Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).

Polarity at illness onset in bipolar I disorder and clinical course of illness.

OBJECTIVES: Studies have suggested that episode polarity at illness onset in bipolar disorder may be predictive of some aspects of lifetime clinical characteristics. We here examine this possibility in a large, well-characterized sample of patients with bipolar I disorder. METHODS: We assessed polarity at onset in patients with bipolar I disorder (N = 553) recruited as part of our ongoing studies of affective disorders. Lifetime clinical characteristics of illness were compared in patients who had a depressive episode at first illness onset (n = 343) and patients who had a manic episode at first illness onset (n = 210). RESULTS: Several lifetime clinical features differed between patients according to the polarity of their onset episode of illness. A logistic regression analysis showed that the lifetime clinical features significantly associated with a depressive episode at illness onset in our sample were: an earlier age at illness onset; a predominantly depressive polarity during the lifetime; more frequent and more severe depressive episodes; and less prominent lifetime psychotic features. CONCLUSIONS: Knowledge of pole of onset may help the clinician in providing prognostic information and management advice to an individual with bipolar disorder.

Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks.

OBJECTIVES: The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course. METHODS: We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks. RESULTS: We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group. CONCLUSIONS: Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.

Differences in depressive symptom profile between males and females.

BACKGROUND: It is widely held that there are no differences in the symptom profile of male and female depression. Studies to date that have found differences have used different methodologies and had inconsistent findings. Here we compare the clinical profile of major depression for men and women from a sample of almost 600 well-characterized individuals with recurrent major depressive disorder (MDD). METHODS: Subjects were recruited as part of a large genetic-epidemiological study of MDD. Clinical assessments included semi-structured interviews and case-note review. Clinical profiles during 'worst ever' (WE) depressive episode were scored using the OPCRIT checklist. Profiles for 199 males were compared to 399 females. RESULTS: Females with depression tended to have an earlier age-at-onset (p<0.0001), exhibited more frequent depressive episodes (p<0.005), had a greater number of depressive symptoms (p<0.001), and reported much higher rates of atypical depressive features (p<0.007) during their WE episode of depression. Logistic regression analysis identified that earlier age-at-onset of depression, excessive self-reproach and diminished libido were the best predictors of female depression. LIMITATIONS: Retrospective recall by subjects of depressive symptoms, which may be prone to recall bias. CONCLUSIONS: There are differences in the clinical course and symptom profile of male and female depression. Further study is required to identify the biological correlates of these differences and to characterize their clinical importance.

Familiality of postpartum depression in unipolar disorder: results of a family study.

OBJECTIVE: The authors previously reported strong evidence for familial aggregation of postpartum (puerperal) psychotic episodes in women with bipolar disorder. The authors here examine whether vulnerability to postpartum triggering of depressive episodes aggregates in families and assess how this aggregation varies with the definition of postpartum onset. METHOD: Postpartum depression occurrence was studied in the female members of 120 sibling pairs recruited at a site within an international multicenter study of sibling pairs with recurrent unipolar depression. Employing a range of definitions of postpartum onset, the authors examined concordance for postpartum episode status between sisters. RESULTS: Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months). Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery. The evidence for familiality maximized with a postpartum onset definition of 6-8 weeks. CONCLUSIONS: These results implicate familial factors in susceptibility to the triggering of narrowly defined postpartum depressive episodes in women with recurrent major depression. They suggest that a postnatal onset definition of within 6-8 weeks of delivery may be optimal in studies of the triggering of depressive illness by childbirth.

Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1).

BACKGROUND: Several studies support the dysbindin (dystrobrevin binding protein 1) gene (DTNBP1) as a susceptibility gene for schizophrenia. We previously reported that variation at a specific 3-locus haplotype influences susceptibility to schizophrenia in a large United Kingdom (UK) Caucasian case-control sample. METHODS: Using similar methodology to our schizophrenia study, we have investigated this same 3-locus haplotype in a large, well-characterized bipolar sample (726 Caucasian UK DSM-IV bipolar I patients; 1407 ethnically matched controls). RESULTS: No significant differences were found in the distribution of the 3-locus haplotype in the full sample. Within the subset of bipolar I cases with predominantly psychotic episodes of mood disturbance (n = 133) we found nominally significant support for association at this haploptype (p < .042) and at SNP rs2619538 (p = .003), with a pattern of findings similar to that in our schizophrenia sample. This finding was not significant after correction for multiple testing. CONCLUSIONS: Our data suggest that variation at the polymorphisms examined does not make a major contribution to susceptibility to bipolar disorder in general. They are consistent with the possibility that DTNBP1 influences susceptibility to a subset of bipolar disorder cases with psychosis. However, our subset sample is small and the hypothesis requires testing in independent, adequately powered samples.

