Genetic Risk For Bipolar Disorder Research Articles

Exploring the intersection of polygenic risk scores and prenatal alcohol exposure: Unraveling the mental health equation.

Prenatal alcohol exposure poses significant risks to offspring mental health. However, the interplay between genetic predispositions to mental health disorders and prenatal alcohol exposure remains incompletely understood, limiting our ability to develop effective interventions for these conditions. Data from the Adolescent Brain and Cognitive Development (ABCD) Study were analyzed to explore associations between polygenic risk scores (PRS) for mental disorders and maternal alcohol consumption during pregnancy. Logistic regression and structural equation modeling were utilized to assess these relationships. Maternal alcohol consumption after pregnancy awareness was significantly associated with an increased genetic risk for specific mental health disorders, particularly bipolar disorder in offspring. The relationship between maternal alcohol consumption and mental health outcomes was influenced by polygenic risk scores, with both externalizing and internalizing problems being affected. Our findings highlight the specific interaction between increased genetic risk for bipolar disorder and prenatal alcohol exposure in shaping offspring mental health outcomes. The significant associations we observed underscore the importance of considering both polygenic risk scores and prenatal alcohol exposure when assessing mental health risks in children. These insights emphasize the need for targeted interventions that address both genetic predispositions and environmental exposures to better understand and mitigate the impact on offspring mental health.

The impact of family-genetic risk scores on social functioning in individuals affected with six major psychiatric and substance use disorders in a Swedish National Sample.

To examine whether the level of genetic risk in psychiatric disorders impacts the social functioning of affected individuals, we examine the relationship between genetic risk factors for major depression (MD), anxiety disorders (AD), bipolar disorder (BD), non-affective psychosis (NAP), alcohol use disorder (AUD), and drug use disorder (DUD) in disordered individuals and five adverse social outcomes: unemployment, residence in areas of social deprivation, social welfare, early retirement, and divorce. We examine all cases with registration for these disorders from 1995 to 2015 in individuals born in Sweden. Genetic risk was assessed by the family genetic risk score (FGRS) and statistical estimates by Cox proportional hazard models. High genetic risk was significantly and modestly associated with poorer social outcomes in 23 of 30 analyses. Overall, genetic risk for MD, AD, AUD, and DUD impacted social functioning more strongly in affected individuals than did genetic risk for BD and NAP. Social welfare had the strongest associations with genetic risk, and residence in areas of high deprivation had the weakest. In individuals suffering from psychiatric and substance use disorders, high levels of genetic risk impact not only clinical features but also diverse measures of social functioning.

Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data.

Bipolar disorder is a chronic and complex polygenic disease with high rates of comorbidity. However, the independent contribution of either diagnosis or genetic risk of bipolar disorder to the medical comorbidity profile of individuals with the disease remains unresolved. Here, we conducted a multi-step phenome-wide association study (PheWAS) of bipolar disorder using phenomes derived from the electronic health records of participants enrolled in the Mayo Clinic Biobank and the Mayo Clinic Bipolar Disorder Biobank. First, we explored the conditions associated with a diagnosis of bipolar disorder by conducting a phenotype-based PheWAS followed by LASSO-penalized regression to account for correlations within the phenome. Then, we explored the conditions associated with bipolar disorder polygenic risk score (BD-PRS) using a PRS-based PheWAS with a sequential exclusion approach to account for the possibility that diagnosis, instead of genetic risk, may drive such associations. 53,386 participants (58.7% women) with a mean age at analysis of 67.8 years (SD = 15.6) were included. A bipolar disorder diagnosis (n = 1479) was associated with higher rates of psychiatric conditions, injuries and poisonings, endocrine/metabolic and neurological conditions, viral hepatitis C, and asthma. BD-PRS was associated with psychiatric comorbidities but, in contrast, had no positive associations with general medical conditions. While our findings warrant confirmation with longitudinal-prospective studies, the limited associations between bipolar disorder genetics and medical conditions suggest that shared environmental effects or environmental consequences of diagnosis may have a greater impact on the general medical comorbidity profile of individuals with bipolar disorder than its genetic risk.

