Risk Factors For Bipolar Disorder Research Articles

Assessing oxidative pathway genes as risk factors for bipolar disorder

There is a growing body of evidence implicating oxidative stress and the glutathione system in the pathogenesis of major psychiatric illnesses, including schizophrenia and bipolar disorder. Here we investigate whether genes involved in oxidative stress regulation are associated with increased risk for bipolar disorder. Four candidate genes were selected a priori from two different steps in the oxidative stress pathway, specifically the synthesis of glutathione [catalytic subunit of glutamate cysteine ligase (GCLC) and regulatory subunit of glutamate cysteine ligase (GCLM)] and the removal of reactive oxygen species [superoxide dismutase 2 (SOD2) and glutathione peroxidase 3 (GPX3)]. Haplotype tagging and functional nucleotide polymorphisms were selected in each gene and tested for association with bipolar disorder under narrow (n = 240) and broad (n = 325) phenotypic models, compared to healthy controls (n = 392, comprising 166 psychiatrically assessed unaffected controls plus 226 healthy individuals). Single marker association analysis did not reveal significant association with bipolar disorder; however, haplotypes in the SOD2 gene showed nominal association (global chi(2) = 8.94, p = 0.03; broad model). Interaction analysis revealed a significant interaction between SOD2 and GPX3 haplotypes, which further increases risk for bipolar disorder (odds ratio = 2.247, chi(2) = 9.526, p = 0.002, corrected p = 0.029). Further characterization of the SOD2 and GPX3 interaction using larger cohorts is required to determine the role of these oxidative pathway genes as risk factors for bipolar disorder.

Vulnerability Factors for Bipolar Disorders as Predictors of Attributions in Ability-Based and Chance-Based Tests

The role of attributional style in bipolar disorder has received empirical support. Research suggests that a pattern of global, stable, and possibly internal attributions for positive events might even trigger mania. We tested whether hypothesized risk factors for bipolar disorder are associated with such attributions after feedback of success in an ability- and chance-based test. University students (n = 115) completed the Behavioral Inhibition and Behavioral Activation Scales (BIS/BAS) and the Hypomanic Personality Scale (HPS) to assess risk for bipolar disorder. In addition, participants were interviewed using the Structured Clinical Interview. All participants performed an ability-based (intelligence) test and a chance-based (dice-throwing) test, and success was induced by providing positive feedback regardless of their actual test performance. Attributions of perceived success were assessed after each test. Results showed that high scores on the BAS scale were generally predictive of self-serving attributions in the ability-based test, while scores on the HPS predicted a more global and self-serving attributional style in the chance-based test. Current depression, lifetime affective disorder, BIS, or the dysregulation of the BAS did not consistently predict attributions on either test. Despite some methodological limitations, results suggest that anticipated or experienced success in skill-related contexts triggers self-serving attributions in individuals scoring high on the BAS scale, while perceived positive outcome in chance-related, more unrealistic contexts triggers similar attributions in individuals scoring high on the HPS. Future research has to examine whether these overly positive attributions after positive, chance-related situations are a stable characteristic with respect to vulnerability to mania.

No association between bipolar disorder and syngr1 or synapsin II polymorphisms in the Han Chinese population

Polymorphisms of the SYNAPTOGYRIN1 (SYNGR1) and SYNASINII (SYNII) genes have been shown to be a risk factor for bipolar disorder or schizophrenia. A case-control study with these two genes was conducted in 506 bipolar disorder patients and 507 healthy individuals from the Han Chinese population. No association was found in this study.

