Familial Risk For Bipolar Disorder Research Articles

Brain Structural Response in Individuals at Familial Risk for Bipolar Disorder: A Tale of Two Outcomes

Brain Structural Response in Individuals at Familial Risk for Bipolar Disorder: A Tale of Two Outcomes

Trait impulsivity as an endophenotype for bipolar I disorder

Impulsivity, conceptualized as impairment in planning and poor attentional and inhibitory control, is a key feature of bipolar disorder. Familial risk for bipolar disorder is known to affect inhibitory control but its impact on the attentional and planning dimensions of impulsivity is still unclear. We administered the Barratt Impulsiveness Scale, version 11 (BIS-11) to 54 euthymic individuals with DSM-IV bipolar I disorder, 57 of their clinically unaffected siblings, and 49 healthy comparison subjects. Groups were compared on the attentional (rapid shifts in attention/impatience with complexity), motor (acting impetuously), and non-planning (absence of weighing upon long-term consequences of actions) subscales of the BIS-11, and on total BIS-11 score. To investigate functional implications of trait impulsivity, total BIS-11 score was examined in relation to current psychosocial functioning and criminal history. Individuals with bipolar I disorder had elevated scores compared to healthy comparison subjects on BIS-11 total score and all three subscales (p < 0.0001). Unaffected siblings had elevated BIS-11 total score (p = 0.0037), motor (p = 0.0027), and non-planning (p = 0.0379) subscales in comparison to unrelated healthy controls. Total BIS-11 score was negatively associated with global assessment of functioning (GAF) score (β = -0.32, p < 0.0001). Our results suggest that impulsivity is sensitive to familial liability for the illness, making it a potential endophenotype for bipolar disorder.

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.

Effects of a mis‐sense DISC1 variant on brain activation in two cohorts at high risk of bipolar disorder or schizophrenia

Bipolar disorder and schizophrenia share a number of clinical features and genetic risk variants of small effect, suggesting overlapping pathogenic mechanisms. The effect of single genetic risk variants on brain function is likely to differ in people at high familial risk versus controls as these individuals have a higher overall genetic loading and are therefore closer to crossing a threshold of disease liability. Therefore, whilst the effects of genetic risk variants on brain function may be similar across individuals at risk of both disorders, they are hypothesized to differ compared to that seen in control subjects. We sought to examine the effects of the DISC1 Leu(607) Phe polymorphism on brain activation in young healthy individuals at familial risk of bipolar disorder (n = 84), in a group of controls (n = 78), and in a group at familial risk of schizophrenia (n = 47), performing a language task. We assessed whether genotype effects on brain activation differed according to risk status. There was a significant genotype × group interaction in a cluster centered on the left pre/postcentral gyrus, extending to the inferior frontal gyrus. The origin of this genotype × group effect originated from a significant effect of the presumed risk variant (Phe) on brain activation in the control group, which was absent in both high-risk groups. Differential effects of this polymorphism in controls compared to the two familial groups suggests a commonality of effect across individuals at high-risk of the disorders, which is likely to be dependant upon existing genetic background.

Amygdala Hyperactivation During Face Emotion Processing in Unaffected Youth at Risk for Bipolar Disorder

Youth at familial risk for bipolar disorder (BD) show deficits in face emotion processing, but the neural correlates of these deficits have not been examined. This preliminary study tests the hypothesis that, relative to healthy comparison (HC) subjects, both BD subjects and youth at risk for BD (i.e., those with a first-degree BD relative) will demonstrate amygdala hyperactivation when viewing fearful and happy faces. The at-risk youth were unaffected, in that they had no history of mood disorder. Amygdala activity was examined in 101 unrelated participants, 8 to 18 years old. Age, gender, and IQ-matched groups included BD (N = 32), unaffected at-risk (N = 13), and HC (N = 56). During functional magnetic resonance imaging, participants attended to emotional and nonemotional aspects of fearful and happy faces. While rating their fear of fearful faces, both BD and unaffected at-risk subjects exhibited amygdala hyperactivity versus HC. There were no between-group differences in amygdala activity in response to happy faces. Post-hoc comparisons revealed that, in at-risk youth, familial risk status (offspring versus sibling), presence of Axis I diagnosis (n = 1 attention-deficit/hyperactivity disorder [ADHD], n = 1 social phobia), and history of medication exposure (n = 1) did not influence imaging findings. We found amygdala hyperactivation in both unaffected at-risk and BD youth while rating their fear of fearful faces. These pilot data suggest that both face emotion labeling deficits and amygdala hyperactivity during face processing should receive further study as potential BD endophenotypes. Longitudinal studies should test whether amygdala hyperactivity to fearful faces predicts conversion to BD in at-risk youth.

