The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD.     

Borderline personality disorder and depression severity predict suicidal outcomes: A six-month prospective cohort study of depression,bipolar depression,and borderline personality disorder

Background

Suicide risk is high in patients with major depressive disorder (MDD), bipolar disorder (BD) and borderline personality disorder (BPD). Whether risk levels of and risk factors for suicidal ideation (SI) and suicide attempts (SA) are similar or different in these disorders remains unclear, as few directly comparative studies exist. The relationship of short-term changes in depression severity and SI is underinvestigated, and might differ across groups, for example, between BPD and non-BPD patients.

Methods

We followed, for 6 months, a cohort of treatment-seeking, major depressive episode (MDE) patients in psychiatric care (original n = 124), stratified into MDE/MDD, MDE/BD and MDE/BPD subcohorts. We examined risks of suicide-related outcomes and their risk factors prospectively. We examined the covariation of SI and depression over time with biweekly online modified Patient Health Questionnaire 9 surveys and analysed this relationship through multi-level modelling.

Results

Risk of SA in BPD (22.2%) was higher than non-BPD (4.23%) patients. In regression models, BPD severity was correlated with risk of SA and clinically significant SI. During follow-up, mean depression severity and changes in depression symptoms were associated with SI risk regardless of diagnosis.

Conclusions

Concurrent BPD in depression seems predictive for high risk of SA. Severity of BPD features is relevant for assessing risk of SA and SI in MDE. Changes in depressive symptoms indicate concurrent changes in risk of SI. BPD status at intake can index risk for future SA, whereas depressive symptoms appear a useful continuously monitored risk index.     

Molecular genetics of bipolar disorder and depression

In this review, all papers relevant to the molecular genetics of bipolar disorder published from 2004 to the present (mid 2006) are reviewed, and major results on depression are summarized. Several candidate genes for schizophrenia may also be associated with bipolar disorder: G72, DISC1, NRG1, RGS4, NCAM1, DAO, GRM3, GRM4, GRIN2B, MLC1, SYNGR1, and SLC12A6. Of these, association with G72 may be most robust. However, G72 haplotypes and polymorphisms associated with bipolar disorder are not consistent with each other. The positional candidate approach showed an association between bipolar disorder and TRPM2 (21q22.3), GPR50 (Xq28), Citron (12q24), CHMP1.5 (18p11.2), GCHI (14q22-24), MLC1 (22q13), GABRA5 (15q11-q13), BCR (22q11), CUX2, FLJ32356 (12q23-q24), and NAPG (18p11). Studies that focused on mood disorder comorbid with somatic symptoms, suggested roles for the mitochondrial DNA (mtDNA) 3644 mutation and the POLG mutation. From gene expression analysis, PDLIM5, somatostatin, and the mtDNA 3243 mutation were found to be related to bipolar disorder. Whereas most previous positive findings were not supported by subsequent studies, DRD1 and IMPA2 have been implicated in follow-up studies. Several candidate genes in the circadian rhythm pathway, BmaL1, TIMELESS, and PERIOD3, are reported to be associated with bipolar disorder. Linkage studies show many new linkage loci. In depression, the previously reported positive finding of a gene-environmental interaction between HTTLPR (insertion/deletion polymorphism in the promoter of a serotonin transporter) and stress was not replicated. Although the role of the TPH2 mutation in depression had drawn attention previously, this has not been replicated either. Pharmacogenetic studies show a relationship between antidepressant response and HTR2A or FKBP5. New technologies for comprehensive genomic analysis have already been applied. HTTLPR and BDNF promoter polymorphisms are now found to be more complex than previously thought, and previous papers on these polymorphisms should be treated with caution. Finally, this report addresses some possible causes for the lack of replication in this field.     

Clinical differentiation between major depression only, major depression with panic disorder and panic disorder only. Childhood, personality and personality disorder

A consecutive sample of 298 nonpsychotic psychiatric outpatients was classified according to DSM-III and divided into 4 diagnostic groups: pure major depression, mixed major depression/panic disorder, pure panic disorder and a remaining group of other disorders. The patients' report of childhood relationship to parents and siblings, family atmosphere, their own personality characteristics as children and precipitating events were compared in the various groups. In addition, differences in personality and frequencies of personality disorders were investigated by means of various instruments. Our results show that the type of relationship to parents in childhood differed in the various groups. The mother seems to be the most crucial person for the development of depression, the father for the development of panic disorder. Patients with major depression are more obsessive and patients with panic disorder more infantile and avoidant with less control of their personality. Finally, patients with mixed conditions are more in accordance with the DSM-III anxious personality disorder cluster.     