Emotional hyper‐reactivity in normothymic bipolar patients

Normothymic states in bipolar disorders are generally considered to be devoid of severe symptoms. However, bipolar patients present subsyndromal symptoms for half of their lives, and often have comorbid psychiatric disorders. If we go beyond the concept of temperamental features, can we identify certain emotional characteristics distinguishing normothymic bipolar patients from normal controls? We previously showed, using self-completed questionnaires, that normothymic bipolar patients display higher levels of emotional lability and intensity than controls. The aim of this study was to assess the emotional reactivity of normothymic bipolar patients, comparing such patients with a normal control group during an experimental mood induction procedure. We evaluated the subjective emotional reactivity of 145 subjects (90 control subjects and 55 normothymic bipolar patients), using an emotional induction method based on the viewing of a set of 18 pictures (6 positive, 6 negative, 6 neutral) extracted from the International Affective Picture System. Subjective valence and arousal were recorded with the Self-Assessment Manikin. We also recorded startle reflexes, triggered by a tone occurring during the viewing of two-thirds of the pictures. We controlled for confounding factors, such as concurrent treatments, in all analyses. Normothymic bipolar patients and normal controls assessed valence and arousal similarly for positive and negative images. However, neutral images were considered more pleasant [F(1,143) = 8.4; p = 0.004] and induced a higher level of arousal [F(1,143) = 12.3; p = 0.001] in normothymic bipolar patients than in control subjects. Neutral pictures also triggered a stronger startle reflex in normothymic bipolar patients compared to controls [F(3,123) = 3.1; p = 0.03]. Normothymic bipolar patients displayed emotional hyper-reactivity, mostly evidenced in neutral situations. This feature may be linked to emotional dysregulation and is a potential endophenotype and/or a risk factor for bipolar disorders. This trait may be responsible for vulnerability to minor stressful events in everyday life. These findings have potential implications for the daily management of bipolar disorder between crises.

Consanguinity: Still a challenge

Byline: T. Sathyanarayana Rao, M. Asha, K. Sambamurthy, K. Jagannatha Rao We are all connected to life. Every choice we make and every belief we hold exerts influence upon the whole of life. And we live with the consequences of our choice. As part of our biological health, this unique truth has physical expressions in honor, loyalty, family and group bonds. Probably this forms the basis of marriage, one of the most vital and powerful of our relationships. The human population has seen modern civilization and is still within family boundaries. One such familial-social bond in consanguineous marriage. The word consanguineous comes from the two Latin words ''con'' meaning shared and ''sanguis'' meaning blood. Consanguinity describes a relationship between two people who share an ancestor, or share blood. Such marriages are favoured by different populations usually bound to traditional customs, beliefs and to keep property in united form within the family. In Arab Muslim communities, first cousin unions between a man and his father's brother's daughter are preferred. However, in population of Dravidian Hindus of South India, marriage of a boy with his mother's brother's daughter, is opposed. But, uncle-niece unions (but not aunt-nephew) are permitted in Judaism. Many studies indicated that consanguineous marriages are strongly favoured in human populations. The highest consanguineous marriages (20% to over 50%) are reported in North of Africa, Asia etc, usually associated with low socioeconomic status, illiteracy, and rural residence.[sup] [1],[2] In India, the main reasons for these marriages are stronger family ties, the integrity of estates and the like. But the current debate in medical sciences is on the health implications of these consanguineous marriages. Consanguineous marriages are major responsible risk factors for Bipolar disorders. This marriage system has been reported as an important factor in the appearance of autosomal recessive diseases and congenital anomalies, including hydrocephalus, postaxial hand polydactyly and bilateral cleft lip cleft palate, bipolar disorders, depression, dysferlinopathy, reproductive disorders, sterility, infant mortality, child deaths, spontaneous abortions and stillbirths etc. Also there are reports indicating positive association between consanguinity and Down syndrome, and also ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defect (AVSD), pulmonary stenosis (PS) and pulmonary atresia (PA). The risk for birth defects in the offspring of first cousin matings has been increased to 5-8% compared to 2-3% in non-consanguineous marriages.[sup] [3] However, first cousin unions are culturally preferred. The reason is ease of marriage decision making when the potential spouse is well-known and considered to be part of the 'extended family'. And these marriages also tend to reinforce social and kin bonds from one to the next generation. Recently Nalini and Gayathri[sup] [4] reported the role of Consanguinity (46.4%) in causing Dysferlinopathy in 28 patients. Further Bindu et al ,[sup] [5] reported the role of Consanguinity (61.5%) as a etiological factor for Hallervorden-Spatz syndrome (HSS), a rare autosomal recessive neurodegenerative disorder of childhood. Reports from India and west proved beyond doubt that consanguinity plays a significant role in mental health problems. All these disorders play a significant role on world economy and productivity and become a huge burden on medical fraternity. In spite of medical advancements, literacy rate and urbanization, still this family linked traditions are not able to be broken. In recent times, the situation appears better in urban areas. In a population with a high degree of inbreeding, the formulation of a public health program with multi-approach strategy, including education about the anticipated genetic consequences, prenatal diagnosis, neonatal screening, and genetic counselling, is a necessity. …

CS09-01 Epidemiology and risk factors of bipolar disorder and schizophrenia in the conceptualization of the disease spectrum