Polygenic risk for major depression, attention deficit hyperactivity disorder, neuroticism, and schizophrenia are correlated with experience of intimate partner violence

Research has suggested that mental illness may be a risk factor for, as well as a sequela of, experiencing intimate partner violence (IPV). The association between IPV and mental illness may also be due in part to gene-environment correlations. Using polygenic risk scores for six psychiatric disorders - attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), neuroticism, and schizophrenia—and a combined measure of overall genetic risk for mental illness, we tested whether women’s genetic risk for mental illness was associated with the experience of three types of intimate partner violence. In this cohort of women of European ancestry (N = 11,095), participants in the highest quintile of genetic risk for ADHD (OR range: 1.38–1.49), MDD (OR range: 1.28–1.43), neuroticism (OR range: (1.18–1.25), schizophrenia (OR range: 1.30–1.34), and overall genetic risk (OR range: 1.30–1.41) were at higher risk for experiencing more severe emotional and physical abuse, and, except schizophrenia, more severe sexual abuse, as well as more types of abuse and chronic abuse. In addition, participants in the highest quintile of genetic risk for neuroticism (OR = 1.43 95% CI: 1.18, 1.72), schizophrenia (OR = 1.33 95% CI: 1.10, 1.62), and the overall genetic risk (OR = 1.40 95% CI: 1.15, 1.71) were at higher risk for experiencing intimate partner intimidation and control. Participants in the highest quintile of genetic risk for ADHD, ASD, MDD, schizophrenia, and overall genetic risk, compared to the lowest quintile, were at increased risk for experiencing harassment from a partner (OR range: 1.22–1.92). No associations were found between genetic risk for BPD with IPV. A better understanding of the salience of the multiple possible pathways linking genetic risk for mental illness with risk for IPV may aid in preventing IPV victimization or re-victimization.

The joint effects of genetic liability and the death of close relatives on risk for major depression and alcohol use disorder in a Swedish national sample.

To determine whether genetic risk factors for major depression (MD) and alcohol use disorder (AUD) interact with a potent stressor - death of spouse, parent, and sibling - in predicting episodes of, respectively, MD and AUD. MD and AUD registrations were assessed from national Swedish registries. In individuals born in Sweden 1960-1970, we identified 7586, 388 459, and 34 370 with the loss of, respectively, a spouse, parent, and sibling. We started following subjects at age 18 or the year 2002 with end of follow-up in 2018. We examined time to event - a registration for MD within 6 months or AUD within a year - on an additive scale, using the Nelson-Aalen estimator. Genetic risk was assessed by the Family Genetic Risk Score (FGRS). In separate models controlling for the main effects of death of spouse, parent, and sibling, FGRS, and sex, significant interactions were seen in all analyses between genetic risk for MD and death of relative in prediction of subsequent MD registration. A similar pattern of results, albeit with weaker interaction effects, was seen for genetic risk for AUD and risk for AUD registration. Genetic risk for bipolar disorder (BD) and anxiety disorders (AD) also interacted with event exposure in predicting MD. Genetic risk for both MD and AUD act in part by increasing the sensitivity of individuals to the pathogenic effects of environmental stressors. For prediction of MD, similar effects are also seen for genetic risk for AD and BD.

Multiple psychiatric polygenic risk scores predict associations between childhood adversity and bipolar disorder

BackgroundIt remains unclear how adverse childhood experiences (ACE) and increased genetic risk for bipolar disorder (BD) interact to influence BD symptom outcomes. Here we calculated multiple psychiatric polygenic risk scores (PRS) and used the measures of ACE to understand these gene-environment interactions. Method885 BD subjects were included for analyses. BD, ADHD, MDD and SCZ PRSs were calculated using the PRS-CS-auto method. ACEs were evaluated using the Children Life Event Questionnaire (CLEQ). Participants were divided into groups based on the presence of ACE and the total number of ACEs. The associations between total ACE number, PRSs and their interactions were evaluated using multiple linear and logistic regressions. Secondary analyses were performed to evaluate the influence of ACE and PRS on sub-phenotypes of BD. ResultsThe number of ACEs increased with the ADHD PRS. BD participants who had ACEs showed an earlier age of BD onset and higher odds of having rapid cycling. Increased BD PRS was associated with increased odds of developing psychotic symptoms. Higher ADHD PRS was associated with increased odds of having rapid cycling. No prediction effect was observed from MDD and SCZ PRS. And, we found no significant interaction between ACE numbers and any of the PRSs in predicting any selected BD sub-phenotypes. LimitationsThe study was limited by sample size, ACE definition, and cross-sectional data collection method. ConclusionsThe findings consolidate the importance of considering multiple psychiatric PRSs in predicting symptom outcomes among BD patients.

