloid load); and structural features related to working memory. Then, linear regressions were used to assess whether TGC is associated with 2-back performance after accounting for these features. Other than age, TGC was not associated with any non-neurophysiological features. In contrast, TGC (ß = 0.27; p = 0.006), age (ß = - 0.29; p = 0.012), and parietal cortical thickness (ß = 0.24; p = 0.020) were associated with 2-back performance. We also examined two other EEG features that are linked to working memory-theta event-related synchronization and alpha event-related desynchronization-and found them not to be associated with any feature or performance after accounting for TGC. Our findings suggest that TGC is a process that is independent of other clinical, genetic, neurochemical, and structural variables, and supports working memory in older adults at risk for dementia. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09938-y.

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.

Genetics of child aggression, a systematic review.

Excessive and persistent aggressiveness is the most common behavioral problem that leads to psychiatric referrals among children. While half of the variance in childhood aggression is attributed to genetic factors, the biological mechanism and the interplay between genes and environment that results in aggression remains elusive. The purpose of this systematic review is to provide an overview of studies examining the genetics of childhood aggression irrespective of psychiatric diagnosis. PubMed, PsycINFO, and MEDLINE databases were searched using predefined search terms for aggression, genes and the specific age group. From the 652 initially yielded studies, eighty-seven studies were systematically extracted for full-text review and for further quality assessment analyses. Findings show that (i) investigation of candidate genes, especially of MAOA (17 studies), DRD4 (13 studies), and COMT (12 studies) continue to dominate the field, although studies using other research designs and methods including genome-wide association and epigenetic studies are increasing, (ii) the published articles tend to be moderate in sizes, with variable methods of assessing aggressive behavior and inconsistent categorizations of tandem repeat variants, resulting in inconclusive findings of genetic main effects, gene-gene, and gene-environment interactions, (iii) the majority of studies are conducted on European, male-only or male-female mixed, participants. To our knowledge, this is the first study to systematically review the effects of genes on youth aggression. To understand the genetic underpinnings of childhood aggression, more research is required with larger, more diverse sample sets, consistent and reliable assessments and standardized definition of the aggression phenotypes. The search for the biological mechanisms underlying child aggression will also benefit from more varied research methods, including epigenetic studies, transcriptomic studies, gene system and genome-wide studies, longitudinal studies that track changes in risk/ameliorating factors and aggression-related outcomes, and studies examining causal mechanisms.

Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults.

BACKGROUND: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD. METHODS: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers. RESULTS: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = -0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = -0.335, p = 0.002). No other associations were found. LIMITATION: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center. CONCLUSION: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.

Integrative Genetic Variation, DNA Methylation, and Gene Expression Analysis of Escitalopram and Aripiprazole Treatment Outcomes in Depression: A CAN-BIND-1 Study.

INTRODUCTION: Little is known about the interplay between genetics and epigenetics on antidepressant treatment (1) response and remission, (2) side effects, and (3) serum levels. This study explored the relationship among single nucleotide polymorphisms (SNPs), DNA methylation (DNAm), and mRNA levels of four pharmacokinetic genes, CYP2C19, CYP2D6, CYP3A4, and ABCB1, and its effect on these outcomes. METHODS: The Canadian Biomarker Integration Network for Depression-1 dataset consisted of 177 individuals with major depressive disorder treated for 8 weeks with escitalopram (ESC) followed by 8 weeks with ESC monotherapy or augmentation with aripiprazole. DNAm quantitative trait loci (mQTL), identified by SNP-CpG associations between 20 SNPs and 60 CpG sites in whole blood, were tested for associations with our outcomes, followed by causal inference tests (CITs) to identify methylation-mediated genetic effects. RESULTS: Eleven cis-SNP-CpG pairs (q<0.05) constituting four unique SNPs were identified. Although no significant associations were observed between mQTLs and response/remission, CYP2C19 rs4244285 was associated with treatment-related weight gain (q=0.027) and serum concentrations of ESCadj (q<0.001). Between weeks 2-4, 6.7% and 14.9% of those with *1/*1 (normal metabolizers) and *1/*2 (intermediate metabolizers) genotypes, respectively, reported ≥2 lbs of weight gain. In contrast, the *2/*2 genotype (poor metabolizers) did not report weight gain during this period and demonstrated the highest ESCadj concentrations. CITs did not indicate that these effects were epigenetically mediated. DISCUSSION: These results elucidate functional mechanisms underlying the established associations between CYP2C19 rs4244285 and ESC pharmacokinetics. This mQTL SNP as a marker for antidepressant-related weight gain needs to be further explored.

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.