Both disorders are worldwide, lifelong, and recurrent illnesses with periods of exacerbation and partial or full remissions. Lifetime prevalence of schizophrenia and bipolar disorder type I is around 1%. Women and men are affected at proximately equal rates and the typical age of onset is similar. Both disorders also share risk factors showing evidence for impaired prenatal development, such as birth seasonality, abnormal dermatoglyphs and higher incidence of perinatal complications. However, there is evidence for differences in prevalence in geographical isolates, in presence of minor physical abnormalities and possibly also in influence of psychosocial factors, urbanicity and use of cannabis. However, based only on similar epidemiological parameters, it is not possible to assume any degree of continuity between bipolar disorder and schizophrenia. The main evidence for partially shared pathophysiology is given by genetic studies.

Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al 2008). The markers lie about 340 kb apart in the gene. Here we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the NIMH Waves 1-4 (p=0.050; OR=1.24) and German (p=0.0006; OR=1.34) samples. This association was replicated in an independent US sample known as NIMH Wave 5 (466 cases, 212 controls; p=0.017; OR=1.38). A random-effects meta-analysis of all three samples was significant (p = 3 × 10−6; OR=1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (p=0.0001; OR=1.70), and similar ORs in the NIMH 1–4 and NIMH 5 samples that were not significant at the p<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (p=1.7 × 10−5; OR=1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

Striatal volumes in affected and unaffected relatives of bipolar patients – high-risk study

Background Striatal volume changes reported in bipolar disorders could represent artifacts of medication or comorbid conditions, or illness related changes, either biological predispositions or consequences of illness burden. We conducted volumetric high-risk study to investigate whether striatal volume changes represent primary biological risk factor for bipolar disorders. Methods High-risk (HR) participants (age range 15–30 years) were recruited from families multiply affected with bipolar disorders. They included 20 affected and 26 unaffected offspring of parents with primary mood disorders, matched by age and sex with 31 controls without a personal or family history of psychiatric disorders. Striatal volumes were measured on 1.5T 3D anatomical MRI images using standard methods. Results There was a significant difference between groups (affected, unaffected HR and control subjects) in caudate volumes ( F = 3.50, DF = 2; 74 and p = 0.04) in absence of putamen volume changes. The caudate volumes were largest in unaffected HR subjects without differences between affected and control or affected and unaffected HR subjects. The maximum changes were found in the head of the caudate. Controlling for non-independence of observations in multiple subjects per family yielded non-significant differences. Conclusions Despite the biological plausibility, partial agreement with previous studies and nominal statistical significance, controlling for non-independence of observations within families changed the increased caudate volumes among unaffected subjects to non-significant. We thus present these findings as negative, pending further replication. Striatal volume abnormalities did not meet criteria for endophenotype in this study.

Self appraisal and behavioural activation in the prediction of hypomanic personality and depressive symptoms

Hypomanic personality is characterised by increased positive mood and energy but also more depression and greater risk of bipolar disorder. It is linked with positive self-appraisals for hypomania-relevant events and Behavioural Activation System (BAS) sensitivity such that hypomanic individuals tend preferentially towards goal-related activities. This study investigated relationships between positive and negative self-appraisal and BAS functioning and hypomanic personality and depressive symptoms. Participants ( N = 231) completed measures of hypomanic personality, mood symptoms, dysfunctional attitudes, self-appraisal and behavioural activation/inhibition. Positive but not negative self-appraisal contributed to prediction of hypomanic personality as did higher BAS fun seeking and lower Behavioural Inhibition System (BIS) scores. Conversely, negative self-appraisal was positively predictive of current depressive mood, whilst BAS reward responsiveness was negatively predictive. There are specific relationships between positive and negative appraisal styles and hypomanic personality and depressive mood, respectively. The findings of complimentary contributions from appraisal style, BAS and BIS to prediction of hypomanic personality are relevant to developing a better understanding of risk factors for bipolar disorder.

