Genetic Liability For Bipolar Disorder Research Articles

Association of healthy lifestyle factors and genetic liability with bipolar disorder: Findings from the UK Biobank

BackgroundThe interplay between genetic and lifestyle factors in the development of bipolar disorder (BD) remains unclear. MethodsA cohort study was carried out on 365,517 participants from the UK Biobank. Lifestyle scores, based on smoking, physical activity, diet, alcohol consumption, sedentary behavior, sleep duration, and social contact, were grouped as favorable (scores 6–7), intermediate (scores 4–5), or unfavorable (scores 0–3). The BD polygenic risk score (PRS) was also categorized into high, intermediate, and low-risk groups using PRS tertiles. Cox regression models determined hazard ratios (HRs) and 95 % confidence intervals (CIs) for BD. ResultsDuring the 12.9-year follow-up, 529 individuals developed BD. Comparing those with favorable lifestyles to those with unfavorable participants, the HR of developing BD was 3.28 (95 % CI, 2.76–3.89). Similarly, individuals with a high PRS had a risk of 3.20 (95 % CI, 2.83–3.63) compared to those with a low PRS. Notably, individuals with both a high PRS and an unfavorable lifestyle had a significantly higher risk of BD (HR = 6.31, 95 % CI, 4.14–9.63) compared to those with a low PRS and a favorable lifestyle. Additionally, the interaction between PRS and lifestyle contributed an additional risk, with a relative excess risk of 1.74 (95 % CI, 0.40–3.07) and an attributable proportion due to the interaction of 0.37 (95 % CI, 0.16–0.58). ConclusionsOur findings suggest that genetic liability for BD, measured as PRS, and lifestyle have an additive effect on the risk of developing BD. A favorable lifestyle was associated with a reduced risk of developing BD.

Risk for Mood, Anxiety, and Psychotic Disorders in Individuals at High and Low Genetic Liability for Bipolar Disorder and Major Depression

The nature of the genetic relationship between major depression and bipolar disorder remains unclear and might be clarified by considering disorders outside of the mood spectrum. To better understand the relationship between genetic liabilities for major depression (MD) and bipolar disorder (BD). A cohort study was conducted with data for individuals born in Sweden to Swedish parents from 1960 to 1990, with follow-up through December 31, 2018. The data included family genetic risk scores for MD and BD and International Classification of Diseases codes for a range of disorders as reported in primary care, specialist, and hospital registries. Data analysis was conducted from April 2022 to July 2022. High and low genetic liability were defined as being in the upper and lower 2 risk deciles. Risk was compared in individuals at high genetic liability to (1) MD only, (2) BD only, and (3) both MD and BD and those at (4) high genetic liability to BD and low genetic liability to MD and (5) high genetic liability to MD and low genetic liability to BD. Risk for nonpsychotic MD and BD, psychotic MD and BD, anxiety disorders, obsessive-compulsive disorder, schizoaffective disorder (SAD), schizophrenia, and other nonaffective psychosis. Data were included for 2 736 950 individuals with a mean (SD) age at follow-up of 43.9 (9.1) years. High genetic liability to only BD increased risk for nonpsychotic BD, psychotic BD, and SAD. High genetic liability to only MD augmented risk for nonpsychotic MD, anxiety disorders, and nonpsychotic BD. High genetic liability to both BD and MD had the strongest association with risk for nonpsychotic BD, anxiety disorders, and nonpsychotic MD. High genetic liability to BD and low genetic liability to MD increased risk for psychotic BD, nonpsychotic BD, and SAD with no increased risk for nonpsychotic MD or anxiety disorders. High genetic liability to MD and low genetic liability to BD increased risk for nonpsychotic MD, nonpsychotic BD, and anxiety disorders with no increased risk for psychotic BD. In this study, hypotheses that BD and MD are either genetically distinct or genetically closely interrelated were not supported. Both BD and MD were associated with a genetic vulnerability to mood disorders, but even that liability was partially selective. However, compared with individuals at high liability to MD, those at elevated genetic liability for BD had a substantially increased risk for psychosis. Compared with individuals at elevated genetic liability to BD, those at high genetic risk for MD had a considerably augmented risk for anxiety disorders. Clarifying genetic relationships between psychiatric syndromes can be substantially aided by the consideration of profiles of risk for a range of disorders.

Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults.

Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD.Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes.Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls.Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.

Genetic risk for bipolar disorder and psychopathology from childhood to early adulthood.

Studying the phenotypic manifestations of increased genetic liability for Bipolar Disorder (BD) can increase understanding of this disorder. We assessed whether genetic risk for BD was associated with childhood psychopathology and features of hypomania in young adulthood within a large population-based birth cohort. We used data from the second Psychiatric Genetics Consortium Genome Wide Association Study (GWAS) for Bipolar Disorder to construct a polygenic risk score (PRS) for each individual in the Avon Longitudinal Study of Parents and Children (ALSPAC). Linear and logistic regression models were used to assess associations between the BD-PRS and emotional/behavioural difficulties, attention deficit hyperactivity disorder (ADHD) and borderline personality disorder (BPD) traits in childhood, as well as hypomania in early adulthood (sample sizes from 2654 to 6111). The BD-PRS was not associated with total hypomania score, but was weakly associated with a binary measure of hypomania (OR = 1.13, 95%CI 0.98,1.32; p = 0.097), and particularly at higher hypomania symptom thresholds (strongest evidence OR = 1.33, 95%CI 1.07, 1.65; p = 0.01). The BD-PRS was also associated with ADHD (OR = 1.31, 95%CI 1.10, 1.57; p = 0.018), but not with other childhood psychopathology. The PRS only captures common genetic variation and currently explains a relatively small proportion of the variance for BD. The BD-PRS was associated with ADHD in childhood, and weakly with adult hypomania, but not with other psychopathology examined. Our findings suggest that genetic risk for BD does not appear to manifest in childhood to the same extent as schizophrenia genetic risk has been reported to do.