Reducing the Hypomania Checklist (HCL-32) to a 16-item version.

BACKGROUND: The under-recognition of hypomanic symptoms by both clinicians and patients is a major clinical problem which contributes to misdiagnosis and diagnostic delay in patients with bipolar disorder. The recent development of validated screening instruments for hypomania, such as the Hypomania Checklist (HCL-32), may help to improve the detection of bipolar disorder. In this study, we assess whether it is possible to reduce the number of items on the HCL-32 without any loss in the screening tool's ability to reliably differentiate between bipolar disorder (BD) and major depressive disorder (MDD). METHODS: Using our large samples of patients with DSM-IV defined bipolar I disorder (BD-I) (n=230) and recurrent MDD (n=322), we performed item correlations in order to identify potentially redundant items in the HCL-32. We then tested the performance of a shortened 16-item HCL questionnaire within a separate sample of patients with BD (including BD-I, BD-II and BD-NOS) (n=59) and MDD (n=76). RESULTS: The structure of the 16-item HCL demonstrated two main factors similar to those identified for the HCL-32 (an 'active-elated' factor and a 'risk-taking/irritable' factor). A score of 8 or more on a shortened 16-item version of the HCL had excellent ability to distinguish between BD and MDD. The sensitivity (83%) and specificity (71%) of the 16-item version were very similar to those for the full 32-item HCL. LIMITATIONS: The HCL-16 was derived after subjects had completed the full HCL-32. It will be important to test the validity of a 'stand-alone' 16-item HCL questionnaire. CONCLUSIONS: A shortened 16-item HCL (the HCL-16) is potentially a useful screening tool for hypomania within busy clinical settings.

Affective temperaments across the bipolar-unipolar spectrum: examination of the TEMPS-A in 927 patients and controls.

OBJECTIVE: There is currently a great deal of interest in the use of affective temperaments as possible intermediate phenotypes for bipolar disorder. However, much of the literature in this area is conflicting. Our aims were to test the hypothesis of a gradient in affective temperament scores, as measured by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A), from bipolar disorder type I (BP-I), through bipolar disorder type II (BP-II), recurrent major depressive disorder (MDD-R), and a control group (CG) in the largest sample to date of 927 subjects. METHODS: Non parametric tests were used to compare TEMPS-A scores between diagnostic groups and multinomial logistic regression was used to test the association between TEMPS-A scores and diagnosis while controlling for current mood state, age and gender. RESULTS: Although the BP-II group scored higher than the BP-I and MDD-R groups on several TEMPS-A subscales, these differences were not significant when confounding variables were controlled for. The dysthymic subscale differentiated between affected and controls and the anxious subscale differentiated the MDD-R group from controls. LIMITATIONS: The cross-sectional design did not allow us to evaluate potential longitudinal changes of temperament scores, which were assessed only with a self-report questionnaire. CONCLUSION: We failed to find evidence of a gradient in affective temperament scores. Both unipolar and bipolar patients reported high dysthymic scores relative to controls, perhaps supporting a unitary view of depression across the bipolar-unipolar spectrum. Taking account of potential confounders will be important in future studies which seek to use affective temperaments as intermediate phenotypes in genetic research.

Identifying hypomanic features in major depressive disorder using the hypomania checklist (HCL-32).

