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Schizophrenia (SCZ) and bipolar disorder (BPD) are both severe psychiatric diseases which can give rise to debilitating symptoms. To understand the nature of molecular pathologies, it is important to look into the genetics underlying the phenotype to understand its role in disease formation. Using recent exome sequence data sets such as those from the UK10K project and SCZ-Swedish exome data facilitated the identification of rare variants which contribute to the risk of developing those illnesses. To identify rare variants with potential susceptibility and strong effects, UCL SCZ families with multiple members affected by the condition contributed to the UK10K data. The pedigrees included in these sets were analysed using GeneSAOcs to find rare variants which run in families and segregate them according to disease. In order to validate this finding, a second data set was investigated for those variants. Another gene variant burden approach was also used which involved analysing unrelated individuals from the UK10K and SED. Variants which were implicated in the risk for disease were analysed bioinformatically and genotyped or replicated in UCL case/control samples. The use of a family-based approach revealed a variant in rs199929459 in WD-repeat domain 6 (WDR6) which was found to have a nominal level of association with both SCZ (P = 4.29x10-7 ) and psychosis (P = 0.0004). Another variant in the MCPH1 gene, rs61749465, previously reported in SCZ Leonenko et al. (2017), was analysed further in BPD (P = 0.0009). Functional analysis, cell viability, cell count assays, DNA damage assays and mRNA stability did not indicate significant changes. However, gene expression analysis using RNA-seq indicated that a number of heat shock and ribosomal proteins were affected by introducing this variant. Combined with gene network analysis, this indicates that this variant may impact protein translation and cellular aging. Using the KEGG pathway, the expression of 47 genes seems to have been significantly affected and the Alzheimer's disease pathway was activated. The data indicates that rare variants may have a role in disease susceptibility. However, validation through larger SCZ/BPD case and control cohorts provide more evidence of association. This applies in most of the variants extracted in our study, especially those in WDR6. Further functional analysis is required to understand the effects of the rs61749465 variant allele on protein folding.

Doctors need to identify when palliative care patients are imminently dying so they can adjust their goals of care and treatment accordingly. The systematic review of the literature, completed as part of this thesis, showed that these decisions are very inaccurate. The aim of this thesis was to determine the judgement policies of expert prognosticators (i.e. those clinicians with a proven ability to identify patients in the last 72 hours of life). This information is needed to help the development of training programmes for less expert clinicians. In order to understand decision-making judgements, it was first necessary to identify an “expert” group of clinicians. Previous studies suggested that expertise is not defined by years of experience or seniority. Therefore to identify an expert group with proven prognostic abilities, palliative care doctors (n = 99) completed a prognostic “test”. The test was developed by compiling case histories from the direct observation of 50 seriously ill patients in a hospice and an acute hospital. In order to complete the test, doctors were asked to review 20 case summaries and to provide a percentage likelihood that each patient would die within the next three days. The top 20% of doctors who performed most accurately on this test were deemed to be “expert prognosticators” and were invited to participate in the next phase of the research. The expert group (n = 19) were asked to complete a further prognostic task so that the decision-making policy of each individual (and the expert group as a whole) could be determined using Judgement Analysis. Through statistical modelling, experts had weighted Cheyne-Stoke breathing (β=15.44), the standardised palliative performance score (β=12.35) and the rapidity of decline in the previous 24 hours (β=11.512) as the most important factors. They gave lower weighting to the standardised level of agitation and sedation (β=5.97), the presence of audible secretions (β=5.95) and the presence of cyanosis (β=5.38).

Background: There is a growing need to improve our understanding of carers' reactions to Behavioural and Psychological Symptoms in Dementia (BPSD): symptoms of disturbed perception, thought content, mood, or behaviour (Finkel & Burns, 1999). This is due to the adverse consequences of BPSD for carer wellbeing, increased rates of psychiatric referral, and institutionalisation resulting from carer burden linked to BPSD. Aim: To understand how BPSD links to family carer distress. Methods: The complementary meta-analytic and meta-ethnographic reviews informed the subsequent empirical analysis. Psychosocial measures from 157 family carers of people with dementia were collected as part of the Challenge Famcare project; correlations, hierarchical regression, moderation, mediation, and path analyses were performed. Results: The impact of BPSD on carer wellbeing is not measured consistently, however, depressive behaviour was found to be the most distressing for carers. Family carers' perceptions of BPSD as "challenging" were found to be associated with a sense of a declining relationship, transgressions against social norms, and an underlying belief that their relative would inevitably lose their personhood. Carer psychosocial factors explained 56% of the variance in BPSD-related distress. Once carer psychosocial factors were controlled for, frequency of BPSD was not a significant predictor of BPSD-related distress. Following path analysis, carer reactivity to BPSD, burden, competence, and relationship quality were found to directly influence BPSD-related distress. Guilt influenced distress indirectly via burden and reactivity to BPSD. The final path model accounted for 41% of the variance in BPSD-related distress and provided a good fit (Χ2 = 23.920, df = 19, p = .199). Conclusion: Interventions for the management of BPSD should acknowledge carer beliefs and unmet psychological needs. Carer psychosocial factors such as their sense of competence, relationship quality, guilt, burden, and reactivity to BPSD contribute to BPSD-related distress. Future interventions for the management of behavioural problems could provide support to address these psychosocial factors.

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