A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550,000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P=1.5 x 10(-8), experiment-wide P<0.01, OR=1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.     

Debate: No bipolar disorder in prepubertal children at high familial risk

The rise in pediatric bipolar disorder (PBD) prevalence rates and the related treatment regimen has an impact on a whole generation of severely affected young children. In Europe, we also see these emotional dysregulated children with a broad range of explosive disruptive behavior. However, classification within the bipolar disorder spectrum is rare. Why are these prepubertal children diagnosed with mania and how does this fit with the findings from bipolar offspring studies? Impact of methods of assessment, recruitment, and parental diagnoses are discussed.     

Fronto-limbic function in unaffected offspring at familial risk for bipolar disorder during an emotional working memory paradigm

Evidence from neuroimaging studies indicate that individuals with bipolar disorder (BD) exhibit altered functioning of fronto-limbic systems implicated in voluntary emotion regulation. Few studies, however, have examined the extent to which unaffected youth at familial risk for BD exhibit such alterations. Using an fMRI emotional working memory paradigm, we investigated the functioning of fronto-limbic systems in fifteen healthy bipolar offspring (8–17 years old) with at least one parent diagnosed with BD (HBO), and 16 age-matched healthy control (HC) participants. Neural activity and functional connectivity analyses focused on a priori neural regions supporting emotion processing (amygdala and ventral striatum) and voluntary emotion regulation (ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC)). Relative to HC, HBO exhibited greater right VLPFC (BA47) activation in response to positive emotional distracters and reduced VLPFC modulation of the amygdala to both the positive and negative emotional distracters; there were no group differences in connectivity for the neutral distracters. These findings suggest that alterations in the functioning of fronto-limbic systems implicated in voluntary emotion regulation are present in unaffected bipolar offspring. Future longitudinal studies are needed to determine the extent to which such alterations represent neurodevelopmental markers of risk for future onset of BD.     

Preliminary investigation of miRNA expression in individuals at high familial risk of bipolar disorder

Bipolar disorder (BD) is a highly heritable psychiatric disorder characterised by recurrent episodes of mania and depression. Many studies have reported altered gene expression in BD, some of which may be attributable to the dysregulated expression of miRNAs. Studies carried out to date have largely studied medicated patients, so it is possible that observed changes in miRNA expression might be a consequence of clinical illness or of its treatment. We sought to establish whether altered miRNA expression might play a causative role in the development of BD by studying young, unmedicated relatives of individuals with BD, who are at a higher genetic risk of developing BD themselves (high-risk individuals). The expression of 20 miRNAs previously implicated in either BD or schizophrenia was measured by qRT-PCR in whole-blood samples from 34 high-risk and 46 control individuals. Three miRNAs, miR-15b, miR-132 and miR-652 were up-regulated in the high-risk individuals, consistent with previous reports of increased expression of these miRNAs in patients with schizophrenia. Our findings suggest that the altered expression of these miRNAs might represent a mechanism of genetic susceptibility for BD. Moreover, our observation of altered miRNA expression in the blood prior to the onset of illness provides hope that one day blood-based tests may aid in the risk-stratification and treatment of BD.     

Association of rapid mood switching with panic disorder and familial panic risk in familial bipolar disorder

OBJECTIVE: Comorbid bipolar and panic disorders aggregate in families. A phenotypic trait shared by both disorders is the sudden shift in affect observed in panic attacks and some rapid cycling states. The authors investigated whether comorbidity of bipolar disorder and panic disorder is associated with rapid mood switching in families with a high rate of bipolar disorder. METHOD: Six hundred six subjects with bipolar disorder from the NIMH Bipolar Disorder Genetics Initiative were included in the study. Logistic regression analysis was used to analyze rapid mood switching as a function of panic disorder diagnosis, sex, and familial risk for panic. RESULTS: Familial panic and the diagnosis of panic disorder in an individual subject increased the odds for rapid mood switching. The familial effect persisted when individuals with panic disorder were excluded from the analysis. CONCLUSIONS: Panic and rapid mood switching occurring together in familial bipolar disorder may define a useful subphenotype for future studies.     

Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder

Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.     

Intelligence,educational attainment,and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder

First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10⁻⁵), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.     

Executive function in parents of patients with familial versus sporadic bipolar disorder

ObjectiveStudies investigating the cognitive function of healthy relatives of patients with bipolar disorder are conflicting, and the neurocognitive profile of relatives of bipolar disorder probands is still unclear. We aimed to evaluate executive function in unaffected parents of familial and sporadic patients with bipolar disorder.MethodsThe study included 24 unaffected familial parents (FP) of patients with bipolar disorder, 26 unaffected sporadic parents (SP) of patients with bipolar disorder and 26 controls matched with the parents for gender, age and duration of education (76 subjects in total). All of the subjects were interviewed with the Structured Clinical Interview for DSM-IV-Axis I. Executive function was assessed using the California Verbal Learning Test (CVLT), the Trail Making Test (TMT), the Wisconsin Card Sorting Test (WCST) and the Stroop test.ResultsIn comparison to their respective matched controls, FP performed significantly worse on the CVLT, TMT, WCST and Stroop test, whereas SP performed significantly worse only on WCST perseverative errors and Stroop color test. FP performed significantly worse than SP on the CVLT, TMT, and WCST.ConclusionThe present study investigated relatives with and without a family history of bipolar disorder separately and found that executive function was impaired in parents with a positive family history of bipolar disorder. These findings bring more evidence suggesting that deficits in prefrontal executive function and verbal memory are associated with familial vulnerability to bipolar disorder and that executive function and verbal memory impairments may represent a potential endophenotype of bipolar disorder.     

Clinical correlates and familial aggregation of age at onset in bipolar disorder

OBJECTIVE: To assess whether age at onset variation reflects underlying genetic heterogeneity in bipolar disorder, the authors examined the clinical and familial characteristics of age at onset in bipolar disorder subjects from families with multiple affected members. METHOD: A total of 211 families with 1,856 subjects were ascertained through bipolar I disorder probands. All the subjects were assessed with the Diagnostic Interview for Genetic Studies and assigned diagnoses by trained clinicians using best estimate procedures. Admixture analysis with the 211 bipolar disorder probands was used to decompose the age-at-onset distribution into a mixture of theoretical normal distributions. Logistic regression with general estimating equations was then used to examine clinical correlates and familial aggregation of age at onset in all 717 bipolar disorder subjects. RESULTS: The age-at-onset distribution consisted of a mixture of three normal distributions with means of 16.6 (SD=5.1), 26.0 (SD=1.4), and 34.7 (SD=6.6) years that comprised 79.7%, 7.2%, and 13.1% of the group, respectively. Cutoff points at ages 21 and 28 were derived from this analysis and used to define age-at-onset subgroups. Early-onset (age at onset 相似文献