Family Environment and Polygenic Risk in the Bipolar High-Risk Context

Objective: The overarching goal of this project was to investigate the role of family environment (FE) in youth at high familial risk for bipolar disorder (BD), a severe and impairing mood disorder associated with genetic and environmental risk—what about the FE is particularly salient, and does it confer risk for psychopathology in offspring, alone or with genetic burden for BD? The specific aims were to: 1) systematically review prospective studies of parental BD, FE, and offspring psychiatric disorders, identifying characteristics of FE associated with risk for psychiatric disorders among offspring of parents with and without BD (Chapter 2); 2) take a person-centered approach to modeling FE among offspring at high or low familial risk for bipolar disorder, by a) identifying latent patterns (classes) of child-perceived FE; and b) testing for demographic and clinical characteristics associated with FE (Chapter 3); and 3) test the main effects of offspring-perceived latent FE and the interaction of polygenic risk (BD-PRS) with FE on offspring mood diagnoses in offspring at high or low familial risk for BD (Chapter 4). Methods: Aim 1: Four databases were searched to identify studies on offspring of BD parents. We followed PRISMA guidelines for best practices in systematic reviews and assessed for risk of bias. Aims 2 and 3: We used data from a multi-site prospective study of adolescents at high or low familial risk for BD in the US and Australia. We focused on a subset of offspring (266 high-risk, 175 controls). In Aim 2, we conducted exploratory factor analysis, latent class analysis, and latent class regressions to develop a person-centered model of offspring-perceived latent FE. In Aim 3, we used a three-step approach to modeling distal outcomes (main effects of latent FE and its interaction with BD-PRS), accounting for the effect of covariates on both the latent variable and offspring diagnosis. Results: Aim 1: We identified 12 studies covering FE domains of family nurturance, communication, system maintenance, and values. Families with a BD parent versus no parental psychiatric disorders reported lower cohesion, and offspring had higher prevalence of psychiatric disorders. Family environment was not different between parents with BD parents and other major psychiatric or physical illnesses, nor was prevalence of offspring psychiatric disorders elevated. Families in which a child was diagnosed with BD had higher conflict than families without a child with BD. Children’s perceptions were infrequently reported. Aim 2: Offspring perceived three patterns of FE: one large ‘well-functioning’ class characterized by nurturance, flexibility, and low conflict, and two smaller classes with high conflict and low warmth and cohesion, with separation based on high conflict with the father or very high conflict and rigidity in the mother-child relationship. Girls were more likely to be in the High Conflict with Mother class. Aim 3: Youth in the conflict classes were more likely to be diagnosed with BD, though the increased risk was only significant for youth in the High Conflict with Father class. High Conflict with Father was significantly and inversely associated with BD in interaction with BD-PRS; among those perceiving High Conflict with Father, increasing BD-PRS was associated with lower risk of BD. Conclusions: Family environment in BD-parented families is heterogeneous, and it is important to assess offspring directly. High-risk youth experiencing FE that is high in conflict and low in warmth and flexibility are also more likely to themselves have BD. Researchers and clinicians working with BD high-risk families may reduce morbidity by attending to family cohesion and communication. Understanding the genetics of intergenerational transmission of BD may be facilitated by taking into account environmental influences, such as the family, which impacts the full spectrum of child development including mental health

Salivary melatonin onset in youth at familial risk for bipolar disorder

Melatonin secretion and polysomnography (PSG) were compared among a group of healthy adolescents who were at high familial risk for bipolar disorder (HR) and a second group at low familial risk (LR). Adolescent participants (n = 12) were a mean age 14 ± 2.3 years and included 8 females and 4 males. Saliva samples were collected under standardized condition light (red light) and following a 200 lux light exposure over two consecutive nights in a sleep laboratory. Red Light Melatonin onset (RLMO) was defined as saliva melatonin level exceeding the mean of the first 3 readings plus 2 standard deviations. Polysomnography was also completed during each night. HR youth, relative to LR, experienced a significantly earlier melatonin onset following 200 lux light exposure. Polysomnography revealed that LR youth, relative to HR, spent significantly more time in combined stages 3 and 4 (deep sleep) following red light exposure. Additionally, regardless of the group status (HR or LR), there was no significant difference in Red Light Melatonin Onset recorded at home or in the laboratory, implying its feasibility and reliability

Patterns and predictors of family environment among adolescents at high and low risk for familial bipolar disorder

Children's perceptions are important to understanding family environment in the bipolar disorder (BD) high-risk context. Our objectives were to empirically derive patterns of offspring-perceived family environment, and to test the association of family environment with maternal or paternal BD accounting for offspring BD and demographic characteristics. Participants aged 12–21 years (266 offspring of a parent with BD, 175 offspring of a parent with no psychiatric history) were recruited in the US and Australia. We modeled family environment using latent profile analysis based on offspring reports on the Conflict Behavior Questionnaire, Family Adaptability and Cohesion Evaluation Scales, and Home Environment Interview for Children. Parent diagnoses were based on the Diagnostic Interview for Genetic Studies and offspring diagnoses were based on the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Latent class regression was used to test associations of diagnosis and family environment. Two-thirds of all offspring perceived well-functioning family environment, characterized by nurturance, flexibility, and low conflict. Two ‘conflict classes’ perceived family environments low in flexibility and cohesion, with substantial separation based on high conflict with the father (High Paternal Conflict), or very high conflict and rigidity and low warmth with the mother (High Maternal Conflict). Maternal BD was associated with offspring perceiving High Maternal Conflict (OR 2.8, p = 0.025). Clinical care and psychosocial supports for mothers with BD should address family functioning, with attention to offspring perceptions of their wellbeing. More research is needed on the effect of paternal BD on offspring and family dynamics

Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts

Objective Bipolar disorder (BD) is one of the most heritable psychiatric conditions and is associated with high suicide risk. To explore the reasons for this link, this study examined the interaction between traumatic stress and BD polygenic risk score in relation to suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) in adolescent and young adult offspring and relatives of persons with BD (BD-relatives) compared with adolescent and young adult offspring of individuals without psychiatric disorders (controls). Method Data were collected from 4 sites in the United States and 1 site in Australia from 2006 through 2012. Generalized estimating equation models were used to compare rates of ideation, attempts, and NSSI between BD-relatives (n = 307) and controls (n = 166) and to determine the contribution of demographic factors, traumatic stress exposure, lifetime mood or substance (alcohol/drug) use disorders, and BD polygenic risk score. Results After adjusting for demographic characteristics and mood and substance use disorders, BD-relatives were at increased risk for suicidal ideation and attempts but not for NSSI. Independent of BD-relative versus control status, demographic factors, or mood and substance use disorders, exposure to trauma within the past year (including bullying, sexual abuse, and domestic violence) was associated with suicide attempts (p = .014), and BD polygenic risk score was marginally associated with attempts (p = .061). Importantly, the interaction between BD polygenic risk score and traumatic event exposures was significantly associated with attempts, independent of demographics, relative versus control status, and mood and substance use disorders (p = .041). Conclusion BD-relatives are at increased risk for suicide attempts and ideation, especially if they are exposed to trauma and have evidence of increased genetic vulnerability

The association between lithium use and neurocognitive performance in patients with bipolar disorder

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1–5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.acceptedVersio

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.publishedVersio

Polygenic scores and onset of major mood or psychotic disorders among offspring of affected parents

Objective: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders. Methods: Eight cohorts were combined to create a sample of 1,884 participants ages 2–36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders. Results: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12–1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04–1.26), depression (hazard ratio=1.11, 95% CI=1.01–1.22), ADHD (hazard ratio=1.10, 95% CI=1.00–1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82–0.99), and p factor (hazard ratio=1.14, 95% CI=1.04–1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08–1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81–0.98) with onsets. Conclusions: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk

Family Environment and Polygenic Risk in the Bipolar High-Risk Context

Objective: The overarching goal of this project was to investigate the role of family environment (FE) in youth at high familial risk for bipolar disorder (BD), a severe and impairing mood disorder associated with genetic and environmental risk—what about the FE is particularly salient, and does it confer risk for psychopathology in offspring, alone or with genetic burden for BD? The specific aims were to: 1) systematically review prospective studies of parental BD, FE, and offspring psychiatric disorders, identifying characteristics of FE associated with risk for psychiatric disorders among offspring of parents with and without BD (Chapter 2); 2) take a person-centered approach to modeling FE among offspring at high or low familial risk for bipolar disorder, by a) identifying latent patterns (classes) of child-perceived FE; and b) testing for demographic and clinical characteristics associated with FE (Chapter 3); and 3) test the main effects of offspring-perceived latent FE and the interaction of polygenic risk (BD-PRS) with FE on offspring mood diagnoses in offspring at high or low familial risk for BD (Chapter 4). Methods: Aim 1: Four databases were searched to identify studies on offspring of BD parents. We followed PRISMA guidelines for best practices in systematic reviews and assessed for risk of bias. Aims 2 and 3: We used data from a multi-site prospective study of adolescents at high or low familial risk for BD in the US and Australia. We focused on a subset of offspring (266 high-risk, 175 controls). In Aim 2, we conducted exploratory factor analysis, latent class analysis, and latent class regressions to develop a person-centered model of offspring-perceived latent FE. In Aim 3, we used a three-step approach to modeling distal outcomes (main effects of latent FE and its interaction with BD-PRS), accounting for the effect of covariates on both the latent variable and offspring diagnosis. Results: Aim 1: We identified 12 studies covering FE domains of family nurturance, communication, system maintenance, and values. Families with a BD parent versus no parental psychiatric disorders reported lower cohesion, and offspring had higher prevalence of psychiatric disorders. Family environment was not different between parents with BD parents and other major psychiatric or physical illnesses, nor was prevalence of offspring psychiatric disorders elevated. Families in which a child was diagnosed with BD had higher conflict than families without a child with BD. Children’s perceptions were infrequently reported. Aim 2: Offspring perceived three patterns of FE: one large ‘well-functioning’ class characterized by nurturance, flexibility, and low conflict, and two smaller classes with high conflict and low warmth and cohesion, with separation based on high conflict with the father or very high conflict and rigidity in the mother-child relationship. Girls were more likely to be in the High Conflict with Mother class. Aim 3: Youth in the conflict classes were more likely to be diagnosed with BD, though the increased risk was only significant for youth in the High Conflict with Father class. High Conflict with Father was significantly and inversely associated with BD in interaction with BD-PRS; among those perceiving High Conflict with Father, increasing BD-PRS was associated with lower risk of BD. Conclusions: Family environment in BD-parented families is heterogeneous, and it is important to assess offspring directly. High-risk youth experiencing FE that is high in conflict and low in warmth and flexibility are also more likely to themselves have BD. Researchers and clinicians working with BD high-risk families may reduce morbidity by attending to family cohesion and communication. Understanding the genetics of intergenerational transmission of BD may be facilitated by taking into account environmental influences, such as the family, which impacts the full spectrum of child development including mental health

FNBO: Lending Advice Engine

The 2020-2021 FNBO Design Studio project is aimed to empower potential FNBO customers by providing them more information surrounding the best options available based on their financial situation. To do this, the team developed a comprehensive lending advice engine that can recommend options tailored to each customer’s individual circumstances and financial goals and created an accessible web application to allow customers to input their financial situation and navigate lending options to pursue with a banker at FNBO