Abnormalities in left inferior frontal gyral thickness and parahippocampal gyral volume in young people at high genetic risk for bipolar disorder

Fronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12-30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk. We compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON). The AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD. The finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: A review of neuroimaging studies of individuals at high genetic risk for bipolar disorder

Cortical and subcortical gray matter abnormalities have been reported in individuals at high genetic risk for bipolar disorder, but the findings are inconsistent. The aim of this study was to review the available literature to identify common findings that could represent brain structural vulnerability factors for bipolar disorder and to discuss challenges for the advancement of the field. A systematic search was conducted using the PubMed database to identify all original articles investigating cortical or subcortical gray matter abnormalities in first-degree relatives of bipolar disorder patients. Very few findings were replicated, with the exception of larger insular cortex volumes in adult first-degree relatives and larger right inferior frontal gyrus in offspring of probands with bipolar disorder, both when compared with healthy controls. Isolated findings included decreased gray matter density in the left thalamus, decreased gray matter volumes in the left hippocampus and parahippocampal gyrus, and thicker right hippocampus in unaffected first-degree relatives. Genetic liability for bipolar disorder was associated with gray matter volumes in regions of the anterior cingulate cortex, ventral striatum, medial frontal gyrus, right precentral gyrus, right insular cortex, and medial orbital gyrus. Some studies found no evidence for gray matter abnormalities in first-degree relatives of bipolar disorder patients. Possible reasons for the discrepancies of findings across studies include small samples sizes, small effect size of susceptibility genes, the phenotypic heterogeneity of bipolar disorder, and the possible confounding effect of other Axis I psychopathologies among the relatives of patients. Future multisite, prospective, large studies with more homogeneous samples would be a key strategy to advance the field. The ultimate benefit would be an understanding of how to use brain imaging tools to identify individuals at increased risk for bipolar disorder and develop preventive strategies for that population.

Genetic Liability for Bipolar Disorder Is Characterized by Excess Frontal Activation in Response to a Working Memory Task

There is evidence that patients with bipolar disorder have working memory deficits even during periods of euthymia. The neural basis of such deficits and its relationship with genetic risk remain unclear. We utilized functional magnetic resonance imaging (fMRI) to investigate neural activity in samples of bipolar disorder patients and their unaffected first-degree relatives while performing working memory tasks of increasing difficulty. Twenty remitted bipolar I disorder patients, 20 of their unaffected first-degree relatives, and 20 healthy volunteers were recruited and successfully completed scanning. Subjects participated in fMRI scans consisting of an n-back working memory task with three stages of increasing difficulty (1-back, 2-back, and 3-back), alternating with a baseline attention task. Groups were analyzed separately to produce brain activation maps, and a group-by-task analysis of variance (ANOVA) with post hoc comparisons was completed. Patients performed more poorly online than control subjects and relatives on the 2-back and 3-back tasks. The group-by-task ANOVA demonstrated a significantly altered region of neural activity involving a cluster located in the left frontal pole/ventrolateral gyrus. Post hoc analyses demonstrated that this cluster was accounted for by significantly greater activation in relatives compared with control subjects for the 2-back task. Patients demonstrated a trend to significantly greater activation than control subjects in the same cluster during 1-back performance. Left prefrontal hyperactivation during working memory is associated with genetic liability for bipolar disorder and represents a potential neurobiological endophenotype for the illness.

209 – Genetic liability for bipolar disorder is characterized by excess prefrontal activation in response to a working memory task

209 – Genetic liability for bipolar disorder is characterized by excess prefrontal activation in response to a working memory task

Creativity and Bipolar Diathesis: Common Behavioural and Cognitive Components

An association between creativity and bipolar disorders has been noted among eminent creative individuals, and in clinical probands and their first degree relatives (e.g. Andreasen, 1987; Jamison, 1989; Richards, 1994). Those studies propose that a genetic liability for bipolar disorder carries with it an increased propensity for creative thought and action. The present study applied strict quantitative criteria to establish bipolar diathesis in order to determine whether the association between bipolarity and creativity would generalise to creative individuals beyond the circle of eminence in a nonclinical population. The Adjective Checklist Creative Personality Scale (ACL-CPS) and the revised General Behavior Inventory (GBI) were completed by 72 undergraduates. ACL-CPS scores were significantly elevated for students displaying periods of hypomania with no depression (hyperthymic), but not for those with alternating periods of hypomania and depression (cyclothymic) or predominantly depressed (dysthymic) mood patterns, as compared with people with predominantly neutral (euthymic) mood patterns (P < .05). GBI scores accounted for 38% of the variance in ACL-CPS scores (P < .001). Further analysis identified six behavioural symptoms underlying this association (P < .001). These six 'symptoms' may represent nonpathological affective and motivational correlates of creative activity which are aetiologically distinct from similar outward manifestations of bipolarity.