Elevated Prevalence of Obesity, Metabolic Syndrome, and Cardiovascular Risk Factors in Bipolar Disorder

Bipolar disorder is associated with excess cardiovascular mortality. We hypothesized outpatients with bipolar disorder would exhibit excess cardiovascular risk factors, particularly among prevalent users of the second-generation antipsychotics associated with weight gain and valproic acid derivatives. This chart review of 217 patients with bipolar disorder examined cardiovascular risk factors of the metabolic syndrome. We also evaluated if certain medications were cross-sectionally associated with metabolic syndrome. Fifty-six patients were not weighed and many did not have available lipid profiles. Over three-quarters of those with available data (n = 161) were overweight or obese (body mass index >or= 25) and nearly half were obese (body mass index >or= 30). A prevalence exceeding general population estimates was also observed for hypertriglyceridemia, elevated blood pressure/hypertension, and elevated fasting glucose/diabetes. Among those with all requisite data (n = 60), over 50% met criteria for National Cholesterol Education Program-defined metabolic syndrome, nearly double the expected prevalence. A trend toward greater prevalence of metabolic syndrome among prevalent users of the second-generation antipsychotics associated with weight gain was observed. Obesity and the metabolic syndrome were common in patients with bipolar disorder. These patients may be under-evaluated for cardiovascular risk and warrant screening and early intervention.

Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult mice: Prevention by chronic lithium treatment

Objectives Emerging data suggests that omega-3 fatty acid deficiency may be a risk factor for bipolar disorder. In the present study, we determined the effects of chronic dietary-induced omega-3 fatty acid deficiency and/or concomitant chronic lithium chloride (LiCl) treatment on amphetamine (AMPH)-induced behavioral sensitization, a phenomenon that may recruit neuroplastic mechanisms relevant to the pathophysiology of bipolar disorder. Method Adult male C57BL/6J mice were randomly assigned to one four diets: Control (α-linolenic-fortified), Control + LiCl (0.255%), α-linolenic-Deficient, or Deficient + LiCl (0.255%), and behavioral testing initiated 65 days later. Locomotor activity was determined following 3 intermittent (separated by 7 d) injections of amphetamine (AMPH) (1 mg/kg). After behavioral testing, red blood cell (RBC) and regional brain (prefrontal cortex, hippocampus, ventral striatum) fatty acid composition was determined by gas chromatography. Results Each diet group exhibited comparable locomotor activity following acute AMPH treatment. However, the development of sensitization following repeated AMPH treatment was significantly augmented in Deficient mice relative to controls, and this augmented response was prevented by chronic LiCl treatment. Relative to controls, Deficient mice exhibited deficits in RBC and regional brain docosahexaenoic acid (DHA, 22:6 n−3) composition, reciprocal elevations in vaccenic acid (18:1 n−7), arachidonic acid (AA, 20:4 n−6), and docosapentaenoic acid (DPA, 22:5 n−6) compositions, and elevations in AA:DHA, oleic acid:DHA, and DPA:DHA ratios. The fatty acid abnormalities in Deficient mice were not altered by concurrent chronic lithium treatment. Mice fed the Control + LiCl diet exhibited a significant increase in AA composition in RBC and all brain regions, and an elevated AA:DHA ratio in the prefrontal cortex and hippocampus, relative to Controls. Fatty acid composition in RBC and different brain regions were predominantly positively correlated. Within the ventral striatum, DHA composition was inversely correlated, and AA:DHA and oleic acid:DHA ratios positively correlated, with total distance traveled following the final AMPH treatment. Conclusion These data indicate that alterations in fatty acid composition resulting from dietary-induced omega-3 fatty acid deficiency augment the development of AMPH-induced behavioral sensitization in a manner that is prevented by chronic lithium treatment. The implications of these findings for understanding the contribution of omega-3 fatty acid deficiency to the pathophysiology and progression of bipolar disorder are discussed.

The Level of Cardiovascular Risk Factors in Bipolar Disorder Equals That of Schizophrenia

In schizophrenia, increased rates of somatic mortality have been shown to correspond with a high prevalence of cardiovascular risk factors, including smoking and the metabolic syndrome. In bipolar disorder, the amount of cardiovascular risk is still largely unknown. This study compares the prevalence of smoking and metabolic disturbances in bipolar disorder and schizophrenia in a representative sample of patients under naturalistic conditions. It also compares the prevalence of risk factors in each diagnostic group with the general population. Longitudinal data on clinical groups from October 2002 through December 2005 were from the Oslo TOP Study (DSM-IV bipolar disorder [N = 110] and schizophrenia [N = 163]). Reference data were from the 2000 to 2001 Oslo Health Study (18,770 individuals of the same area). Background variables, prevalence of smoking, and age-adjusted levels of metabolic risk factors were compared between diagnostic groups. Risk factors in both groups were then compared with the general population. Patients with bipolar disorder had higher levels of education, better social functioning, fewer psychiatric symptoms, and less use of medication than patients with schizophrenia. There was no significant difference between diagnostic groups in the prevalence of smoking, obesity, metabolic syndrome, or diabetes. The mean level of high density lipoprotein cholesterol was lower in schizophrenia (p < .001), and systolic blood pressure was higher in bipolar disorder (p < .05). Both diagnostic groups had a prevalence of cardiovascular risk factors about twice that of the general population. The prevalence of cardiovascular risk factors was alarmingly high for bipolar disorder and schizophrenia patients compared with the general population, and the prevalence was approximately the same in both diagnostic groups.

