A number of behavioural symptoms are commonly displayed by Alzheimer's disease (AD) sufferers. Behavioural disturbances in AD can include affective symptoms, agitation, aggression and psychosis (Burns et al. 1990a Burns et al. 1990b Burns et al. 1990c). Alois Alzheimer was the first to document psychosis in the disease bearing his name, during his description of the clinical presentation of a patient upon admission to the Frankfurt asylum in 1906 (Alzheimer 1995 Schneider and Dagerman 2004).

It was concluded that some of the schizophrenia susceptibility genes were regulated in association with hippocampal-dependent LTM processes but not schizophrenia susceptibility genes were identified to be causally involved in hippocampal-dependent LTM processes.

The Mendelian randomization approach is concerned with the causal pathway between a gene, an intermediate phenotype and a disease. The aim of the approach is to estimate the causal association between the phenotype and the disease when confounding or reverse causation may affect the direct estimate of this association. The approach represents the use of genes as instrumental variables in epidemiological research and is justified through Mendel's second law. Instrumental variable analysis was developed in econometrics as an alternative to regression analyses affected by confounding and reverse causation. Methods such as two-stage least squares are appropriate for instrumental variable analyses where the phenotype and disease are continuous. However, case-control and cohort studies typically report binary outcomes and instrumental variable methods for these studies are less well developed. For a binary outcome study three estimators of the phenotype-disease log odds ratio are compared. An adjusted instrumental variable estimator is shown to have the least bias compared with the other two estimators. However, significance tests of the adjusted estimator are shown to have an inflated type I error rate, so the standard estimator, which had the correct type I error rate, could be used for testing. A single study may not have adequate statistical power to detect a causal association in a Mendelian randomization analysis. Meta-analysis models that extend existing approaches are investigated. The ratio of coefficients approach is applied within the meta-analysis models and a Taylor series approximation is used to investigate its finite sample bias. The increasing awareness of the Mendelian randomization approach has made researchers aware of the need for instrumental variable methods appropriate for epidemiological study designs. The work in this thesis viewed in the context of the research into instrumental variable analysis in other areas of biostatistics such as non-compliance in clinical trials and other subject areas such as econometrics and causal inference contributes to the development of methods for Mendelian randomization analyses.

Troponin I mutations have been linked to genetic hypertrophic and dilated cardiomyopathies. We aimed to understand, at the molecular level, how six HCM mutations (R21C, Q130R, R145G, G203S, and K206Q) and one DCM mutation (A2V) in troponin I affect its structure and function. Circular dichroism, co-sedimentation with actin and ATPase assays demonstrated that these mutations had little or no effect on the folding or the thermal stability of the troponin complex. Isothermal calorimetry, fluorescence spectroscopy, and transient kinetics were used to assess the effect of these mutations on the function of troponin I. We found that: 1) all TnI mutations increased the affinity of the troponin complex for actin in the presence of Ca²+ and increased the Ca²+ affinity of troponin within thin filaments. This suggests an uncoupling between Ca²+ binding and actin binding. 2) The size of the cooperative unit n was not affected by troponin I mutations. 3) A2V, R21C, Q130R, A157V, G203S, and K206Q mutations did not affect the proportion of thin filaments in the blocked state (at low Ca²+). In contrast R145G mutation dramatically reduced the amount of thin filaments switched to the blocked state. This effect was also observed using electron microscopy and helical reconstruction. 4) A2V, R21C, Q130R, R145G, G203S, and K206Q did not affect the observed rate constant of Ca²+ dissociation from troponin and thin filaments. In contrast troponin I A157V showed a decrease in the Ca²+ dissociation rate constant. 5) Finally, we found that calcium alone is sufficient to fully activate the cardiac thin filament while skeletal muscle thin filaments complete activation required both Ca²+ and myosin heads. Overall these results provide insight into the mechanism by which troponin I mutations affect contractility in hypertrophic and dilated cardiomyopathy. These findings could have important clinical consequences.

Pulmonary arterial hypertension (PAH) can be idiopathic, hereditary, or develop in association with other diseases. Hereditary PAH is inherited as an autosomal dominant trait with reduced penetrance and variable age of onset. Heterozygous mutations in BMPR2, encoding a type II receptor in the TGF-β signalling pathway, underlie the majority of hereditary cases of PAH. PAH can occur as a rare complication of hereditary haemorrhagic telangiectasia (HHT), a vascular dysplasia caused by mutations in ALK-1, encoding a type I TGF-β receptor and ENG, encoding the accessory TGF-β receptor endoglin. BMP signalling plays an important role in cardiac embryogenesis and PAH is a common complication of congenital heart disease. In this thesis clinical and molecular studies have been performed upon a number of subjects, including those presenting with the combination of HHT and pulmonary hypertension, children presenting with PAH in childhood, and a cohort of adults and children presenting with congenital heart defects unselected for the presence of PAH. Novel heterozygous mutations were identified within the gene encoding ALK-1 and cell-based functional analysis was undertaken to characterise the consequences of these molecular defects. Novel single base pair substitutions in BMPR2 were identified in association with cardiac defects of the outflow tract, indicating that disrupted BMPRII signalling may play a role in the pathogenesis of congenital heart disease. Segregation analysis to determine allele-specific penetrance in a single multigenerational kindred demonstrated that penetrance was significantly higher than previous estimates with profound implications for clinical screening and management of families with hereditary PAH. Taken together, these studies provide insight into the molecular genetic basis of PAH, and identify disrupted signalling in the TGF-β cell-signalling pathway as a fundamental primary defect in the pathophysiology of this devastating disorder.

Neurofibromatosis Type 1 (NF1) is a dominantly inherited disorder (births incidence: 1/3000) with a high spontaneous mutation rate. NF1 has been described as a condition without parameters; physical features, cognitive symptomatology, and complications such as malignancy, are highly variable, both within and between families, and over the lifetime of affected individuals. This thesis explores the significance of the recent classifications of NF1 as a ‘genetic syndrome’, in terms of the subjecthood of affected individuals, their family experiences and the way it is managed within the healthcare system. The research is based on qualitative semi-structured interviews of NF1 individuals, their families (n=30) and healthcare professionals who work with NF1 (n=11) and employs Grounded Theory and Narrative Analysis inspired methods of analysis. As such, it provides an empirical investigation of many of the sociological theories which have been developed in response to genetic disease, particularly genetic responsibility, biocitizenship and the medicalization of the family. NF1 was still experienced by patients and treated by the healthcare system, as a condition without parameters i.e., as a disparate set of symptoms with uncertain meaning, rather than as a ‘whole’. The majority of the respondents - regardless of the severity of NF1 - rejected NF1 genetic identities, employing diverse downplaying strategies to normalise it. NF1 was salient at certain critical junctures in individuals’ lifecourses, especially in relation to reproductive choices, disclosure and management of pressing symptoms. Family experiences with genetic conditions, the relations of family or kinship, health behaviours, familial surveillance and disclosure did not necessarily follow the lines of biomedical knowledge and genetic inheritance. The analysis also revealed a degree of mirroring between the structure of the healthcare provision for NF1 and patients’ constructions of the condition, for example the lack of illness identity. The example of NF1 shows that the identification of the genetic basis of a condition does not necessarily provide patients and healthcare professionals with more parameters to manage it.

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