Brief report: A family risk study exploring bipolar spectrum problems and cognitive biases in adolescent children of bipolar parents

Children of parents with bipolar disorder are at increased risk of bipolar spectrum diagnoses. This cross-sectional study explores cognitive factors in the prediction of vulnerability to bipolar disorder. Adolescents at high-risk (with a parent with bipolar disorder; n = 23) and age and gender matched adolescents (n = 24) were recruited. Parent and adolescent diagnoses were evaluated (SCID and SADS-L). Adolescents completed self-report measures assessing attributional style (ASQ), appraisal of hypomania-relevant experiences (HIQ), and hypomanic personality/temperament (HPS). Despite limitations in the power of the study, significantly more adolescents at high-risk for disorder received bipolar spectrum diagnoses. Groups did not differ in attributional style, hypomanic temperament or appraisals of hypomania-relevant experiences. A trend in ASQ results and general implications are discussed. The current study suggests that familial risk of bipolar disorder is not inevitably associated with cognitive biases in adolescence.

Effect of Variation in Diacylglycerol Kinase Eta (DGKH) Gene on Brain Function in a Cohort at Familial Risk of Bipolar Disorder

Several lines of evidence indicate that the diacylglycerol kinase eta (DGKH) gene is implicated in the etiology of bipolar disorder (BD). However, the functional neural mechanisms of DGKH's risk association remain unknown. Therefore, we examined the effects of three haplotype-tagging risk variants in DGKH (single nucleotide polymorphisms rs9315885, rs1012053, and rs1170191) on brain activation using a verbal fluency functional magnetic resonance imaging task. The subject groups consisted of young individuals at high familial risk of BD (n=81) and a comparison group of healthy controls (n=75). Individuals were grouped based on risk haplotypes described in previous studies. There was a significant risk haplotype*group interaction in the left medial frontal gyrus (BA10, involving anterior cingulate BA32), left precuneus, and right parahippocampal gyrus. All regions demonstrated greater activation during the baseline condition than sentence completion. Individuals at high familial risk for BD homozygous for the DGKH risk haplotype demonstrated relatively greater activation (poor suppression) of these regions during the task vs the low-risk haplotype subjects. The reverse pattern was seen for the control subjects. These findings suggest that there are differential effects of the DGKH gene in healthy controls vs the bipolar high-risk group, which manifests as a failure to disengage default-mode regions in those at familial risk carrying the risk haplotype.

Altered Development of White Matter in Youth at High Familial Risk for Bipolar Disorder

Altered Development of White Matter in Youth at High Familial Risk for Bipolar Disorder

Altered Development of White Matter in Youth at High Familial Risk for Bipolar Disorder: A Diffusion Tensor Imaging Study

To study white matter (WM) development in youth at high familial risk for bipolar disorder (BD). WM alterations are reported in youth and adults with BD. WM undergoes important maturational changes in adolescence. Age-related changes in WM microstructure using diffusion tensor imaging with tract-based spatial statistics in healthy offspring having a parent with BD were compared with those in healthy controls. A total of 45 offspring participated, including 20 healthy offspring with a parent diagnosed with BD (HBO) and 25 healthy control offspring of healthy parents (CONT). All were free of medical and psychiatric disorders. Mean fractional anisotropy (FA), radial diffusivity (RD), and longitudinal diffusivity were examined using whole-brain analyses, co-varying for age. Group-by-age interactions showed a linear increase in FA and a linear decrease in RD in CONT in the left corpus callosum and right inferior longitudinal fasciculus. In HBO, there was a linear decrease in FA and an increase in RD with age in the left corpus callosum and no relation between FA or RD and age in the right inferior longitudinal fasciculus. Curve fitting confirmed linear and showed nonlinear relations between FA and RD and age in these regions in CONT and HBO. This is the first study to examine WM in healthy offspring at high familial risk for BD. Results from this cross-sectional study suggest altered development of WM in HBO compared with CONT in the corpus callosum and temporal associative tracts, which may represent vulnerability markers for future BD and other psychiatric disorders in HBO.

C.11.03 The bipolar environment: the need for effective treatment in bipolar disorder

