The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding ...phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (cAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular cAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated cAMP.
Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls ...and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD.
A family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical phenotype that includes schizophrenia and affective disorders is described. This translocation generates a LOD score ...of 3.6 when the disease phenotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all classed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features by which the psychiatric phenotype could be distinguished from unrelated cases of either schizophrenia or affective disorders, and no physical, neurological, or dysmorphic conditions co-occurred with psychiatric symptoms. Translocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and different from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carriers of the translocation who had no psychiatric symptoms—a pattern found in other families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes
DISC1 and
DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.
Objective: Patients with remitted major depressive disorder (MDD) and bipolar disorder have persistent impairments in executive function and verbal memory that may represent endophenotypic ...abnormalities. In this study, we examine neurocognitive function in a sample of euthymic young adults with bipolar spectrum disorder (BSD) (Can J Psychiatry 2002; 47: 125–134) and compare this to well‐matched samples of young adults with recurrent MDD and controls.
Method: Twenty‐one euthymic young adult patients with BSD were compared with 42 young adult patients with MDD and 33 controls on a neuropsychological battery assessing attention, executive function and verbal memory.
Results: Patients with BSD were significantly more impaired than MDD patients and controls on tests of executive function and verbal memory. MDD patients did not differ significantly from controls on verbal memory function but performed less well on a test of executive function.
Conclusion: Euthymic young adults with BSD had greater impairment on neurocognitive measures associated with prefrontal and hippocampal function than MDD patients and controls. This is a reflection of a strong bipolar diathesis in the BSD group rather than being a consequence of a more severe unipolar illness.
A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is ...the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a ...t(1;11) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative sample of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of individual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.
Neurocognitive impairments in euthymic patients with bipolar disorder may represent trait rather than state variables.
To test the hypothesis that euthymic patients with bipolar disorder would ...exhibit impairment in verbal learning and memory and executive function compared with healthy controls matched for age, gender and premorbid IQ.
Twenty euthymic patients with bipolar disorder were matched, on a case-by-case basis, to twenty healthy community controls. Cases and controls were tested with a battery of neuropsychological tests.
Impairments were found in cases compared with controls in tests of verbal learning and memory. Verbal learning and memory correlated negatively with the number of manic episodes.
Impaired verbal learning and memory may be a trait variable in bipolar disease. There are implications for adherence to medication and relapse and for the role of early treatment interventions. Prospective designs and targeting first-episode groups may help to differentiate trait v. disease process effects.
The personality dimensions of harm avoidance (HA) and self-directedness (SD), as measured by the Temperament and Character Inventory (TCI), have been widely associated with depression and there is ...preliminary evidence that they may represent trait markers for depression. However, many studies in this area are limited by the use of heterogeneous samples of depressed patients and by the confounding effect of depressed mood during personality testing. The current study compares TCI personality dimension scores in a group of euthymic young adults with recurrent early-onset major depressive disorder (RE-MDD) to well-matched euthymic controls.
Fifty-two young adults with a past history of RE-MDD were recruited from consecutive referrals to a psychiatric clinic at a university health service. Eighty nine controls were also recruited. Euthymia was established in patients by a score of less than 9 on the Hamilton Rating Scale for Depression (HRSD) and in controls by a Becks Depression Inventory (BDI) score of less than 10. All participants completed the TCI-125.
Patients and controls were well matched in terms of sociodemographic profile. Euthymic RE-MDD patients scored significantly higher than controls on the temperament dimension of harm avoidance (HA; mean score 14.5 versus 7.8,
p
<
0.0001) and significantly lower than controls on the character dimension of self-directedness (SD; mean score 14.1 versus 19.9,
p
<
0.0001). Covariance analysis suggested that both HA and SD contributed independently to the familial risk of depression.
Subjects and controls all came from relatively affluent social backgrounds—these findings may not generalise to more socioeconomically diverse populations. The possibility of a ‘scarring effect’ of depressive episodes on self-reported personality dimension scores cannot be excluded.
High HA and low SD represent trait markers for liability to recurrent major depressive disorder in young adults. Further research is needed to replicate these findings and to assess the contribution that the experience of depressive episodes makes to self-reported personality dimension scores.
Background: Young adults with early-onset major depressive disorder (MDD) may be at high risk of progression to bipolar disorder. Although hypomanic symptoms are common in young people with ...depression, many do not reach the strict DSM-IV and ICD-10 criteria for hypomania. We used an emerging innovative framework for bipolar spectrum to evaluate this question.
Methods: Consecutive referrals to a psychiatric outpatient clinic at a university health service were assessed for recurrent episodes of depression. DSM-IV diagnoses were based on a SCID-1 interview. We used two approaches to delineate bipolar spectrum. The first focused on bipolar spectrum disorder (BSD, as defined by Ghaemi et al. Can. J. Psychiatry 47 (2002) 125), and the second on a symptoms perspective based on MDD with a history of hypomanic symptoms, using a 15-point hypomanic symptoms checklist with a cut-off ≥8 or more symptoms (modified from J. Affect. Disord. 73 (2003) 39 and J. Affect. Disord. 73 (2003) 73). Data were also obtained on family history of affective disorder, course and number of episodes of depression, symptom severity, psychosocial functioning, suicidality and deliberate self-harm, and drug and alcohol use.
Results: High rates of bipolar and bipolar spectrum disorder were identified. Under DSM-IV, 14 subjects (16.1%) had bipolar affective disorder and 73 subjects (83.9%) had recurrent MDD. Depending on the method used to diagnose bipolar spectrum, between 47.1% and 77.0% of the total cohort could be so diagnosed. Hypomanic symptom counts, irrespective of duration, yielded the highest estimates for bipolar spectrum. High rates of pharmacological hypomania were also identified: 12 subjects (16.4%) with recurrent MDD group reported this, and all could be diagnosed with bipolar spectrum.
Limitations: The reliability of using the 15-point hypomanic scale for the diagnostic assignments was not tested. All subjects were recruited from a university health service and, given the affluence of their parents, findings may not generalise to other populations. Most importantly, because bipolar family history and pharmacological hypomania were part of the diagnostic criteria of the BSD group, they could not be used as external validators for Ghaemi's BSD construct.
Conclusions: Bipolar disorders emerge as extremely common in this cohort of young adults with recurrent depression. Antidepressant-induced hypomania and high scores on a hypomanic symptoms checklist help to identify patients who are likely to have a bipolar spectrum illness, but who do not meet DSM-IV criteria for bipolar disorder. This is a preliminary study, and further evidence from external validating strategies are needed to verify the bipolar status of these patients in a larger and unselected cohort representing a broader socio-economic demographic profile.
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