Investigating susceptibility to bipolar disorder, migraine and epilepsy

Epidemiological and clinical studies demonstrate a high degree of comorbidity between bipolar disorder (BD) and migraine. A relationship between BD and epilepsy is also suggested, with both disorders displaying phenotypically similar symptom profiles. The overall aim of this thesis was to further explore the relationship between BD and the neurological conditions of migraine, and epilepsy, within a large, well-characterised sample of individuals with BD. Data were utilised from the Bipolar Disorder Research Network (BDRN); a large (n>6000) UK sample of individuals with a diagnosis of BD. Lifetime history of migraine and epilepsy were assessed within BDRN using questionnaire and telephone interview methods. Migraine was highly prevalent within the bipolar sample and was found to disproportionately affect those with bipolar II disorder. Bipolar subjects with comorbid migraine experienced a relatively distinct illness profile, with a multivariate model revealing migraine comorbidity to be characterised by an increased risk of suicide attempt and anxiety disorder. Further analysis of the migraine phenotype revealed that observed differences in the clinical presentation of BD associated with migraine were largely associated with the migraine with aura subtype. A high rate of self-reported epilepsy was identified within the bipolar sample and group differences were revealed in the clinical course of the bipolar illness according to the presence of self-reported epilepsy. Multivariate analysis revealed an independent association of a history of suicide attempt with self-reported epilepsy within BD. Findings from this thesis highlight the importance of identifying migraine and epilepsy within BD, and that their recognition and treatment may have a beneficial impact on the course of illness and outcome in BD. This thesis also suggests that these comorbidities may represent a clinically useful subgroup characterised by specific clinical features, and may provide an opportunity for subcategorising for future aetiological studies, potentially facilitating the identification of shared pathophysiological mechanisms

The Unusual Linear Plasmid Generating Systems of Prokaryotes

Linear DNA is vulnerable to exonuclease degradation and suffers from genetic loss due to the end replication problem. Eukaryotes overcome these problems by locating repetitive telomere sequences at the end of each chromosome. In humans and other vertebrates this noncoding terminal sequence is repeated between hundreds and thousands of times, ensuring important genetic information is protected. In most prokaryotes, the end-replication problem is solved by utilizing circular DNA molecules as chromosomes. However, some phage and bacteria do store genetic information in linear constructs, and the ends of these structures form either invertrons or hairpin telomeres. Hairpin telomere formation is catalyzed by a protelomerase, a unique protein that modifies DNA by a two-step transesterification reaction, proceeding via a covalent protein bound intermediate. The specifics of this mechanism are largely unknown and conflicting data suggests variations occur between different systems. These proteins, and the DNA constructs they produce, have valuable applications in the biotechnology industry. They are also an essential component of some human pathogens, an increased understanding of how they operate is therefore of fundamental importance. Although this review will focus on phage encoded protelomerase, protelomerases found from Agrobacterium and Borellia will be discussed in terms of mechanism of action

History of Premenstrual Mood Change and Postpartum Episodes are Associated with Perimenopausal Episodes in Women with Bipolar Disorder

Background and Aims: Reproductive life events are potential triggers of mood episodes in women with bipolar disorder. We aimed to establish whether a history of premenstrual mood change and postpartum episodes are associated with perimenopausal episodes in women who have bipolar disorder. Methods: Participants were 339 post-menopausal women with DSM-IV bipolar disorder recruited into the Bipolar Disorder Research Network (www.bdrn.org). Women self-reported presence (N = 200) or absence (N = 139) of an illness episode during the perimenopausal period. History of premenstrual mood change was measured using the self-report Premenstrual Symptoms Screening Tool (PSST), and history of postpartum episodes was measured via semi-structured interview (Schedules for Clinical Assessment in Neuropsychiatry, SCAN) and inspection of case-notes. Results: History of a postpartum episode within 6 months of delivery (OR = 2.13, p = 0.03) and history of moderate/severe premenstrual syndrome (OR = 6.33, p < 0.001) were significant predictors of the presence of a perimenopausal episode, even after controlling for demographic factors. When we narrowed the definition of premenstrual mood change to premenstrual dysphoric disorder, it remained significant (OR = 2.68, p = 0.007). Conclusions: Some women who have bipolar disorder may be particularly sensitive to reproductive life events. Previous mood episodes in relation to the female reproductive lifecycle may help clinicians predict individual risk for women with bipolar disorder approaching the menopause. There is a need for prospective longitudinal studies of women with bipolar disorder providing frequent contemporaneous ratings of their mood to overcome the limitations of retrospective self-report data