Polymorphisms in the homeobox gene OTX2 may be a risk factor for bipolar disorder

We investigated the possible involvement of OTX2, a homeobox gene crucial for forebrain development, in the pathogenesis of schizophrenia and bipolar disorder. The disruption of this gene results in cortical malformations and causes serotonergic and dopaminergic cells in the midbrain to be expressed in aberrant locations. Resequencing of DNA from OTX2 exons and surrounding introns from 60 individuals (15 schizophrenia, 15 bipolar disorder, 15 depression, and 15 control) revealed two intronic polymorphisms, rs2277499 (C/T) and rs28757218 (G/T), but no other variations. The minor allele of rs2277499 (T) did not associate with clinical diagnosis. However, using a Taqman genotyping assay, we found the rs28757218 minor allele (T) in 30 out of 720 (4.2%) individuals with bipolar disorder but only in 6 out of 526 (1.1%) control individuals (odds ratio 3.5, 95% confidence interval 1.4-10.4, P = 0.003). On the other hand, the rs28757218 minor allele was only found in 6 out of 458 (1.3%) individuals with schizophrenia. All individuals with the rs28757218 polymorphism were heterozygous for the allele. Based on this positive case-control association finding, we conclude that variations in OTX2 might confer risk for the development of bipolar disorder.

Indicators of fetal growth and bipolar disorder: a Danish national register-based study

Several studies have found an association between indicators of fetal growth and/or obstetric complications and schizophrenia but only a few studies have investigated the possible association between these factors and bipolar disorder. Furthermore, the results of these studies have been contradictory. The aim of this study was to investigate whether the risk of bipolar disorder is associated with exposure to indicators of fetal growth. A national population nested case-control study based on Danish longitudinal register databases was carried out. Conditional logistic regression was used, controlling for potential confounding factors such as parental age at birth, socio-economic indicators and psychiatric history. We identified 196 cases, and each case was time-, age- and sex-matched with 25 normal population-based controls. All cases were between the ages of 12 and 26 years at the time of diagnosis, were born between 1973 and 1983 and were admitted and diagnosed between 1987 and 1999. During the study period 1973-1983, none of the individual variables available for analyses (birthweight, birth length, gestational age and number of previous pregnancies in the mother) was associated with receiving a diagnosis of bipolar disorder. None of the indicators of fetal growth under study could be identified as risk factors for bipolar disorder, suggesting that the etiologies of schizophrenia and bipolar disorder, at least in part, are different.

Assessing the Dysregulation of the Behavioral Activation System: The Hypomanic Personality Scale and the BIS–BAS Scales

We discuss the Hypomanic Personality Scale (Hyp; Eckblad & Chapman, 1986) and the Behavioral Inhibition System (BIS–BAS; Carver & White, 1994) and Behavioral Activation System (BAS; Gray, 1991) Scales as risk factors for bipolar disorders. The dysregulation of the BAS is considered to be central and results in higher variability in mood. Therefore, we examined how those scales are associated with mood fluctuations. A total of 59 participants completed a diary for at least 17 days. It included a modified Center for Epidemiologic Studies–Depression Scale (Meyer & Hautzinger, 2001) assessing depression and mania and the Positive and Negative Affect Schedule (Watson, Clark, & Tellegen, 1988). Hyp and BAS predicted levels of mania and of positive affect but also fluctuations of mania. Hyp also predicted instability of negative affect. Our data also suggest that mood variability is a trait-like feature. Both scales seem not to be perfect measures of the dysregulation factor. Future research should assess this dysregulation more directly.