双相情感障碍抑郁相与单相抑郁发作临床分析

目的:对双相情感障碍抑郁相和单相抑郁发作进行临床分析。方法:对双相情感障碍抑郁相和单相抑郁发作患者各30例进行临床分析。结果:双相情感障碍抑郁相有如下特点:①发病年龄早;②女性多见;③具有“精力过盛”性人格;④一级亲属中有双相障碍的家族史;⑤症状多为非典型抑郁发作或伴有精神病性症状。结论:如首次抑郁发作的症状符合以上特点,则可能以后发展为双相情感障碍,应使用足量心境稳定剂,谨慎使用抗抑郁剂,以免转为躁狂发作。     

Allelic association study between phospholipase A2 genes and bipolar affective disorder

Objectives:  In vivo studies demonstrating that lithium is a powerful phospholipase A2 (PLA2) inhibitor suggest that PLA2 activation, and subsequent cell signaling overactivation by increased fatty acid release may be the primary abnormality in bipolar affective disorder (BPAD), thus making PLA2 genes attractive candidates for the susceptibility to BPAD. The present study investigates polymorphisms in cytosolic phospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2), and secretory phospholipase (sPLA2) genes in a Brazilian sample.
Methods:  A cross-sectional study was performed with 181 unrelated DSM-IIIR BPAD subjects and 312 controls. A polymerase chain reaction–restriction fragment length polymorphism assay for Ban I cPLA2 and Avr II iPLA2 polymorphisms was performed, and an ATT repeat in sPLA2 was assessed using a semiautomated genetic analyzer (ALFexpress).
Results:  There was no significant difference observed in the allelic and genotypic distribution between the BPAD and control groups for cPLA2 (genotype: χ² = 0.8, 2df, p = 0.6; allele χ² = 0, 1df, p = 0.9), iPLA2 (genotype: χ² = 1.7, 2df, p = 0.4; allele: χ² = 0.3, 1df, p = 0.6), and sPLA2 (allele: χ² = 3.6, 6df, p = 0.8).
Conclusion:  Our results failed to demonstrate that the studied PLA2 polymorphisms were associated with an increased risk for BPAD in our sample.     

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder

Background

Obstetric complications (OCs) are key contributors to psychosis risk. However, it is unclear whether they increase psychosis vulnerability independently of genetic risk, in interaction with it, or are a manifestation of psychosis proneness. We examined the role of distinct types of OCs in terms of psychosis risk and tested whether they interact differently with genetic vulnerability, whilst accounting for other known environmental risk factors.

Study Design

405 participants (219 first episode psychosis patients and 186 healthy volunteers) underwent a comprehensive assessment of OCs, measured using the Lewis-Murray scale and divided into complications of pregnancy, abnormalities of foetal growth and development, and complications of delivery. Participants were compared in terms of history of OCs, polygenic risk score for schizophrenia (PRS-SZ) and interactions between these.

Results

Both complications of pregnancy and abnormalities of foetal growth were significantly associated with case–control status (p = 0.02 and 0.03, respectively), whereas complications of delivery were not. PRS-SZ showed a significant association with psychosis (p = 0.04), but there were no significant interactions between genetic risk for schizophrenia and OCs, either when these were considered globally or separated based on their timeframe.

Conclusions

We observed no significant interaction between genetic and obstetric vulnerability, yet distinct types of OCs may have a different impact on psychosis risk, based on their nature and timeframe. Examining their differential role might clarify their relative contributions to this risk.     

The relationship of DSM-III-R personality disorder to clinical variables in patients with major depression: Possible difference between personality disorder clusters

Abstract The relationship of DSM-III-R personality disorder (PD) to demographic and clinical variables was investigated based on 96 consecutive outpatients with major depression. No significant difference in the variables was found between those with and those without PD. Those with PD from each cluster were compared with those without PD in terms of the variables. In these comparisons many relationships of PD to the variables were found, and these relationships were different between the three PD clusters detailed in DSM-III-R. Patients with cluster B PD demonstrated a prominent uniqueness in his/her relationship to the variables. This uniqueness was similar to what had been reported previously with regard to patients with PD. There was no significant difference in the variables between those with cluster C PD and those without PD. Those with cluster A PD may have a negative family history of affective disorders.