Children of a parent with bipolar disorder (bipolar offspring) have an increased risk for mood disorders. While genetic factors play a significant role in this population, susceptibility to environmental stress may also significantly contribute to this vulnerability for mood disorders. Childhood trauma has consistently been found to increase the risk for mood disorders, with persisting consequences for hypothalamic-pituitary-adrenal (HPA) axis functionality. However, it is currently unknown whether childhood trauma specifically affects HPA axis activity in individuals with a familial risk for bipolar disorder. Therefore, we investigated the effects of childhood trauma on daytime and evening cortisol levels and dexamethasone suppression in bipolar offspring (N = 70) and healthy controls (N = 44). In our study we found no significant differences in daytime and evening cortisol levels as well as dexamethasone suppression between bipolar offspring and healthy controls (all p-values > 0.43). In contrast, childhood trauma differentially affected daytime cortisol levels in the bipolar offspring compared to healthy controls (childhood trauma X bipolar offspring interaction, β = −7.310, p = 0.0414) with an effect of childhood trauma on daytime cortisol in bipolar offspring at trend level (p = 0.058). In the bipolar offspring group, lifetime or current psychiatric diagnoses, and stressful life events separately did not affect cortisol levels or dexamethasone suppression (all p-values > p = 0.50). These findings were independent of current or lifetime psychiatric diagnosis. In conclusion, trauma-related changes in daytime HPA axis activity appear to be a specific trait in bipolar offspring who have increased risk for mood disorders compared to healthy individuals.

Risk for Bipolar Disorder Is Associated With Face-Processing Deficits Across Emotions

ObjectiveYouths with euthymic bipolar disorder (BD) have a deficit in face-emotion labeling that is present across multiple emotions. Recent research indicates that youths at familial risk for BD, but without a history of mood disorder, also have a deficit in face-emotion labeling, suggesting that such impairments may be an endophenotype for BD. It is unclear whether this deficit in at-risk youths is present across all emotions or if the impairment presents initially as an emotion-specific dysfunction that then generalizes to other emotions as the symptoms of BD become manifest. MethodThirty-seven patients with pediatric BD, 25 unaffected children with a first-degree relative with BD, and 36 typically developing youths were administered the Emotional Expression Multimorph Task, a computerized behavioral task, which presents gradations of facial emotions from 100% neutrality to 100% emotional expression (happiness, surprise, fear, sadness, anger, and disgust). ResultsRepeated-measures analysis of covariance revealed that, compared with the control youths, the patients and the at-risk youths required significantly more intense emotional information to identify and correctly label face emotions. The patients with BD and the at-risk youths did not differ from each other. Group-by-emotion interactions were not significant, indicating that the group effects did not differ based on the facial emotion. ConclusionsThe youths at risk for BD demonstrate nonspecific deficits in face-emotion recognition, similar to patients with the illness. Further research is needed to determine whether such deficits meet all the criteria for an endophenotype. J. Am. Acad. Child Adolesc. Psychiatry, 2008;47(12):1455–1461.

Cerebellar ataxia in youths at risk for bipolar disorder

Structural, biochemical, and functional cerebellar abnormalities occur in individuals with or at-risk for developing bipolar disorder (BD), but the clinical implications of these abnormalities are unknown. The present study examined cerebellar function in youths who were at familial risk for BD by comparing ataxia battery scores of youths with a bipolar parent to those of healthy youths. Trained raters administered an ataxia battery, consisting of three tasks, to children (aged 8-12 years) with at least one parent with BD type I (BDI) who themselves did not have BDI (at-risk or AR group, n = 21) and healthy comparison children (aged 8-12 years) with parents free of DSM-IV Axis I psychopathology (HC group, n = 23). AR youths performed worse than HC youths on the Sharpened Romberg test (subjects standing heel-to-toe) and standing on one foot with eyes open (p < 0.02). The results indicate that youths at familial risk for BD have more difficulty performing a Sharpened Romberg test than a HC group, suggesting that midline cerebellar dysfunction may be a biomarker for the future development of BD. Further studies examining the relationships among youths at risk for BD, coordination abnormalities, and cerebellar dysfunction are needed.

Obstetrical complications in children at high risk for bipolar disorder

Objective To examine obstetrical complications as a risk factor for developing bipolar disorder (BPD). We hypothesized that children with a bipolar parent would be at greater risk for obstetrical complications than demographically matched children of healthy adults. Additionally, within this “at-risk” (AR) sample, we hypothesized that obstetrical complications would be associated with the development of psychiatric disorders. Methods The Washington University in St. Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U KSADS) was administered to children (AR) who had at least one parent with BPD ( N = 36) and children of healthy parents (HC) ( N = 27), by raters who were blind to diagnostic category. To assess obstetrical risk history, the Rochester Research Obstetrical Scale (ROS) was administered to parents of AR and HC children. Results Children at familial risk for BPD had greater total ( p = 0.02) and prenatal ( p = 0.006) obstetrical complication scores than children of healthy parents. However, obstetrical complications were not associated with the development of affective, anxiety, or disruptive behavioral disorders within the at-risk group. Conclusion Our data suggest that compared with children of families without BPD, children of parents with BPD may be at greater risk for obstetrical complications, particularly those that occur during the prenatal period; however, at this early follow-up period factors other than obstetrical complications appear to contribute to the differences in rates of psychiatric disorders between these groups.