Long-term exposure to ambient air pollution, genetic susceptibility, and the incidence of bipolar disorder: A prospective cohort study

There is mounting recent evidence showing that air pollution exposure may be related to the risk of mental health, yet the association between long-term exposure to air pollution and the risk of incident bipolar disorder (BD) remains unclear. Thus we aim to identify associations between air pollution and the incidence of BD in a prospective population-based cohort. In total, 482,726 participants who were free of BD from the UK Biobank were included in this prospective study. We applied time-varying Cox proportional hazards models, accounting for relevant confounders, and used annual-year moving averages of air pollution as time-varying exposures. The genetic risk for BD was categorized into three categories (low, intermediate, and high) according to the tertiles of polygenic risk score. During a median of 10.79-year follow-up, 923 incident BD events were recorded. Long-term exposures to PM2.5, PM10, NO2, and NOx were associated with increased BD risk. Estimated HRs (95% CIs) for each interquartile range increase in PM2.5, PM10, NO2, and NOx concentrations were 1.31 (1.18–1.45), 1.19 (1.09–1.31), 1.19 (1.08–1.30), and 1.16 (1.07–1.26), respectively. Associations were still observed and even stronger at pollutant concentrations lower than WHO air quality guideline. In subgroup analysis stratified by genetic risk, we observed consistent associations between all pollutants and BD risk in intermediate and high genetic risk groups, but not in low genetic risk group. For example, the HRs (95% CIs) for PM2.5 were 1.00 (0.94–1.53), 1.30 (1.06–1.59), and 1.34 (1.16–1.54) in low, intermediate, and high genetic groups, respectively. In conclusion, long-term exposure to air pollution was significantly associated with an elevated risk of BD. Associations of air pollution with BD occurred only within intermediate and high genetic risk categories and were even stronger at the pollutants levels below WHO air quality guidelines. These findings could help inform policy makers regarding ambient air quality standards and BD management.

Developmental manifestations of polygenic risk for bipolar disorder from infancy to middle childhood

Knowledge on how genetic risk for bipolar disorder manifests in developmental, emotional or behavioral traits during childhood is lacking. This issue is important to address to inform early detection and intervention efforts. We investigated whether polygenic risk for bipolar disorder is associated with developmental outcomes during early to middle childhood in the general population, and if associations differ between boys and girls. Our sample consisted of 28 001 children from the Norwegian Mother, Father and Child Cohort study, a prospective pregnancy cohort with available genotype and developmental data. Mothers reported on a range of developmental outcomes in their children at 6 and 18 months, 3, 5 and 8 years. Polygenic risk scores reflecting common variant liability to bipolar disorder were calculated. Linear regression models were used in a multi-group framework to investigate associations between polygenic risk score and developmental outcomes, using sex as a grouping variable. We found robust evidence for an association between polygenic risk scores for bipolar disorder and conduct difficulties (β = 0.041, CI = 0.020–0.062) and oppositional defiant difficulties (β = 0.032, CI = 0.014–0.051) at 8 years. Associations with most other outcomes were estimated within the region of practical equivalence to zero (equivalence range D = −0.1 to 0.1), with the exceptions of negative association for activity levels (β = −0.028, CI = −0.047– −0.010) at age 5 and benevolence (β = −0.025, CI = –0.043 to –0.008) at age 8, and positive association for motor difficulties (β = 0.025, CI = 0.008–0.043) at age 3, inattention (β = 0.021, CI = 0.003–0.041) and hyperactivity (β = 0.025, CI = 0.006–0.044) at age 8. Our results suggest that genetic risk for bipolar disorder manifests as disruptive behaviors like oppositional defiant and conduct difficulties in childhood in the general population.

Cognitive performances across individuals at high genetic risk for schizophrenia, high genetic risk for bipolar disorder, and low genetic risks: a combined polygenic risk score approach.

Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD. Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia. SCZ-, BD-, SCZ v. BD-PRSs were associated with case-control status (R2 = 0.020-0.061), and SCZ-PRS was associated with relative-control status (R2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients (p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs (p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > -0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group (d > -0.20). Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD.

Hippocampal cingulum white matter increases over time in young people at high genetic risk for bipolar disorder

BackgroundBipolar disorder (BD) is a strongly familial psychiatric disorder associated with white matter (WM) brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about WM trajectories in those at increased genetic risk. MethodsDiffusion magnetic resonance imaging (dMRI) data were acquired at baseline and after two years in 91 unaffected individuals with a first-degree relative with bipolar disorder (HR), and 85 individuals with no family history of mental illness (CON). All participants were aged between 12 and 30 years at baseline. We examined longitudinal change in Fractional Anisotropy (FA) using tract-based spatial statistics (TBSS). ResultsCompared to the CON group, HR participants showed a significant increase in FA in the right cingulum (hippocampus) (CGH) over a two-year period (p < .05, FDR corrected). This effect was more pronounced in HR individuals without a lifetime diagnosis of a mood disorder than those with a mood disorder. LimitationsWhile our study is well powered to achieve the primary objectives, our sub-group analyses were under powered. ConclusionsIn one of the very few longitudinal neuroimaging studies of young people at high risk for BD, this study reports novel evidence of atypical white matter development in HR individuals in a key cortico-limbic tract involved in emotion regulation. Our findings also suggest that this different white matter developmental trajectory may be stronger in HR individuals without affective psychopathology. As such, increases in FA in the right CGH of HR participants may be a biomarker of resilience to mood disorders.

