Georgina M. Hosang

Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis

BackgroundMajor depression is a disabling psychiatric illness with complex origins. Life stress (childhood adversity and recent stressful events) is a robust risk factor for depression. The relationship between life stress and Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene has received much attention. The aim of the present work was to review and conduct a meta-analysis on the results from published studies examining this interaction.MethodsA literature search was conducted using PsychINFO and PubMed databases until 22 November 2013. A total of 22 studies with a pooled total of 14,233 participants met the inclusion criteria, the results of which were combined and a meta-analysis performed using the Liptak-Stouffer z-score method.ResultsThe results suggest that the Met allele of BDNF Val66Met significantly moderates the relationship between life stress and depression (P = 0.03). When the studies were stratified by type of environmental stressor, the evidence was stronger for an interaction with stressful life events (P = 0.01) and weaker for interaction of BDNF Val66Met with childhood adversity (P = 0.051).ConclusionsThe interaction between BDNF and life stress in depression is stronger for stressful life events rather than childhood adversity. Methodological limitations of existing studies include poor measurement of life stress.

Genome-wide association study of bipolar disorder in Canadian and UK populations corroborates disease loci including SYNE1 and CSMD1

BackgroundRecently, genome-wide association studies (GWAS) for cases versus controls using single nucleotide polymorphism microarray data have shown promising findings for complex neuropsychiatric disorders, including bipolar disorder (BD).MethodsHere we describe a comprehensive genome-wide study of bipolar disorder (BD), cross-referencing analysis from a family-based study of 229 small families with association analysis from over 950 cases and 950 ethnicity-matched controls from the UK and Canada. Further, loci identified in these analyses were supported by pathways identified through pathway analysis on the samples.ResultsAlthough no genome-wide significant markers were identified, the combined GWAS findings have pointed to several genes of interest that support GWAS findings for BD from other groups or consortia, such as at SYNE1 on 6q25, PPP2R2C on 4p16.1, ZNF659 on 3p24.3, CNTNAP5 (2q14.3), and CDH13 (16q23.3). This apparent corroboration across multiple sites gives much confidence to the likelihood of genetic involvement in BD at these loci. In particular, our two-stage strategy found association in both our combined case/control analysis and the family-based analysis on 1q21.2 (closest gene: sphingosine-1-phosphate receptor 1 gene, S1PR1) and on 1q24.1 near the gene TMCO1, and at CSMD1 on 8p23.2, supporting several previous GWAS reports for BD and for schizophrenia. Pathway analysis suggests association of pathways involved in calcium signalling, neuropathic pain signalling, CREB signalling in neurons, glutamate receptor signalling and axonal guidance signalling.ConclusionsThe findings presented here show support for a number of genes previously implicated genes in the etiology of BD, including CSMD1 and SYNE1, as well as evidence for previously unreported genes such as the brain-expressed genes ADCY2, NCALD, WDR60, SCN7A and SPAG16.

Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder

BACKGROUND Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val(66)Met polymorphism and stressful life events (SLEs) in bipolar disorder. METHOD A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val(66)Met polymorphism (rs6265). RESULTS Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene x environment interaction). LIMITATIONS The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. DISCUSSION The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder.

An update on the debated association between ADHD and bipolar disorder across the lifespan

Diagnostic formulations for attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) both include symptoms of distractibility, psychomotor agitation and talkativeness, alongside associated emotional features (irritability and emotional lability). Treatment studies suggest the importance of accurate delineation of ADHD and BD. However, boundaries between the two disorders are blurred by the introduction of broader conceptualisations of BD. This review attempts to elucidate whether associations between ADHD and BD are likely to be driven by superficial symptomatological similarities or by a more meaningful etiological relationship between the disorders. This is achieved by outlining findings on comorbidity, temporal progression of the disorders, familial co-variation, and neurobiology in ADHD and BD across the lifespan. Longitudinal studies fail to consistently show developmental trajectories between ADHD and BD. Comparative research investigating neurobiology is in its infancy, and although some similarities are seen between ADHD and BD, studies also emphasise differences between the two disorders. However, comorbidity and family studies appear to show that the two disorders occur together and aggregate in families at higher than expected rates. Furthermore close inspection of results from population studies reveals heightened co-occurrence of ADHD and BD even in the context of high comorbidity commonly noted in psychopathology. These results point towards a meaningful association between ADHD and BD, going beyond symptomatic similarities. However, future research needs to account for heterogeneity of BD, making clear distinctions between classical episodic forms of BD, and broader conceptualisations of the disorder characterised by irritability and emotional lability, when evaluating the relationship with ADHD.

Comorbid medical illness in bipolar disorder

Background Individuals with a mental health disorder appear to be at increased risk of medical illness. Aims To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden. Method Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria. Results We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset. Conclusions Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.

Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder

BACKGROUND There is inconsistent evidence of interaction between stressful events and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. Recent studies have indicated that the moderating effect of 5-HTTLPR may be strongest when adverse experiences have occurred in childhood and the depressive symptoms persist over time. However, it is unknown whether this gene-environment interaction is present for recurrent depressive disorder and different forms of maltreatment. Therefore, patients with recurrent clinically diagnosed depression and controls screened for the absence of depression were utilised to examine the moderating effect of 5-HTTLPR on associations between specific forms of childhood adversity and recurrent depression. METHOD A sample of 227 recurrent unipolar depression cases and 228 never psychiatrically ill controls completed the Childhood Trauma Questionnaire to assess exposure to sexual, physical and emotional abuse, physical and emotional neglect in childhood. DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS All forms of childhood maltreatment were reported as more severe by cases than controls. There was no direct association between 5-HTTLPR and depression. Significant interactions with additive and recessive 5-HTTLPR genetic models were found for overall severity of maltreatment, sexual abuse and to a lesser degree for physical neglect, but not other maltreatment types. LIMITATIONS The cross-sectional design limits causal inference. Retrospective report of childhood adversity may have reduced the accuracy of the findings. CONCLUSIONS This study provides support for the role of interplay between 5-HTTLPR and a specific early environmental risk in recurrent depressive disorder.

Adverse life event reporting and worst illness episodes in unipolar and bipolar affective disorders measuring environmental risk for genetic research

BACKGROUND Studies exploring gene-environment interplay in affective disorders now include very large numbers of participants. Methods for evaluating the role of adversity in such studies need to be developed that do not rely on lengthy and labour-intensive interviews. In the present study, a brief questionnaire method for measuring 11 adverse events reported before interview and before their worst illness episodes by bipolar, unipolar and healthy control participants, participating in genetic association studies, was evaluated. METHOD Five hundred and twelve bipolar disorder (BD) participants, 1447 participants with recurrent unipolar depression (UPD) and 1346 psychiatrically healthy control participants underwent the researcher-administered version of the List of Threatening Experiences Questionnaire (LTE-Q) for the 6 months before their worst affective episodes for UPD and BD participants, and for the 6 months before interview for the UPD participants and controls. RESULTS UPD and BD cases were significantly more likely to report at least one event, as well as more events in the 6 months before interview and before their worst illness episodes, than healthy controls. Both manic and depressive episodes were significantly associated with adverse events in the BD cases. Depressed mood at the time of interview influenced event reporting in UPD and control participants but not the BD cases. Age was negatively correlated with the number of events reported by controls. CONCLUSIONS The researcher-administered LTE-Q provides a measure of case-control differences for adversity that is applicable in large genetic association studies. Confounding factors for event reporting include present mood and age.

Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients

Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD) and bipolar disorder (BPD). These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties. This exploratory study attempts to identify disorder-specific transcriptional biomarkers within the inflammatory cytokine pathway, which can distinguish between control subjects, MDD patients and BPD patients. This is achieved using RNA extracted from subject blood and applying synthesized complementary DNA to quantitative PCR arrays containing primers for 87 inflammation-related genes. Initially, we use ANOVA to test for transcriptional differences in a ‘discovery cohort’ (total n = 90) and then we use t-tests to assess the reliability of any identified transcriptional differences in a ‘validation cohort’ (total n = 35). The two most robust and reliable biomarkers identified across both the discovery and validation cohort were Chemokine (C-C motif) ligand 24 (CCL24) which was consistently transcribed higher amongst MDD patients relative to controls and BPD patients, and C-C chemokine receptor type 6 (CCR6) which was consistently more lowly transcribed amongst MDD patients relative to controls. Results detailed here provide preliminary evidence that transcriptional measures within inflammation-related genes might be useful in aiding clinical diagnostic decision-making processes. Future research should aim to replicate findings detailed in this exploratory study in a larger medication-free sample and examine whether identified biomarkers could be used prospectively to aid clinical diagnosis.

Life-event specificity: bipolar disorder compared with unipolar depression

BACKGROUND Little is known about the impact of different types of stressful events (for example divorce v. bereavement) on unipolar depression compared with bipolar disorder. Inconsistencies exist concerning the association between independent events (beyond an individuals control, such as bereavement) and bipolar disorder. AIMS To examine the role of specific, independent and dependent events in mood disorders. METHOD Life-event information was collected from 512 people with bipolar disorder, 1448 people with unipolar depression and over 600 controls. RESULTS Various events were associated with unipolar depression and bipolar disorder, but some event specificity was detected. For example, financial crisis was more strongly related to bipolar disorder rather than unipolar depression. Independent events were only related to unipolar depression and not bipolar disorder. CONCLUSIONS The events that were linked to bipolar disorder and unipolar depression were similar. Independent events were not associated with bipolar episodes, suggesting that life stress may be a consequence of, rather than a trigger for, bipolar episodes.

Evaluation of the validity and utility of a transdiagnostic psychosis dimension encompassing schizophrenia and bipolar disorder

BACKGROUND In recent years, the Kraepelinian dichotomy has been challenged in light of evidence on shared genetic and environmental factors for schizophrenia and bipolar disorder, but empirical efforts to identify a transdiagnostic phenotype of psychosis remain remarkably limited. AIMS To investigate whether schizophrenia spectrum and bipolar disorder lie on a transdiagnostic spectrum with overlapping non-affective and affective psychotic symptoms. METHOD Multidimensional item-response modelling was conducted on symptom ratings of the OPerational CRITeria (OPCRIT) system in 1168 patients with schizophrenia spectrum and bipolar disorder. RESULTS A bifactor model with one general, transdiagnostic psychosis dimension underlying affective and non-affective psychotic symptoms and five specific dimensions of positive, negative, disorganised, manic and depressive symptoms provided the best model fit and diagnostic utility for categorical classification. CONCLUSIONS Our findings provide support for including dimensional approaches into classification systems and a directly measurable clinical phenotype for cross-disorder investigations into shared genetic and environmental factors of psychosis.