Y-box protein-1 is actively secreted through a non-classical pathway and acts as an extracellular mitogen

Y-box protein (YB)-1 of the cold-shock protein family functions in gene transcription and RNA processing. Extracellular functions have not been reported, but the YB-1 staining pattern in inflammatory glomerular diseases, without adherence to cell boundaries, suggests an extracellular occurrence. Here, we show the secretion of YB-1 by mesangial and monocytic cells after inflammatory challenges. It should be noted that YB-1 was secreted through a non-classical mode resembling that of the macrophage migration inhibitory factor. YB-1 release requires ATP-binding cassette transporters, and microvesicles protect YB-1 from protease degradation. Two lysine residues in the YB-1 carboxy-terminal domain are crucial for its release, probably because of post-translational modifications. The addition of purified recombinant YB-1 protein to different cell types results in increased DNA synthesis, cell proliferation and migration. Thus, the non-classically secreted YB-1 has extracellular functions and exerts mitogenic as well as promigratory effects in inflammation

Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder

Importance Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes/mechanisms. Objectives To investigate the relationship between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRS) and psychotic presentations of BD, using clinical descriptions which consider both occurrence and level of mood-incongruent psychotic features. Design Case-control design: using multinomial logistic regression, to estimate differential associations of PRS across categories of cases and controls. Settings & Participants 4399 BD cases, 2966 (67%) female, mean age-at-interview 46 [sd 12] years, from the BD Research Network (BDRN) were included in the final analyses. For comparison genotypic data for 4976 schizophrenia cases and 9012 controls from the Type-1 diabetes genetics consortium and Generation Scotland were included. Exposure Standardised PRS, calculated using alleles with an association p-value threshold < 0.05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, adjusted for the first 10 population principal components and genotyping-platform. Main outcome measure Multinomial logit models estimated PRS associations with BD stratified by (1) Research Diagnostic Criteria (RDC) BD subtypes (2) Lifetime occurrence of psychosis.(3) Lifetime mood-incongruent psychotic features and (4) ordinal logistic regression examined PRS associations across levels of mood-incongruence. Ratings were derived from the Schedule for Clinical Assessment in Neuropsychiatry interview (SCAN) and the Bipolar Affective Disorder Dimension Scale (BADDS). Results Across clinical phenotypes, there was an exposure-response gradient with the strongest PRS association for schizophrenia (RR=1.94, (95% C.I. 1.86, 2.01)), then schizoaffective BD (RR=1.37, (95% C.I. 1.22, 1.54)), BD I (RR= 1.30, (95% C.I. 1.24, 1.36)) and BD II (RR=1.04, (95% C.I. 0.97, 1.11)). Within BD cases, there was an effect gradient, indexed by the nature of psychosis, with prominent mood-incongruent psychotic features having the strongest association (RR=1.46, (95% C.I. 1.36, 1.57)), followed by mood-congruent psychosis (RR= 1.24, (95% C.I. 1.17, 1.33)) and lastly, BD cases with no history of psychosis (RR=1.09, (95% C.I. 1.04, 1.15)). Conclusion We show for the first time a polygenic-risk gradient, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms

Investigation of relationships between bipolar disorder phenotypes and genome-wide significant loci from PGC2 schizophrenia