Clinical and Genetic Correlates of Bipolar Disorder With Childhood-Onset Attention Deficit Disorder.

Background:Bipolar disorder (BD) with co-occurring attention deficit-hyperactivity disorder (ADHD) is associated with an unfavorable course of illness. We aimed to identify potential clinical and genetic correlates of BD with and without ADHD.MethodsAmong patients with BD (N = 2,198) enrolled in the Mayo Clinic Bipolar Biobank we identified those with ADHD diagnosed in childhood (BD+cADHD; N = 350), those with adult-onset attention deficit symptoms (BD+aAD; N = 254), and those without ADHD (N = 1,594). We compared the groups using linear or logistic regression adjusting for age, sex, and recruitment site. For genotyped patients (N = 1,443), logistic regression was used to compare ADHD and BD polygenic risk scores (PRSs) between the BD groups, as well as to non-BD controls (N = 777).ResultsCompared to the non-ADHD BD group, BD+cADHD patients were younger, more often men and had a greater number of co-occurring anxiety and substance use disorders (all p < 0.001). Additionally, BD+cADHD patients had poorer responses to lithium and lamotrigine (p = 0.005 and p = 0.007, respectively). In PRS analyses, all BD patient subsets had greater genetic risk for BD and ADHD when compared to non-BD controls (p < 0.001 in all comparisons). BD+cADHD patients had a higher ADHD-PRS than non-ADHD BD patients (p = 0.012). However, BD+aAD patients showed no evidence of higher ADHD-PRS than non-ADHD BD patients (p = 0.38).ConclusionsBD+cADHD was associated with a greater number of comorbidities and reduced response to mood stabilizing treatments. The higher ADHD PRS for the BD+cADHD group may reflect a greater influence of genetic factors on early presentation of ADHD symptoms.

Longitudinal Changes in Structural Connectivity in Young People at High Genetic Risk for Bipolar Disorder.

Recent studies of patients with bipolar disorder or at high genetic risk reveal structural dysconnections among key brain networks supporting cognitive and affective processes. Understanding the longitudinal trajectories of these networks across the peak age range of bipolar disorder onset could inform mechanisms of illness onset or resilience. Longitudinal diffusion-weighted MRI and phenotypic data were acquired at baseline and after 2 years in 183 individuals ages 12-30 years in two cohorts: 97 unaffected individuals with a first-degree relative with bipolar disorder (the high-risk group) and 86 individuals with no family history of mental illness (the control group). Whole-brain structural networks were derived using tractography, and longitudinal changes in these networks were studied using network-based statistics and mixed linear models. Both groups showed widespread longitudinal changes, comprising both increases and decreases in structural connectivity, consistent with a shared neurodevelopmental process. On top of these shared changes, high-risk participants showed weakening of connectivity in a network encompassing the left inferior and middle frontal areas, left striatal and thalamic structures, the left fusiform, and right parietal and occipital regions. Connections among these regions strengthened in the control group, whereas they weakened in the high-risk group, shifting toward a cohort with established bipolar disorder. There was marginal evidence for even greater network weakening in those who had their first manic or hypomanic episode before follow-up. Neurodevelopment from adolescence into early adulthood is associated with a substantial reorganization of structural brain networks. Differences in these maturational processes occur in a multisystem network in individuals at high genetic risk of bipolar disorder. This may represent a novel candidate to understand resilience and predict conversion to bipolar disorder.

Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways.

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD, and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls, and the transcriptional effects of BD-associated genetic variants. We found two co-expressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the post-synaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (eQTLs), and these data converged on several individual genes, including SCN2A and GRIN2A. Thus, these data implicate specific genes and pathways that may contribute to the pathology of bipolar disorder.

Polygenic risk score for bipolar disorder associates with divergent thinking and brain structures in the prefrontal cortex.