BACKGROUND: Recent studies have challenged the traditional unipolar/bipolar divide with increasing support for a more dimensional view of affective disorders. We here examine the occurrence of hypomanic symptoms in individuals with a history of major depression selected to exclude indicators of underlying bipolarity. METHODS: The presence of hypomanic symptoms was assessed by the Hypomania Checklist (HCL-32) self-report questionnaire in a sample of almost 600 patients meeting DSM-IV criteria for Bipolar I disorder (BPI N=260) or Major Recurrent Depressive disorder (MDDR N=322). Subjects were recruited and assessed using consistent, robust methodology. RESULTS: We found that a score of 20 or more on the HCL-32 yielded the best combination of sensitivity (68%) and specificity (83%) to distinguish between BPI and MDDR. Within our highly selected and well defined MDDR sample (for which exclusion criteria included personal or family histories of bipolar or psychotic illness), 17% of MDDR subjects scored over the threshold of 20 on the HCL-32. CONCLUSIONS: The HCL-32 identified a substantial number of patients meeting DSM-IV criteria for recurrent major depression (even when selected to exclude personal and family histories of bipolar illness) who reported bipolar symptoms at a level similar to that reported by patients meeting diagnostic criteria for bipolar disorder. This demonstrates the limitations of using DSM-IV criteria to distinguish those with and without bipolar features of illness.

Age-at-onset in bipolar-I disorder: mixture analysis of 1369 cases identifies three distinct clinical sub-groups.

BACKGROUND: To assess whether bipolar disorder type I segregates into three clinically distinct sub-groups defined by age-at-onset. METHODS: Clinical data were available on 1369 individuals with DSM-IV bipolar I disorder. Mixture analysis was performed on the age-at-onset (AAO) data to determine whether they were composed of more than one normal distribution. Individuals were allocated to groups according to the results of the mixture analysis. Categorical logistic regression was then used to investigate relationships between AAO and nine clinical characteristics. RESULTS: The distribution of AAOs in our sample comprised a mixture of three normal distributions with means of 18.7 (SD=3.7), 28.3 (SD=5.5) and 43.3 (SD=9.1) years, with relative proportions of 0.47, 0.39 and 0.14 respectively. Individuals were allocated into three groups dependent on their AAO: < or = 22; 25-37; and > or = 40 years, producing a sample of 1225 individuals (144 with borderline values were excluded). Eight out of the nine clinical characteristics showed evidence for a statistical association with AAO group. LIMITATIONS: Systematic and non-systematic recruitment of participants. Some data relied on retrospective recall. CONCLUSIONS: Our results provide further robust evidence to suggest that the AAO distribution of individuals affected with bipolar disorder is composed of three normal distributions. Substantial clinical heterogeneity between the three AAO groups may reflect genetic heterogeneity within bipolar I disorder. Future genetic studies should consider AAO grouping as potential sub-phenotypes.

Clinical differences between bipolar and unipolar depression.

It is commonly -- but wrongly -- assumed that there are no important differences between the clinical presentations of major depressive disorder and bipolar depression. Here we compare clinical course variables and depressive symptom profiles in a large sample of individuals with major depressive disorder (n=593) and bipolar disorder (n=443). Clinical characteristics associated with a bipolar course included the presence of psychosis, diurnal mood variation and hypersomnia during depressive episodes, and a greater number of shorter depressive episodes. Such features should alert a clinician to a possible bipolar course. This is important because optimal management is not the same for bipolar and unipolar depression.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Cognitive style in bipolar disorder.

BACKGROUND: Abnormalities of cognitive style in bipolar disorder are of both clinical and theoretical importance. AIMS: To compare cognitive style in people with affective disorders and in healthy controls. METHOD: Self-rated questionnaires were administered to 118 individuals with bipolar I disorder, 265 with unipolar major recurrent depression and 268 healthy controls. Those with affective disorder were also interviewed using the Schedules for Clinical Assessment in Neuropsychiatry and case notes were reviewed. RESULTS: Those with bipolar disorder and those with unipolar depression demonstrated different patterns of cognitive style from controls; negative self-esteem best discriminated between those with affective disorders and controls; measures of cognitive style were substantially affected by current levels of depressive symptomatology; patterns of cognitive style were similar in bipolar and unipolar disorder when current mental state was taken into account. CONCLUSIONS: Those with affective disorder significantly differed from controls on measures of cognitive style but there were no differences between unipolar and bipolar disorders when current mental state was taken into account.