Association analysis of the glycogen synthase kinase-3β gene in bipolar disorder

Glycogen synthase kinase-3β (GSK3β) is a target of lithium as well as sodium valproate, both of which are effective mood stabilizing prophylatics/treatments for bipolar disorder, a highly heritable psychiatric disorder. Though it is not clear whether the mood stabilizing effects of these drugs act directly through GSK3β, it is a good candidate for mediating at least part of lithium's action, and is an aetiological candidate gene for the disease itself. Recently, a potential locus for bipolar disorder was reported on chromosome 3q, close to 3q13.37 where GSK3β maps. We conducted an association study to test the hypothesis that polymorphism of GSK3β is involved in susceptibility to bipolar disorder by examining association between GSK3β-gene polymorphisms and bipolar disorder. Of the five polymorphisms we examined, three were very rare in the study population and were not examined further. Neither of the remaining two polymorphisms we examined showed association with bipolar disorder. Thus, it is unlikely that the GSK3β-gene is a risk factor for bipolar disorder in our sample, but we cannot exclude the gene completely as other unknown polymorphisms in the gene may increase susceptibility.

No evidence for verbal memory impairment in individuals putatively at risk for bipolar disorder

Background Hypomanic temperament and rigid personality are putative risk factors for affective episodes and even bipolar disorder. Individuals with bipolar disorder exhibit neuropsychological impairments, especially memory difficulties, not only during mood episodes but also when they are euthymic. Such cognitive impairments may also constitute a risk factor for bipolar disorder. The purpose of the present study was to investigate the presence of memory difficulties in individuals with hypomanic and rigid personality traits. Methods Study participants were 6000 German students recruited from high schools, colleges, and vocational schools in Germany. The students completed the Hypomanic Personality Scale and the Rigidity subscale of the Munich Personality Test. Four groups of students were selected from this sample based on their scores in the Hypomanic Personality Scale and Rigidity subscale: individuals with (1) hypomanic temperament, (2) rigid temperament, or (3) hypomanic-rigid temperament and (4) control participants. These students (n = 153) completed the Rey-Auditory Verbal Learning Test, a well-established measure of verbal learning and memory, as well an IQ test (Leistungsprüfsystem). Results Multiple regression analyses indicated that sex and IQ, but not temperament, predicted learning of the Auditory Verbal Learning Test word list, the number of words recalled at short-delayed recall, and recognition. Limitations The risk for affective disorders was only defined by psychometric measures, and we did not control for family history of bipolar disorders. Conclusions Hypomanic temperament and Rigid personality were not associated with verbal learning and memory. Cognitive impairment may be associated with repeated mood episodes rather than constituting a risk factor for bipolar disorder.

Neuroanatomical abnormalities as risk factors for bipolar disorder

Neuroimaging studies show structural brain abnormalities in bipolar patients. Some of the abnormalities may represent biological risk factors conveying vulnerability for the disease. This paper aims to identify neuroanatomical risk factors for bipolar disorder (BD). We reviewed magnetic resonance imaging (MRI) findings in populations in which the effects of the disease or treatment are minimal or where the chances of finding genetically coded risk factors shared within the families are increased. Such populations include unaffected relatives of bipolar patients, first-episode patients, children or adolescents with BD and patients with familial BD. MEDLINE search revealed 30 relevant scientific papers. Abnormalities in the volume of the striatum, left hemispheric white matter, thalamus and anterior cingulate as well as quantitative MRI signal hyperintensities were identified already in unaffected relatives of bipolar patients. Subjects in the early stages of the disease showed volume changes of the ventricles, white matter, caudate, putamen, amygdala, hippocampus and the subgenual prefrontal cortex. Reduction in the subgenual prefrontal cortex volume was replicated in three of four studies in patients with familial BD. Possible candidates for neuroanatomical risk factors for BD are volumetric abnormalities of the subgenual prefrontal cortex, striatum, white matter, and probably also the hippocampus and amygdala. Qualitative finding of white matter hyperintensities was already utilized as an endophenotype.

Functional polymorphisms of HSPA5: Possible association with bipolar disorder

Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 ( GRP78/ BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.

Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI

There have been several researches on the role of personality in the pathophysiology of bipolar disorder. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum (ER) stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Therefore, in this study, we examined the relationship between the XBP1 gene polymorphism and the personality traits assessed by two self-rating scales, a shortened version of Temperament and Character Inventory (TCI) and NEO-Five Factor Inventory (NEO-FFI) in healthy subjects. The present results suggested that the XBP1 gene polymorphism was associated with the NEO-FFI score of neuroticism in female subjects. However, no significant differences in the other personality scale scores of both assessments were observed among normal subjects with −116C/C, C/G and G/G genotypes. Further investigations are necessary to examine the relationship in patients with bipolar disorder, or use full version of various self-rating personality assessments.