When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population.

Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 48 putative affected and 180 putative carriers for TGDs were identified, with known or likely pathogenic variants in 79 genes. Despite screening for only 108 genetic disorders, this study showed a two-fold (2.09%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases is greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.

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.

Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls.

OBJECTIVE: There is a pronounced gap in knowledge regarding polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk scores (PRSs) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls. METHOD: Participants were 344 youths of European ancestry (13-20 years old), including 136 youths with BD, 121 HR youths, and 87 controls. PRSs for BD, schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs HR vs controls). All genetic analyses controlled for age, sex, and 2 genetic principal components. RESULTS: The BD group showed significantly higher BD-PRS than the control group (odds ratio = 1.54, 95% CI = 1.13-2.10, p = .006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRSs for schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were not significantly different among groups. In the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, or family history of BD. CONCLUSION: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRSs for other psychiatric disorders supports the specificity of BD-PRS in youth. These findings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future genome-wide association studies that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

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.

Interplay between polygenic risk for mood disorders and stressful life events in bipolar disorder.

BACKGROUND: Although genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. METHODS: This study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. RESULTS: For the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (ß = 0.13, 95 % CI:0.04-0.22, p = 0.003) and dependent SLEs (ß = 0.09, 95 % CI:0.02-0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (ß = 0.11, 95 % CI:0.02-0.20, p = 0.015) and dependent SLEs (ß = 0.08, 95 % CI:0.01-0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: ß = 0.19, 95 % CI:0.04-0.35, p = 0.015; PRS-BD: ß = 0.16, 95 % CI:0.01-0.32, p = 0.042) and dependent SLEs (PRS-MDD: ß = 0.14, 95 % CI:0.03-0.26, p = 0.015; PRS-BD: ß = 0.12, 95 % CI:0.004-0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LIMITATIONS: Use of a larger sample size would be beneficial. CONCLUSIONS: The relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Heart rate variability: Evaluating a potential biomarker of anxiety disorders.

Establishing quantifiable biological markers associated with anxiety will increase the objectivity of phenotyping and enhance genetic research of anxiety disorders. Heart rate variability (HRV) is a physiological measure reflecting the dynamic relationship between the sympathetic and parasympathetic nervous systems, and is a promising target for further investigation. This review summarizes evidence evaluating HRV as a potential physiological biomarker of anxiety disorders by highlighting literature related to anxiety and HRV combined with investigations of endophenotypes, neuroimaging, treatment response, and genetics. Deficient HRV shows promise as an endophenotype of pathological anxiety and may serve as a noninvasive index of prefrontal cortical control over the amygdala, and potentially aid with treatment outcome prediction. We propose that the genetics of HRV can be used to enhance the understanding of the genetics of pathological anxiety for etiological investigations and treatment prediction. Given the anxiety-HRV link, strategies are offered to advance genetic analytical approaches, including the use of polygenic methods, wearable devices, and pharmacogenetic study designs. Overall, HRV shows promising support as a physiological biomarker of pathological anxiety, potentially in a transdiagnostic manner, with the heart-brain entwinement providing a novel approach to advance anxiety treatment development.

COMT Val/Met, stressful life events and externalizing behaviors in youth: A longitudinal study from the ABCD sample.

Early adolescence is a crucial time for understanding and detecting the risk factors that may influence youth externalizing/disruptive behaviors and disorders. Previous literature reported evidence that risk factors for disruptive behaviors include catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and environmental influences. An unanswered question is whether there is a change in these risk factors over stages of youth development. This longitudinal study examines the interaction effect of Val158Met and stressful life events (SLE) on youth externalizing behaviors from ages 9-11. Participants were 2363 children of European ancestry recruited as part of the Adolescent Brain Cognitive Development study. Repeated measures linear mixed models were used to examine the effect of the interaction between Val158Met and SLE (G × E) on disruptive behaviors over development. Externalizing behaviors were analyzed at both baseline and two-year follow-up. Both Val158Met genotype and SLE scores demonstrated significant main effects on disruptive behaviors in youth, and those effects were consistent at both time points. G × E was not associated with externalizing behaviors. Youth who carried the Val allele and/or were exposed to higher SLE consistently had increased externalizing behavior scores. To our knowledge, this is the first study to longitudinally examine the interaction effects of Val158Met and SLE on externalizing behaviors in youth. The results highlight the importance of understanding the genetic and environmental factors underlying externalizing behaviors for better detection of at-risk youth, helping further with early prevention efforts. The findings propose that COMT Val158Met genotype may act as a biomarker for development of novel treatment strategies for disruptive behaviors.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).