Defining Suicidal Thought and Behavior Phenotypes for Genetic Studies.

Background: Standardized definitions of suicidality phenotypes, including suicidal ideation (SI), attempt (SA), and death (SD) are a critical step towards improving understanding and comparison of results in suicide research. The complexity of suicidality contributes to heterogeneity in phenotype definitions, impeding evaluation of clinical and genetic risk factors across studies and efforts to combine samples within consortia. Here, we present expert and data-supported recommendations for defining suicidality and control phenotypes to facilitate merging current/legacy samples with definition variability and aid future sample creation. Methods: A subgroup of clinician researchers and experts from the Suicide Workgroup of the Psychiatric Genomics Consortium (PGC) reviewed existing PGC definitions for SI, SA, SD, and control groups and generated preliminary consensus guidelines for instrument-derived and international classification of disease (ICD) data. ICD lists were validated in two independent datasets (N = 9,151 and 12,394). Results: Recommendations are provided for evaluated instruments for SA and SI, emphasizing selection of lifetime measures phenotype-specific wording. Recommendations are also provided for defining SI and SD from ICD data. As the SA ICD definition is complex, SA code list recommendations were validated against instrument results with sensitivity (range = 15.4% to 80.6%), specificity (range = 67.6% to 97.4%), and positive predictive values (range = 0.59-0.93) reported. Conclusions: Best-practice guidelines are presented for the use of existing information to define SI/SA/SD in consortia research. These proposed definitions are expected to facilitate more homogeneous data aggregation for genetic and multisite studies. Future research should involve refinement, improved generalizability, and validation in diverse populations.

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.

A Secondary Analysis of the Complex Interplay between Psychopathology, Cognitive Functions, Brain Derived Neurotrophic Factor Levels, and Suicide in Psychotic Disorders: Data from a 2-Year Longitudinal Study.

Identifying phenotypes at high risk of suicidal behaviour is a relevant objective of clinical and translational research and can facilitate the identification of possible candidate biomarkers. We probed the potential association and eventual stability of neuropsychological profiles and serum BDNF concentrations with lifetime suicide ideation and attempts (LSI and LSA, respectively) in individuals with schizophrenia (SCZ) and schizoaffective disorder (SCA) in a 2-year follow-up study. A secondary analysis was conducted on a convenience sample of previously recruited subjects from a single outpatient clinic. Retrospectively assessed LSI and LSA were recorded by analysing the available longitudinal clinical health records. LSI + LSA subjects consistently exhibited lower PANSS-defined negative symptoms and better performance in the BACS-letter fluency subtask. There was no significant association between BDNF levels and either LSI or LSA. We found a relatively stable pattern of lower negative symptoms over two years among patients with LSI and LSA. No significant difference in serum BDNF concentrations was detected. The translational viability of using neuropsychological profiles as a possible avenue for the identification of populations at risk for suicide behaviours rather than the categorical diagnosis represents a promising option but requires further confirmation.

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.

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.

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.

Symptomatic remission and recovery in major psychosis: Is there a role for BDNF? A secondary analysis of the LABSP cohort data.

Remission, relapse prevention, and clinical recovery are crucial areas of interest in schizophrenia (SCZ) research. Although SCZ is a chronic disorder with poor overall outcomes, years of research demonstrated that recovery is possible. There are considerable data linking brain-derived neurotrophic factor (BDNF) to SCZ, however, evidence on the role of BDNF in remission in SCZ is scarce. This secondary analysis of the Longitudinal Assessment of BDNF in Sardinian patients (LABSP) data aimed to investigate the relationship between serum BDNF levels and symptomatic remission, simultaneous clinical and functional remission, and recovery in patients with SCZ. A total of 105 patients with SCZ or schizoaffective disorder were recruited for a longitudinal assessment of BDNF levels over 24 months. Longitudinal data were analyzed using mixed-effects linear regression models. The study found significant associations between use of long acting injectables (χ2 = 7.075, df = 1, p = 0.008), baseline serum BDNF levels (U = 701, z = -2.543, p = 0.011), and "childhood" (U = 475, z = -2.124, p = 0.034) and "general" (U = 55, z = -2.014, p = 0.044) subscales of the Premorbid Adjustment Scale (PAS) with patients maintaining remission and recovery. The diagnosis of SCZ was significantly associated with lower BDNF levels for patients with simultaneous clinical and functional remission (Z = 2.035, p = 0.0419) and recovery (Z = 2.009, p = 0.0445) compared to those without. There were no significant associations between remission in the entire sample and longitudinal serum BDNF levels or genetic variants within the BDNF gene. These findings provide further insight into the complex relationship between BDNF and SCZ.

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.

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.

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.

The Diagnostic Landscape of Adult Neurogenetic Disorders.

Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

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.

Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth.

There is a gap in knowledge regarding the polygenic underpinnings of brain anomalies observed in youth bipolar disorder (BD). This study examined the association of a polygenic risk score for BD (BD-PRS) with grey matter structure and white matter integrity in youth with and without BD. 113 participants were included in the analyses, including 78 participants with both T1-weighted and diffusion-weighted MRI images, 32 participants with T1-weighted images only, and 3 participants with diffusion-weighted images only. BD-PRS was calculated using PRS-CS-auto and was based on independent adult genome-wide summary statistics. Vertex- and voxel-wise analyses examined the associations of BD-PRS with grey matter metrics (cortical volume [CV], cortical surface area [CSA], cortical thickness [CTh]) and fractional anisotropy [FA] in the combined sample, and separately in BD and HC. In the combined sample of participants with T1-weighted images (n = 110, 66 BD, 44 HC), higher BD-PRS was associated with smaller grey matter metrics in frontal and temporal regions. In within-group analyses, higher BD-PRS was associated with lower CTh of frontal, temporal, and fusiform gyrus in BD, and with lower CV and CSA of superior frontal gyrus in HC. In the combined sample of participants with diffusion-weighted images (n = 81, 49 BD, 32 HC), higher BD-PRS was associated with lower FA in widespread white matter regions. In summary, BD-PRS calculated based on adult genetic data was negatively associated with grey matter structure and FA in youth in regions implicated in BD, which may suggest neuroimaging markers of vulnerability to BD. Future longitudinal studies are needed to examine whether BD-PRS predicts neurodevelopmental changes in BD vs. HC and its interaction with course of illness and long-term medication use.

Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.

Association of polygenic risk for bipolar disorder with resting-state network functional connectivity in youth with and without bipolar disorder.

Little is known regarding the polygenic underpinnings of anomalous resting-state functional connectivity (rsFC) in youth bipolar disorder (BD). The current study examined the association of polygenic risk for BD (BD-PRS) with whole-brain rsFC at the large-scale network level in youth with and without BD. 99 youth of European ancestry (56 BD, 43 healthy controls [HC]), ages 13-20 years, completed resting-state fMRI scans. BD-PRS was calculated using summary statistics from the latest adult BD genome-wide association study. Data-driven independent component analyses of the resting-state fMRI data were implemented to examine the association of BD-PRS with rsFC in the overall sample, and separately in BD and HC. In the overall sample, higher BD-PRS was associated with lower rsFC of the salience network and higher rsFC of the frontoparietal network with frontal and parietal regions. Within the BD group, higher BD-PRS was associated with higher rsFC of the default mode network with orbitofrontal cortex, and altered rsFC of the visual network with frontal and occipital regions. Within the HC group, higher BD-PRS was associated with altered rsFC of the frontoparietal network with frontal, temporal and occipital regions. In conclusion, the current study found that BD-PRS generated based on adult genetic data was associated with altered rsFC patterns of brain networks in youth. Our findings support the usefulness of BD-PRS to investigate genetically influenced neuroimaging markers of vulnerability to BD, which can be observed in youth with BD early in their course of illness as well as in healthy youth.

Vascular Endothelial Growth Factor Polymorphism rs699947 Is Associated with Neurostructural Phenotypes in Youth with Bipolar Disorder.

Background: Vascular endothelial growth factor (VEGF) may be relevant to bipolar disorder (BD) and brain structure. We evaluated VEGF rs699947 single-nucleotide polymorphism in relation to structural neuroimaging phenotypes in youth BD. Methods: We collected 3 T anatomical magnetic resonance images from 154 youth (79 BD and 75 healthy control [HC]) genotyped for VEGF rs699947. The participants were age (BD = 17.28 ± 1.40 and HC = 17.01 ± 1.83, t = -1.02, p = 0.31) and sex (BD = 63.3% females and HC = 52.0% females, χ2 = 2.01, p = 0.16) matched. Cortical thickness, surface area (SA), and volume were examined by region-of-interest (ROI) and vertex-wise analyses using general linear models (GLMs). ROI investigations selected for the prefrontal cortex (PFC), amygdala, and hippocampus. Vertex-wise analyses controlled for age, sex, and intracranial volume. Results: ROI results found lower PFC SA (p = 0.003, ηp2 = 0.06) and volume (p = 0.04, ηp2 = 0.03) in BD and a main effect of rs699947 on hippocampal volume (p = 0.03, ηp2 = 0.05). The latter two findings did not survive multiple comparisons. Vertex-wise analyses found rs699947 main effects on left postcentral gyrus volume (p < 0.001), right rostral anterior cingulate SA (p = 0.004), and right superior temporal gyrus thickness (p = 0.004). There were significant diagnosis-by-genotype interactions in the left superior temporal, left caudal middle frontal, left superior frontal, right fusiform, and right lingual gyri, and the left insular cortex. Posthoc analyses revealed the AA allele was associated with larger brain structures among HC, but smaller brain structures in BD for most clusters. Conclusions: Overall, we found preliminary evidence of divergent associations between BD and HC youth in terms of neurostructural correlates of VEGF rs699947 encompassing highly relevant frontotemporal regions.

A genome-wide association study of antidepressant-induced mania.

Antidepressant-induced mania (AIM) is a side effect of antidepressant treatment that is characterized by mania or hypomania after the start of medication. It is likely polygenic, but its genetic component remains largely unexplored. We aim to conduct the first genome-wide association study of AIM in 814 bipolar disorder patients of European ancestry. We report no significant findings from our single-marker or gene-based analyses. Our polygenic risk score analyses also did not yield significant results with bipolar disorder, antidepressant response, or lithium response. Our suggestive findings on the hypothalamic-pituitary-adrenal axis and the opioid system in AIM require independent replications.

White matter volume and myelin oligodendrocyte glycoprotein (MOG) microsatellites in pediatric obsessive-compulsive disorder.

The myelin oligodendrocyte glycoprotein ( MOG ) gene plays an important role in myelination and has been implicated in the genetics of white matter changes in obsessive-compulsive disorder (OCD). We examined the association between variations of two microsatellite markers across MOG for association and total white matter volume as measured using volumetric MRI in 37 pediatric OCD patients 7-18 years. We compared white matter volumes between microsatellite allele groups using analysis of covariance with covariates of age, gender, and total intracranial volume. After controlling for multiple comparisons, a significant relationship was detected between MOG (TAAA)n and increased total white matter volume ( P  = 0.018-0.028). Although preliminary, our findings provide further support for the involvement of MOG in OCD.