Background Schizophrenia (SZ) and Bipolar disorder (BD) show evidence for partial overlap in phenotypic and genetic influences based on family, twins, adoption and Psychiatric Genetic Consortium (PGC) studies. They have lifetime prevalence of about 1% and 2.4%, and heritability estimates of 60-80% and 40-70%, respectively. In the last decade BD has been investigated using dimensional structuring of psychoses based on symptomatic-functional checklists that provides reliable approach to phenotypic assessment. Recent research suggests moving towards developing Phenotype-based Genetic Association Studies. In this approach, patients will only be put into groups consisting of others with symptoms similar to their own. Canonical Correlation Analysis (CCA) is statistical technique designed to identify relationships (usually hidden) between two sets of variables. We use CCA to combine genotypic and phenotypic variables and measure correlation between those sets. This analysis estimates canonical correlation between psychotic symptoms measured using validated item check list (OPCRIT), and genome-wide significant (GWS) loci from PGC2 schizophrenia. Methods For our analysis we used phenotype and genetic data for 5,507 BD cases. Imputation of genetic data was performed with 1000Genomes (Phase 3, 2014) then quality control was applied (INFO>0.8, HWE>1e-6, MAF>0.01). Additional quality control was performed on phenotypic symptom coverage. CCA was employed as implemented in R, using package “CCA” with GWS loci from PGC2 SZ and OPCRIT items. SNPs were standardised and adjusted for 10 population covariates calculated from imputed data using principal component approach prior to CCA. Results Canonical correlation analysis was run on 4422 cases on 89 available GWS PGC2 SZ SNPs or their proxies (with r2>0.6). 60 phenotypic variables were taken from OPCRIT measurements including mood disturbance, biological indices, atypical depression, substance use, psychosis and social functioning. We found no significant canonical correlations indicating absence of hidden sub-clusters at individual symptom level of BD associated with SZ GWS loci. Discussion Our analysis was focused to find correlation from bipolar phenotype by using OPCRIT questionnaire and GWS SZ loci from PGC2. We have shown that there were no significant canonical correlation coefficients suggesting that there is no direct association between SZ associated genetic loci and BP at individual symptom level. CCA is canonical correlation analysis is one of potential of data-driven approaches to identify hidden genotype-phenotype relationships. It provides opportunities to generate and test different hypotheses and understand more about complex architecture of psychiatric disorders. In the next stage we plan to extend our analysis to more fine grained systematic descriptors of BD and test for correlation with genetic profiles from a number of co-morbid disorders, as well as the full range of phenotypic and genetic data that are available

Psychosis and the level of mood incongruence in Bipolar Disorder are related to genetic liability for Schizophrenia

Abstract Importance Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes/mechanisms. Objectives To investigate the relationship between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRS) and psychotic presentations of BD, using clinical descriptions which consider both occurrence and level of mood-incongruent psychotic features. Design Case-control design: using multinomial logistic regression, to estimate differential associations of PRS across categories of cases and controls. Settings & Participants 4399 BDcases, mean [sd] age-at-interview 46[12] years, of which 2966 were woman (67%) from the BD Research Network (BDRN) were included in the final analyses, with data for 4976 schizophrenia cases and 9012 controls from the Type-1 diabetes genetics consortium and Generation Scotland included for comparison. Exposure Standardised PRS, calculated using alleles with an association p-value threshold < 0.05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, adjusted for the first 10 population principal components and genotyping-platform. Main outcome measure Multinomial logit models estimated PRS associations with BD stratified by (1) Research Diagnostic Criteria (RDC) BD subtypes (2) Lifetime occurrence of psychosis.(3) Lifetime mood-incongruent psychotic features and (4) ordinal logistic regression examined PRS associations across levels of mood-incongruence. Ratings were derived from the Schedule for Clinical Assessment in Neuropsychiatry interview (SCAN) and the Bipolar Affective Disorder Dimension Scale (BADDS). Results Across clinical phenotypes, there was an exposure-response gradient with the strongest PRS association for schizophrenia (RR=1.94, (95% C.I. 1.86, 2.01)), then schizoaffective BD (RR=1.37, (95% C.I. 1.22, 1.54)), BD I (RR= 1.30, (95% C.I. 1.24, 1.36)) and BD II (RR=1.04, (95% C.I. 0.97, 1.11)). Within BD cases, there was an effect gradient, indexed by the nature of psychosis, with prominent mood-incongruent psychotic features having the strongest association (RR=1.46, (95% C.I. 1.36, 1.57)), followed by mood-congruent psychosis (RR= 1.24, (95% C.I. 1.17, 1.33)) and lastly, BD cases with no history of psychosis (RR=1.09, (95% C.I. 1.04, 1.15)). Conclusion We show for the first time a polygenic-risk gradient, across schizophrenia and bipolar disorder, indexed by the occurrence and level of mood-incongruent psychotic symptoms