ABSTRACTIt has been hypothesized that a higher genetic risk of bipolar disorder (BD) is associated with greater creativity. Given the clinical importance of bipolar disorder and the importance of creativity to human society and cultural development, it is essential to reveal their associations and the neural basis of the genetic risk of bipolar disorder to gain insight into its etiology. However, despite the previous demonstration of the associations of polygenic risk score (PRS) of BD and creative jobs, the associations of BD‐PRS and creativity measured by the divergent thinking (CMDT) and regional gray matter volume (rGMV) as well as regional white matter volume (rWMV) have not been investigated. Using psychological analyses and whole‐brain voxel‐by‐voxel analyses, we examined these potential associations in 1558 young, typically developing adult students. After adjusting for confounding variables and multiple comparisons, a greater BD‐PRS was associated with a greater total CMDT fluency score, and a significant relationship was found in fluency subscores. A greater BD‐PRS was also associated with lower total mood disturbance. Neuroimaging analyses revealed that the BD‐PRS was associated with greater rGMV in the right inferior frontal gyrus, which is a consistently affected area in BD, as well as a greater rWMV in the left middle frontal gyrus, which has been suggested to play a central role in the increased creativity associated with the risk of BD with creativity. These findings suggest a relationship between the genetic risk of BD and CMDT and prefrontal cortical structures among young educated individuals.

Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex.

Background:Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders.Methods:We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics.Results:Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network.Limitations:Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined.Conclusion:Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging–genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.

The Greater Houston Area Bipolar Registry-Clinical and Neurobiological Trajectories of Children and Adolescents With Bipolar Disorders and High-Risk Unaffected Offspring.

The aims of this article are to discuss the rationale, design, and procedures of the Greater Houston Area Bipolar Registry (HBR), which aims at contributing to the effort involved in the investigation of neurobiological mechanisms underlying bipolar disorder (BD) as well as to identify clinical and neurobiological markers able to predict BD clinical course. The article will also briefly discuss examples of other initiatives that have made fundamental contributions to the field. This will be a longitudinal study with participants aged 6–17 at the time of enrollment. Participants will be required to meet diagnostic criteria for BD, or to be offspring of a parent with BD. We will also enroll healthy controls. Besides clinical information, which includes neurocognitive performance, participants will be asked to provide blood and saliva samples as well as to perform neuroimaging exams at baseline and follow-ups. Several studies point to the existence of genetic, inflammatory, and brain imaging alterations between individuals at higher genetic risk for BD compared with healthy controls. Longitudinal designs have shown high conversion rates to BD among high-risk offspring, with attempts to identify clinical predictors of disease onset, as well as clarifying the burden associated with environmental stressors. The HBR will help in the worldwide effort investigating the clinical course and neurobiological mechanisms of affected and high-risk children and adolescents with BD.

Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals

The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. To explore the genetic basis of BD in the Han Chinese population. A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10-8; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 1.27%; P = 1.30 × 10-19) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10-9; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10-8; OR, 0.932; 95% CI, 0.909-0.956). This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Accelerated cortical thinning and volume reduction over time in young people at high genetic risk for bipolar disorder.

Bipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk. Neuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12-30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions. Compared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval. This study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.

Polygenic Risk Scores for Bipolar Disorders Associated With Worse Global Functioning

Polygenic risk scores for bipolar disorders (PRS-BD) have been related to clinical and neurobiological variables. The aim of this preliminary study was to investigate the association between genetic risk for bipolar disorders (BD) with measures of functioning.

Facial emotion recognition deficits in patients with bipolar disorder and their healthy parents

BackgroundThere is evidence on deficits in facial emotion recognition (FER) in patients with bipolar disorder (BD), and these deficits may be present in individuals with genetic risk for BD. This study investigated facial emotion identification and discrimination abilities in patients with BD, their parents, and healthy controls. Materials and methodsThis study included 38 patients with bipolar I disorder and 30 healthy controls for patients as well as 30 healthy mothers and 30 healthy fathers of these patients and 30 healthy controls who matched the mothers and fathers for age, gender, and education (total 188 participants). Facial Emotion Identification and Discrimination Tests were applied to all participants; the Hamilton Depression Rating Scale and Young Mania Rating Scale were applied to patients and their control group. ResultsFacial Emotion Identification and Discrimination Test scores of patients and their parents were reasonably lower than their matching control groups. Moreover, we found that difficulty in FER affected more emotions in mothers than in fathers and mothers performed significantly worse than patients in the identification of angry and embarrassed faces. ConclusionThese findings indicate that parents of patients with BD have impairment with recognizing facial emotions and suggest that there may be an association between FER of patients with BD and that of their mothers.